PcG and trxG in plants - friends or foes.

PubMed

Pu, Li; Sung, Zinmay Renee

2015-05-01

The highly-conserved Polycomb group (PcG) and trithorax group (trxG) proteins play major roles in regulating gene expression and maintaining developmental states in many organisms. However, neither the recruitment of Polycomb repressive complexes (PRC) nor the mechanisms of PcG and trxG-mediated gene silencing and activation are well understood. Recent progress in Arabidopsis research challenges the dominant model of PRC2-dependent recruitment of PRC1 to target genes. Moreover, evidence indicates that diverse forms of PRC1, with shared components, are a common theme in plants and mammals. Although trxG is known to antagonize PcG, emerging data reveal that trxG can also repress gene expression, acting cooperatively with PcG. We discuss these recent findings and highlight the employment of diverse epigenetic mechanisms during development in plants and animals. Copyright © 2015 Elsevier Ltd. All rights reserved.

Long non-coding RNA and Polycomb: an intricate partnership in cancer biology.

PubMed

Achour, Cyrinne; Aguilo, Francesca

2018-06-01

High-throughput analyses have revealed that the vast majority of the transcriptome does not code for proteins. These non-translated transcripts, when larger than 200 nucleotides, are termed long non-coding RNAs (lncRNAs), and play fundamental roles in diverse cellular processes. LncRNAs are subject to dynamic chemical modification, adding another layer of complexity to our understanding of the potential roles that lncRNAs play in health and disease. Many lncRNAs regulate transcriptional programs by influencing the epigenetic state through direct interactions with chromatin-modifying proteins. Among these proteins, Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) have been shown to be recruited by lncRNAs to silence target genes. Aberrant expression, deficiency or mutation of both lncRNA and Polycomb have been associated with numerous human diseases, including cancer. In this review, we have highlighted recent findings regarding the concerted mechanism of action of Polycomb group proteins (PcG), acting together with some classically defined lncRNAs including X-inactive specific transcript ( XIST ), antisense non-coding RNA in the INK4 locus ( ANRIL ), metastasis associated lung adenocarcinoma transcript 1 ( MALAT1 ), and HOX transcript antisense RNA ( HOTAIR ).

Mediator complex cooperatively regulates transcription of retinoic acid target genes with Polycomb Repressive Complex 2 during neuronal differentiation.

PubMed

Fukasawa, Rikiya; Iida, Satoshi; Tsutsui, Taiki; Hirose, Yutaka; Ohkuma, Yoshiaki

2015-11-01

The Mediator complex (Mediator) plays key roles in transcription and functions as the nexus for integration of various transcriptional signals. Previously, we screened for Mediator cyclin-dependent kinase (CDK)-interacting factors and identified three proteins related to chromatin regulation. One of them, SUZ12 is required for both stability and activity of Polycomb Repressive Complex 2 (PRC2). PRC2 primarily suppresses gene expression through histone H3 lysine 27 trimethylation, resulting in stem cell maintenance and differentiation; perturbation of this process leads to oncogenesis. Recent work showed that Mediator contributes to the embryonic stem cell state through DNA loop formation, which is strongly associated with chromatin architecture; however, it remains unclear how Mediator regulates gene expression in cooperation with chromatin regulators (i.e. writers, readers and remodelers). We found that Mediator CDKs interact directly with the PRC2 subunit EZH2, as well as SUZ12. Known PRC2 target genes were deregulated by Mediator CDK knockdown during neuronal differentiation, and both Mediator and PRC2 complexes co-occupied the promoters of developmental genes regulated by retinoic acid. Our results provide a mechanistic link between Mediator and PRC2 during neuronal differentiation. © The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Polycomb Repressive Complex 2 Regulates MiR-200b in Retinal Endothelial Cells: Potential Relevance in Diabetic Retinopathy

PubMed Central

Ruiz, Michael Anthony; Feng, Biao; Chakrabarti, Subrata

2015-01-01

Glucose-induced augmented vascular endothelial growth factor (VEGF) production is a key event in diabetic retinopathy. We have previously demonstrated that downregulation of miR-200b increases VEGF, mediating structural and functional changes in the retina in diabetes. However, mechanisms regulating miR-200b in diabetes are not known. Histone methyltransferase complex, Polycomb Repressive Complex 2 (PRC2), has been shown to repress miRNAs in neoplastic process. We hypothesized that, in diabetes, PRC2 represses miR-200b through its histone H3 lysine-27 trimethylation mark. We show that human retinal microvascular endothelial cells exposed to high levels of glucose regulate miR-200b repression through histone methylation and that inhibition of PRC2 increases miR-200b while reducing VEGF. Furthermore, retinal tissue from animal models of diabetes showed increased expression of major PRC2 components, demonstrating in vivo relevance. This research established a repressive relationship between PRC2 and miR-200b, providing evidence of a novel mechanism of miRNA regulation through histone methylation. PMID:25884496

The NUCLEAR FACTOR-CONSTANS complex antagonizes Polycomb repression to de-repress FLOWERING LOCUS T expression in response to inductive long days in Arabidopsis.

PubMed

Luo, Xiao; Gao, Zheng; Wang, Yizhong; Chen, Zhijuan; Zhang, Wenju; Huang, Jirong; Yu, Hao; He, Yuehui

2018-07-01

Many plants sense the seasonal cues, day length or photoperiod changes, to align the timing of the developmental transition to flowering with changing seasons for reproductive success. Inductive day lengths through the photoperiod pathway induce the expression of FLOWERING LOCUS T (FT) or FT relatives that encode a major mobile florigen to promote flowering. In Arabidopsis thaliana, under inductive long days the photoperiod pathway output CONSTANS (CO) accumulates toward the end of the day, and associates with the B and C subunits of Nuclear Factor Y (NF-Y) to form the NF-CO complex that acts to promote FT expression near dusk, whereas Polycomb group (PcG) proteins function to silence FT expression. How NF-CO acts to antagonize the function of PcG proteins to regulate FT expression remains unclear. Here, we show that the NF-CO complex bound to the proximal FT promoter, through chromatin looping, acts in concert with an NF-Y complex bound to a distal enhancer to reduce the levels of PcG proteins, including both Polycomb repressive complex 1 (PRC1) and PRC2 at the FT promoter, leading to a relieving of Polycomb silencing and thus FT de-repression near dusk. Thus, our study provides molecular insights on how the 'active' photoperiod pathway and the 'repressive' Polycomb silencing system interact to control temporal FT expression, conferring the long-day induction of flowering in Arabidopsis. © 2018 The Authors The Plant Journal © 2018 John Wiley & Sons Ltd.

Arabidopsis Polycomb Repressive Complex 2 binding sites contain putative GAGA factor binding motifs within coding regions of genes

PubMed Central

2013-01-01

Background Polycomb Repressive Complex 2 (PRC2) is an essential regulator of gene expression that maintains genes in a repressed state by marking chromatin with trimethylated Histone H3 lysine 27 (H3K27me3). In Arabidopsis, loss of PRC2 function leads to pleiotropic effects on growth and development thought to be due to ectopic expression of seed and embryo-specific genes. While there is some understanding of the mechanisms by which specific genes are targeted by PRC2 in animal systems, it is still not clear how PRC2 is recruited to specific regions of plant genomes. Results We used ChIP-seq to determine the genome-wide distribution of hemagglutinin (HA)-tagged FERTLIZATION INDEPENDENT ENDOSPERM (FIE-HA), the Extra Sex Combs homolog protein present in all Arabidopsis PRC2 complexes. We found that the FIE-HA binding sites co-locate with a subset of the H3K27me3 sites in the genome and that the associated genes were more likely to be de-repressed in mutants of PRC2 components. The FIE-HA binding sites are enriched for three sequence motifs including a putative GAGA factor binding site that is also found in Drosophila Polycomb Response Elements (PREs). Conclusions Our results suggest that PRC2 binding sites in plant genomes share some sequence features with Drosophila PREs. However, unlike Drosophila PREs which are located in promoters and devoid of H3K27me3, Arabidopsis FIE binding sites tend to be in gene coding regions and co-localize with H3K27me3. PMID:24001316

Deciphering the Role of POLYCOMB REPRESSIVE COMPLEX1 Variants in Regulating the Acquisition of Flowering Competence in Arabidopsis1

PubMed Central

Picó, Sara; Merini, Wiam

2015-01-01

Polycomb group (PcG) proteins play important roles in regulating developmental phase transitions in plants; however, little is known about the role of the PcG machinery in regulating the transition from juvenile to adult phase. Here, we show that Arabidopsis (Arabidopsis thaliana) B lymphoma Moloney murine leukemia virus insertion region1 homolog (BMI1) POLYCOMB REPRESSIVE COMPLEX1 (PRC1) components participate in the repression of microRNA156 (miR156). Loss of AtBMI1 function leads to the up-regulation of the primary transcript of MIR156A and MIR156C at the time the levels of miR156 should decline, resulting in an extended juvenile phase and delayed flowering. Conversely, the PRC1 component EMBRYONIC FLOWER (EMF1) participates in the regulation of SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE and MIR172 genes. Accordingly, plants impaired in EMF1 function displayed misexpression of these genes early in development, which contributes to a CONSTANS-independent up-regulation of FLOWERING LOCUS T (FT) leading to the earliest flowering phenotype described in Arabidopsis. Our findings show how the different regulatory roles of two functional PRC1 variants coordinate the acquisition of flowering competence and help to reach the threshold of FT necessary to flower. Furthermore, we show how two central regulatory mechanisms, such as PcG and microRNA, assemble to achieve a developmental outcome. PMID:25897002

Deciphering the Role of POLYCOMB REPRESSIVE COMPLEX1 Variants in Regulating the Acquisition of Flowering Competence in Arabidopsis.

PubMed

Picó, Sara; Ortiz-Marchena, M Isabel; Merini, Wiam; Calonje, Myriam

2015-08-01

Polycomb group (PcG) proteins play important roles in regulating developmental phase transitions in plants; however, little is known about the role of the PcG machinery in regulating the transition from juvenile to adult phase. Here, we show that Arabidopsis (Arabidopsis thaliana) B lymphoma Moloney murine leukemia virus insertion region1 homolog (BMI1) POLYCOMB REPRESSIVE COMPLEX1 (PRC1) components participate in the repression of microRNA156 (miR156). Loss of AtBMI1 function leads to the up-regulation of the primary transcript of MIR156A and MIR156C at the time the levels of miR156 should decline, resulting in an extended juvenile phase and delayed flowering. Conversely, the PRC1 component EMBRYONIC FLOWER (EMF1) participates in the regulation of SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE and MIR172 genes. Accordingly, plants impaired in EMF1 function displayed misexpression of these genes early in development, which contributes to a CONSTANS-independent up-regulation of FLOWERING LOCUS T (FT) leading to the earliest flowering phenotype described in Arabidopsis. Our findings show how the different regulatory roles of two functional PRC1 variants coordinate the acquisition of flowering competence and help to reach the threshold of FT necessary to flower. Furthermore, we show how two central regulatory mechanisms, such as PcG and microRNA, assemble to achieve a developmental outcome. © 2015 American Society of Plant Biologists. All Rights Reserved.

Polycomb-like 2 Associates with PRC2 and Regulates Transcriptional Networks during Mouse Embryonic Stem Cell Self-Renewal and Differentiation

PubMed Central

Walker, Emily; Chang, Wing Y.; Hunkapiller, Julie; Cagney, Gerard; Garcha, Kamal; Torchia, Joseph; Krogan, Nevan J.; Reiter, Jeremy F.; Stanford, William L.

2010-01-01

Summary Polycomb group (PcG) proteins are conserved epigenetic transcriptional repressors that control numerous developmental gene expression programs and have recently been implicated in modulating embryonic stem cell (ESC) fate. We identified the PcG protein PCL2 (polycomb-like 2) in a genome-wide screen for regulators of self-renewal and pluripotency and predicted that it would play an important role in mouse ESC fate determination. Using multiple biochemical strategies, we provide evidence that PCL2 is a Polycomb Repressive Complex 2 (PRC2)-associated protein in mouse ESCs. Knockdown of Pcl2 in ESCs resulted in heightened self-renewal characteristics, defects in differentiation and altered patterns of histone methylation. Integration of global gene expression and promoter occupancy analyses allowed us to identify PCL2 and PRC2 transcriptional targets and draft regulatory networks. We describe the role of PCL2 in both modulating transcription of ESC self-renewal genes in undifferentiated ESCs as well as developmental regulators during early commitment and differentiation. PMID:20144788

MLL-ENL inhibits polycomb repressive complex 1 to achieve efficient transformation of hematopoietic cells

PubMed Central

Maethner, Emanuel; Garcia-Cuellar, Maria-Paz; Breitinger, Constanze; Takacova, Sylvia; Divoky, Vladimir; Hess, Jay L.; Slany, Robert K.

2014-01-01

Summary Stimulation of transcriptional elongation is a key activity of leukemogenic MLL fusion proteins. Here we provide evidence that MLL-ENL also inhibits polycomb-mediated silencing as a prerequisite for efficient transformation. Biochemical studies identified ENL as scaffold that contacted the elongation machinery as well as the PRC1 (polycomb repressive complex 1) component CBX8. These interactions were mutually exclusive in vitro corresponding to an antagonistic behavior of MLL-ENL and CBX8 in vivo. CBX8 inhibited elongation in a specific reporter assay and this effect was neutralized by direct association with ENL. Correspondingly MLL-ENL defective in CBX8 binding could not fully activate gene loci necessary for transformation. Finally, we demonstrate dimerization of MLL-ENL as neomorphic activity that may augment polycomb inhibition and transformation. PMID:23623499

Live-cell single-molecule tracking reveals co-recognition of H3K27me3 and DNA targets polycomb Cbx7-PRC1 to chromatin

PubMed Central

Zhen, Chao Yu; Tatavosian, Roubina; Huynh, Thao Ngoc; Duc, Huy Nguyen; Das, Raibatak; Kokotovic, Marko; Grimm, Jonathan B; Lavis, Luke D; Lee, Jun; Mejia, Frances J; Li, Yang; Yao, Tingting; Ren, Xiaojun

2016-01-01

The Polycomb PRC1 plays essential roles in development and disease pathogenesis. Targeting of PRC1 to chromatin is thought to be mediated by the Cbx family proteins (Cbx2/4/6/7/8) binding to histone H3 with a K27me3 modification (H3K27me3). Despite this prevailing view, the molecular mechanisms of targeting remain poorly understood. Here, by combining live-cell single-molecule tracking (SMT) and genetic engineering, we reveal that H3K27me3 contributes significantly to the targeting of Cbx7 and Cbx8 to chromatin, but less to Cbx2, Cbx4, and Cbx6. Genetic disruption of the complex formation of PRC1 facilitates the targeting of Cbx7 to chromatin. Biochemical analyses uncover that the CD and AT-hook-like (ATL) motif of Cbx7 constitute a functional DNA-binding unit. Live-cell SMT of Cbx7 mutants demonstrates that Cbx7 is targeted to chromatin by co-recognizing of H3K27me3 and DNA. Our data suggest a novel hierarchical cooperation mechanism by which histone modifications and DNA coordinate to target chromatin regulatory complexes. DOI: http://dx.doi.org/10.7554/eLife.17667.001 PMID:27723458

The Human Immunodeficiency Virus 1 ASP RNA promotes viral latency by recruiting the Polycomb Repressor Complex 2 and promoting nucleosome assembly

PubMed Central

Zapata, Juan C.; Campilongo, Federica; Barclay, Robert A.; DeMarino, Catherine; Iglesias-Ussel, Maria D.; Kashanchi, Fatah; Romerio, Fabio

2017-01-01

Various epigenetic marks at the HIV-1 5′LTR suppress proviral expression and promote latency. Cellular antisense transcripts known as long noncoding RNAs (lncRNAs) recruit the polycomb repressor complex 2 (PRC2) to gene promoters, which catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3), thus promoting nucleosome assembly and suppressing gene expression. We found that an HIV-1 antisense transcript expressed from the 3′LTR and encoding the antisense protein ASP promotes proviral latency. Expression of ASP RNA reduced HIV-1 replication in Jurkat cells. Moreover, ASP RNA expression promoted the establishment and maintenance of HIV-1 latency in Jurkat E4 cells. We show that this transcript interacts with and recruits PRC2 to the HIV-1 5′LTR, increasing accumulation of the suppressive epigenetic mark H3K27me3, while reducing RNA Polymerase II and thus proviral transcription. Altogether, our results suggest that the HIV-1 ASP transcript promotes epigenetic silencing of the HIV-1 5′LTR and proviral latency through the PRC2 pathway. PMID:28340355

The Human Immunodeficiency Virus 1 ASP RNA promotes viral latency by recruiting the Polycomb Repressor Complex 2 and promoting nucleosome assembly.

PubMed

Zapata, Juan C; Campilongo, Federica; Barclay, Robert A; DeMarino, Catherine; Iglesias-Ussel, Maria D; Kashanchi, Fatah; Romerio, Fabio

2017-06-01

Various epigenetic marks at the HIV-1 5'LTR suppress proviral expression and promote latency. Cellular antisense transcripts known as long noncoding RNAs (lncRNAs) recruit the polycomb repressor complex 2 (PRC2) to gene promoters, which catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3), thus promoting nucleosome assembly and suppressing gene expression. We found that an HIV-1 antisense transcript expressed from the 3'LTR and encoding the antisense protein ASP promotes proviral latency. Expression of ASP RNA reduced HIV-1 replication in Jurkat cells. Moreover, ASP RNA expression promoted the establishment and maintenance of HIV-1 latency in Jurkat E4 cells. We show that this transcript interacts with and recruits PRC2 to the HIV-1 5'LTR, increasing accumulation of the suppressive epigenetic mark H3K27me3, while reducing RNA Polymerase II and thus proviral transcription. Altogether, our results suggest that the HIV-1 ASP transcript promotes epigenetic silencing of the HIV-1 5'LTR and proviral latency through the PRC2 pathway. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The Long Non-coding RNA HOTTIP Enhances Pancreatic Cancer Cell Proliferation, Survival and Migration

EPA Science Inventory

ABSTRACTHOTTIP is a long non-coding RNA (lncRNA) transcribed from the 5' tip of the HOXA locus and is associated with the polycomb repressor complex 2 (PRC2) and WD repeat containing protein 5 (WDR5)/mixed lineage leukemia 1 (MLL1) chromatin modifying complexes. HOTTIP is expres...

Targeting MUC1-C suppresses polycomb repressive complex 1 in multiple myeloma.

PubMed

Tagde, Ashujit; Markert, Tahireh; Rajabi, Hasan; Hiraki, Masayuki; Alam, Maroof; Bouillez, Audrey; Avigan, David; Anderson, Kenneth; Kufe, Donald

2017-09-19

The polycomb repressive complex 1 (PRC1) includes the BMI1, RING1 and RING2 proteins. BMI1 is required for survival of multiple myeloma (MM) cells. The MUC1-C oncoprotein is aberrantly expressed by MM cells, activates MYC and is also necessary for MM cell survival. The present studies show that targeting MUC1-C with (i) stable and inducible silencing and CRISPR/Cas9 editing and (ii) the pharmacologic inhibitor GO-203, which blocks MUC1-C function, downregulates BMI1, RING1 and RING2 expression. The results demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism. MUC1-C thus promotes MYC occupancy on the BMI1 promoter and thereby activates BMI1 expression. We also show that the MUC1-C→MYC pathway induces RING2 expression. Moreover, in contrast to BMI1 and RING2, we found that MUC1-C drives RING1 by an NF-κB p65-dependent mechanism. Targeting MUC1-C and thereby the suppression of these key PRC1 proteins was associated with downregulation of the PRC1 E3 ligase activity as evidenced by decreases in ubiquitylation of histone H2A. Targeting MUC1-C also resulted in activation of the PRC1-repressed tumor suppressor genes, PTEN, CDNK2A and BIM . These findings identify a heretofore unrecognized role for MUC1-C in the epigenetic regulation of MM cells.

Site-Specific Expression of Polycomb-Group Genes Encoding the HPC-HPH/PRC1 Complex in Clinically Defined Primary Nodal and Cutaneous Large B-Cell Lymphomas

PubMed Central

Raaphorst, Frank M.; Vermeer, Maarten; Fieret, Elly; Blokzijl, Tjasso; Dukers, Danny; Sewalt, Richard G.A.B.; Otte, Arie P.; Willemze, Rein; Meijer, Chris J.L.M.

2004-01-01

Polycomb-group (PcG) genes preserve cell identity by gene silencing, and contribute to regulation of lymphopoiesis and malignant transformation. We show that primary nodal large B-cell lymphomas (LBCLs), and secondary cutaneous deposits from such lymphomas, abnormally express the BMI-1, RING1, and HPH1 PcG genes in cycling neoplastic cells. By contrast, tumor cells in primary cutaneous LBCLs lacked BMI-1 expression, whereas RING1 was variably detected. Lack of BMI-1 expression was characteristic for primary cutaneous LBCLs, because other primary extranodal LBCLs originating from brain, testes, and stomach were BMI-1-positive. Expression of HPH1 was rarely detected in primary cutaneous LBCLs of the head or trunk and abundant in primary cutaneous LBCLs of the legs, which fits well with its earlier recognition as a distinct clinical pathological entity with different clinical behavior. We conclude that clinically defined subclasses of primary LBCLs display site-specific abnormal expression patterns of PcG genes of the HPC-HPH/PRC1 PcG complex. Some of these patterns (such as the expression profile of BMI-1) may be diagnostically relevant. We propose that distinct expression profiles of PcG genes results in abnormal formation of HPC-HPH/PRC1 PcG complexes, and that this contributes to lymphomagenesis and different clinical behavior of clinically defined LBCLs. PMID:14742259

Origin of the polycomb repressive complex 2 and gene silencing by an E(z) homolog in the unicellular alga Chlamydomonas.

PubMed

Shaver, Scott; Casas-Mollano, J Armando; Cerny, Ronald L; Cerutti, Heriberto

2010-05-16

Polycomb group proteins play an essential role in the maintenance of cell identity and the regulation of development in both animals and plants. The Polycomb Repressive Complex 2 (PRC2) is involved in the establishment of transcriptionally silent chromatin states, in part through its ability to methylate lysine 27 of histone H3 by the Enhancer of zeste [E(z)] subunit. The absence of PRC2 in unicellular model fungi and its function in the repression of genes vital for the development of higher eukaryotes led to the proposal that this complex may have evolved together with the emergence of multicellularity. However, we report here on the widespread presence of PRC2 core subunits in unicellular eukaryotes from the Opisthokonta, Chromalveolata and Archaeplastida supergroups. To gain insight on the role of PRC2 in single celled organisms, we characterized an E(z) homolog, EZH, in the green alga Chlamydomonas reinhardtii. RNAi-mediated suppression of EZH led to defects in the silencing of transgenes and retrotransposons as well as to a global increase in histone post-translational modifications associated with transcriptional activity, such as trimethylation of histone H3 lysine 4 and acetylation of histone H4. On the basis of the parsimony principle, our findings suggest that PRC2 appeared early in eukaryotic evolution, even perhaps in the last unicellular common ancestor of eukaryotes. One of the ancestral roles of PCR2 may have been in defense responses against intragenomic parasites such as transposable elements, prior to being co-opted for lineage specific functions like developmental regulation in multicellular eukaryotes.

MUC1-C activates polycomb repressive complexes and downregulates tumor suppressor genes in human cancer cells.

PubMed

Rajabi, Hasan; Hiraki, Masayuki; Kufe, Donald

2018-04-01

The PRC2 and PRC1 complexes are aberrantly expressed in human cancers and have been linked to decreases in patient survival. MUC1-C is an oncoprotein that is also overexpressed in diverse human cancers and is associated with a poor prognosis. Recent studies have supported a previously unreported function for MUC1-C in activating PRC2 and PRC1 in cancer cells. In the regulation of PRC2, MUC1-C (i) drives transcription of the EZH2 gene, (ii) binds directly to EZH2, and (iii) enhances occupancy of EZH2 on target gene promoters with an increase in H3K27 trimethylation. Regarding PRC1, which is recruited to PRC2 sites in the hierarchical model, MUC1-C induces BMI1 transcription, forms a complex with BMI1, and promotes H2A ubiquitylation. MUC1-C thereby contributes to the integration of PRC2 and PRC1-mediated repression of tumor suppressor genes, such as CDH1, CDKN2A, PTEN and BRCA1. Like PRC2 and PRC1, MUC1-C is associated with the epithelial-mesenchymal transition (EMT) program, cancer stem cell (CSC) state, and acquisition of anticancer drug resistance. In concert with these observations, targeting MUC1-C downregulates EZH2 and BMI1, inhibits EMT and the CSC state, and reverses drug resistance. These findings emphasize the significance of MUC1-C as a therapeutic target for inhibiting aberrant PRC function and reprogramming the epigenome in human cancers.

Loss of Polycomb Group Protein Pcgf1 Severely Compromises Proper Differentiation of Embryonic Stem Cells

PubMed Central

Yan, Yun; Zhao, Wukui; Huang, Yikai; Tong, Huan; Xia, Yin; Jiang, Qing; Qin, Jinzhong

2017-01-01

The Polycomb repressive complex 1 (PRC1) is essential for fate decisions of embryonic stem (ES) cells. Emerging evidence suggests that six major variants of PRC1 complex, defined by the mutually exclusive presence of Pcgf subunit, regulate distinct biological processes, yet very little is known about the mechanism by which each version of PRC1 instructs and maintains cell fate. Here, we disrupted the Pcgf1, also known as Nspc1 and one of six Pcgf paralogs, in mouse ES cells by the CRISPR/Cas9 technology. We showed that although these mutant cells were viable and retained normal self-renewal, they displayed severe defects in differentiation in vitro. To gain a better understanding of the role of Pcgf1 in transcriptional control of differentiation, we analysed mRNA profiles from Pcgf1 deficient cells using RNA-seq. Interestingly, we found that Pcgf1 positively regulated expression of essential transcription factors involved in ectoderm and mesoderm differentiation, revealing an unexpected function of Pcgf1 in gene activation during ES cell lineage specification. Chromatin immunoprecipitation experiments demonstrated that Pcgf1 deletion caused a decrease in Ring1B and its associated H2AK119ub1 mark binding to target genes. Altogether, our results suggested an unexpected function of Pcgf1 in gene activation during ES cell maintenance. PMID:28393894

Kicking against the PRCs – A Domesticated Transposase Antagonises Silencing Mediated by Polycomb Group Proteins and Is an Accessory Component of Polycomb Repressive Complex 2

PubMed Central

Perera, Pumi; Mora-García, Santiago; de Leau, Erica; Thornton, Harry; de Alves, Flavia Lima; Rapsilber, Juri; Yang, Suxin; James, Geo Velikkakam; Schneeberger, Korbinian; Finnegan, E. Jean; Turck, Franziska; Goodrich, Justin

2015-01-01

The Polycomb group (PcG) and trithorax group (trxG) genes play crucial roles in development by regulating expression of homeotic and other genes controlling cell fate. Both groups catalyse modifications of chromatin, particularly histone methylation, leading to epigenetic changes that affect gene activity. The trxG antagonizes the function of PcG genes by activating PcG target genes, and consequently trxG mutants suppress PcG mutant phenotypes. We previously identified the ANTAGONIST OF LIKE HETEROCHROMATIN PROTEIN1 (ALP1) gene as a genetic suppressor of mutants in the Arabidopsis PcG gene LIKE HETEROCHROMATIN PROTEIN1 (LHP1). Here, we show that ALP1 interacts genetically with several other PcG and trxG components and that it antagonizes PcG silencing. Transcriptional profiling reveals that when PcG activity is compromised numerous target genes are hyper-activated in seedlings and that in most cases this requires ALP1. Furthermore, when PcG activity is present ALP1 is needed for full activation of several floral homeotic genes that are repressed by the PcG. Strikingly, ALP1 does not encode a known chromatin protein but rather a protein related to PIF/Harbinger class transposases. Phylogenetic analysis indicates that ALP1 is broadly conserved in land plants and likely lost transposase activity and acquired a novel function during angiosperm evolution. Consistent with this, immunoprecipitation and mass spectrometry (IP-MS) show that ALP1 associates, in vivo, with core components of POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), a widely conserved PcG protein complex which functions as a H3K27me3 histone methyltransferase. Furthermore, in reciprocal pulldowns using the histone methyltransferase CURLY LEAF (CLF), we identify not only ALP1 and the core PRC2 components but also plant-specific accessory components including EMBRYONIC FLOWER 1 (EMF1), a transcriptional repressor previously associated with PRC1-like complexes. Taken together our data suggest that ALP1 inhibits PcG silencing by blocking the interaction of the core PRC2 with accessory components that promote its HMTase activity or its role in inhibiting transcription. ALP1 is the first example of a domesticated transposase acquiring a novel function as a PcG component. The antagonistic interaction of a modified transposase with the PcG machinery is novel and may have arisen as a means for the cognate transposon to evade host surveillance or for the host to exploit features of the transposition machinery beneficial for epigenetic regulation of gene activity. PMID:26642436

Deregulation of polycomb repressor complex 1 modifier AUTS2 in T-cell leukemia.

PubMed

Nagel, Stefan; Pommerenke, Claudia; Meyer, Corinna; Kaufmann, Maren; Drexler, Hans G; MacLeod, Roderick A F

2016-07-19

Recently, we identified deregulated expression of the B-cell specific transcription factor MEF2C in T-cell acute lymphoid leukemia (T-ALL). Here, we performed sequence analysis of a regulatory upstream section of MEF2C in T-ALL cell lines which, however, proved devoid of mutations. Unexpectedly, we found strong conservation between the regulatory upstream region of MEF2C (located at chromosomal band 5q14) and an intergenic stretch at 7q11 located between STAG3L4 and AUTS2, covering nearly 20 kb. While the non-coding gene STAG3L4 was inconspicuously expressed, AUTS2 was aberrantly upregulated in 6% of T-ALL patients (public dataset GSE42038) and in 3/24 T-ALL cell lines, two of which represented very immature differentiation stages. AUTS2 expression was higher in normal B-cells than in T-cells, indicating lineage-specific activity in lymphopoiesis. While excluding chromosomal aberrations, examinations of AUTS2 transcriptional regulation in T-ALL cells revealed activation by IL7-IL7R-STAT5-signalling and MEF2C. AUTS2 protein has been shown to interact with polycomb repressor complex 1 subtype 5 (PRC1.5), transforming this particular complex into an activator. Accordingly, expression profiling and functional analyses demonstrated that AUTS2 activated while PCGF5 repressed transcription of NKL homeobox gene MSX1 in T-ALL cells. Forced expression and pharmacological inhibition of EZH2 in addition to H3K27me3 analysis indicated that PRC2 repressed MSX1 as well. Taken together, we found that AUTS2 and MEF2C, despite lying on different chromosomes, share strikingly similar regulatory upstream regions and aberrant expression in T-ALL subsets. Our data implicate chromatin complexes PRC1/AUTS2 and PRC2 in a gene network in T-ALL regulating early lymphoid differentiation.

Samd7 is a cell type-specific PRC1 component essential for establishing retinal rod photoreceptor identity

PubMed Central

Omori, Yoshihiro; Kubo, Shun; Kon, Tetsuo; Furuhashi, Mayu; Narita, Hirotaka; Kominami, Taro; Ueno, Akiko; Tsutsumi, Ryotaro; Chaya, Taro; Yamamoto, Haruka; Suetake, Isao; Ueno, Shinji; Koseki, Haruhiko; Furukawa, Takahisa

2017-01-01

Precise transcriptional regulation controlled by a transcription factor network is known to be crucial for establishing correct neuronal cell identities and functions in the CNS. In the retina, the expression of various cone and rod photoreceptor cell genes is regulated by multiple transcription factors; however, the role of epigenetic regulation in photoreceptor cell gene expression has been poorly understood. Here, we found that Samd7, a rod-enriched sterile alpha domain (SAM) domain protein, is essential for silencing nonrod gene expression through H3K27me3 regulation in rod photoreceptor cells. Samd7-null mutant mice showed ectopic expression of nonrod genes including S-opsin in rod photoreceptor cells and rod photoreceptor cell dysfunction. Samd7 physically interacts with Polyhomeotic homologs (Phc proteins), components of the Polycomb repressive complex 1 (PRC1), and colocalizes with Phc2 and Ring1B in Polycomb bodies. ChIP assays showed a significant decrease of H3K27me3 in the genes up-regulated in the Samd7-deficient retina, showing that Samd7 deficiency causes the derepression of nonrod gene expression in rod photoreceptor cells. The current study suggests that Samd7 is a cell type-specific PRC1 component epigenetically defining rod photoreceptor cell identity. PMID:28900001

Samd7 is a cell type-specific PRC1 component essential for establishing retinal rod photoreceptor identity.

PubMed

Omori, Yoshihiro; Kubo, Shun; Kon, Tetsuo; Furuhashi, Mayu; Narita, Hirotaka; Kominami, Taro; Ueno, Akiko; Tsutsumi, Ryotaro; Chaya, Taro; Yamamoto, Haruka; Suetake, Isao; Ueno, Shinji; Koseki, Haruhiko; Nakagawa, Atsushi; Furukawa, Takahisa

2017-09-26

Precise transcriptional regulation controlled by a transcription factor network is known to be crucial for establishing correct neuronal cell identities and functions in the CNS. In the retina, the expression of various cone and rod photoreceptor cell genes is regulated by multiple transcription factors; however, the role of epigenetic regulation in photoreceptor cell gene expression has been poorly understood. Here, we found that Samd7, a rod-enriched sterile alpha domain (SAM) domain protein, is essential for silencing nonrod gene expression through H3K27me3 regulation in rod photoreceptor cells. Samd7- null mutant mice showed ectopic expression of nonrod genes including S-opsin in rod photoreceptor cells and rod photoreceptor cell dysfunction. Samd7 physically interacts with Polyhomeotic homologs (Phc proteins), components of the Polycomb repressive complex 1 (PRC1), and colocalizes with Phc2 and Ring1B in Polycomb bodies. ChIP assays showed a significant decrease of H3K27me3 in the genes up-regulated in the Samd7 -deficient retina, showing that Samd7 deficiency causes the derepression of nonrod gene expression in rod photoreceptor cells. The current study suggests that Samd7 is a cell type-specific PRC1 component epigenetically defining rod photoreceptor cell identity.

Increased Maternal Genome Dosage Bypasses the Requirement of the FIS Polycomb Repressive Complex 2 in Arabidopsis Seed Development

PubMed Central

Kradolfer, David; Hennig, Lars; Köhler, Claudia

2013-01-01

Seed development in flowering plants is initiated after a double fertilization event with two sperm cells fertilizing two female gametes, the egg cell and the central cell, leading to the formation of embryo and endosperm, respectively. In most species the endosperm is a polyploid tissue inheriting two maternal genomes and one paternal genome. As a consequence of this particular genomic configuration the endosperm is a dosage sensitive tissue, and changes in the ratio of maternal to paternal contributions strongly impact on endosperm development. The FERTILIZATION INDEPENDENT SEED (FIS) Polycomb Repressive Complex 2 (PRC2) is essential for endosperm development; however, the underlying forces that led to the evolution of the FIS-PRC2 remained unknown. Here, we show that the functional requirement of the FIS-PRC2 can be bypassed by increasing the ratio of maternal to paternal genomes in the endosperm, suggesting that the main functional requirement of the FIS-PRC2 is to balance parental genome contributions and to reduce genetic conflict. We furthermore reveal that the AGAMOUS LIKE (AGL) gene AGL62 acts as a dosage-sensitive seed size regulator and that reduced expression of AGL62 might be responsible for reduced size of seeds with increased maternal genome dosage. PMID:23326241

Regulating RNA polymerase pausing and transcription elongation in embryonic stem cells

PubMed Central

Min, Irene M.; Waterfall, Joshua J.; Core, Leighton J.; Munroe, Robert J.; Schimenti, John; Lis, John T.

2011-01-01

Transitions between pluripotent stem cells and differentiated cells are executed by key transcription regulators. Comparative measurements of RNA polymerase distribution over the genome's primary transcription units in different cell states can identify the genes and steps in the transcription cycle that are regulated during such transitions. To identify the complete transcriptional profiles of RNA polymerases with high sensitivity and resolution, as well as the critical regulated steps upon which regulatory factors act, we used genome-wide nuclear run-on (GRO-seq) to map the density and orientation of transcriptionally engaged RNA polymerases in mouse embryonic stem cells (ESCs) and mouse embryonic fibroblasts (MEFs). In both cell types, progression of a promoter-proximal, paused RNA polymerase II (Pol II) into productive elongation is a rate-limiting step in transcription of ∼40% of mRNA-encoding genes. Importantly, quantitative comparisons between cell types reveal that transcription is controlled frequently at paused Pol II's entry into elongation. Furthermore, “bivalent” ESC genes (exhibiting both active and repressive histone modifications) bound by Polycomb group complexes PRC1 (Polycomb-repressive complex 1) and PRC2 show dramatically reduced levels of paused Pol II at promoters relative to an average gene. In contrast, bivalent promoters bound by only PRC2 allow Pol II pausing, but it is confined to extremely 5′ proximal regions. Altogether, these findings identify rate-limiting targets for transcription regulation during cell differentiation. PMID:21460038

Polycomb Repressive Complex 2 Enacts Wnt Signaling in Intestinal Homeostasis and Contributes to the Instigation of Stemness in Diseases Entailing Epithelial Hyperplasia or Neoplasia.

PubMed

Oittinen, Mikko; Popp, Alina; Kurppa, Kalle; Lindfors, Katri; Mäki, Markku; Kaikkonen, Minna U; Viiri, Keijo

2017-02-01

Canonical Wnt/β-catenin signaling regulates the homeostasis of intestinal epithelium by controlling the balance between intestinal stem cell self-renewal and differentiation but epigenetic mechanisms enacting the process are not known. We hypothesized that epigenetic regulator, Polycomb Repressive Complex-2 (PRC2), is involved in Wnt-mediated epithelial homeostasis on the crypt-villus axis and aberrancies therein are implicated both in celiac disease and in intestinal malignancies. We found that PRC2 establishes repressive crypt and villus specific trimethylation of histone H3 lysine 27 (H3K27me3) signature on genes responsible for, for example, nutrient transport and cell killing in crypts and, for example, proliferation and differentiation in mature villi, suggesting that PRC2 facilitates the Wnt-governed intestinal homeostasis. When celiac patients are on gluten-containing diet PRC2 is out-of-bounds active and consequently its target genes were found affected in intestinal epithelium. Significant set of effective intestinal PRC2 targets are also differentially expressed in colorectal adenoma and carcinomas. Our results suggest that PRC2 gives rise and maintains polar crypt and villus specific H3K27me3 signatures. As H3K27me3 is a mark enriched in developmentally important genes, identified intestinal PRC2 targets are possibly imperative drivers for enterocyte differentiation and intestinal stem cell maintenance downstream to Wnt-signaling. Our work also elucidates the mechanism sustaining the crypt hyperplasia in celiac disease and suggest that PRC2-dependent fostering of epithelial stemness is a common attribute in intestinal diseases in which epithelial hyperplasia or neoplasia prevails. Finally, this work demonstrates that in intestine PRC2 represses genes having both pro-stemness and pro-differentiation functions, fact need to be considered when designing epigenetic therapies including PRC2 as a drug target. Stem Cells 2017;35:445-457. © 2016 AlphaMed Press.

EZH2: biology, disease, and structure-based drug discovery

PubMed Central

Tan, Jin-zhi; Yan, Yan; Wang, Xiao-xi; Jiang, Yi; Xu, H Eric

2014-01-01

EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which is a highly conserved histone methyltransferase that methylates lysine 27 of histone 3. Overexpression of EZH2 has been found in a wide range of cancers, including those of the prostate and breast. In this review, we address the current understanding of the oncogenic role of EZH2, including its PRC2-dependent transcriptional repression and PRC2-independent gene activation. We also discuss the connections between EZH2 and other silencing enzymes, such as DNA methyltransferase and histone deacetylase. We comprehensively address the architecture of the PRC2 complex and the crucial roles of each subunit. Finally, we summarize new progress in developing EZH2 inhibitors, which could be a new epigenetic therapy for cancers. PMID:24362326

Polycomb Repressive Complex 2 Confers BRG1 Dependency on the CIITA Locus.

PubMed

Abou El Hassan, Mohamed; Yu, Tao; Song, Lan; Bremner, Rod

2015-05-15

CIITA (or MHC2TA) coordinates constitutive and IFN-γ-induced expression of MHC class II genes. IFN-γ responsiveness of CIITA requires BRG1 (SMARCA4), the ATPase engine of the chromatin remodeling SWI/SNF complex (also called BAF). SWI/SNF is defective in many human cancers, providing a mechanism to explain IFN-γ resistance. BRG1 dependency is mediated through remote elements. Short CIITA reporters lacking these elements respond to IFN-γ, even in BRG1-deficient cells, suggesting that BRG1 counters a remote repressive influence. The nature of this distal repressor is unknown, but it would represent a valuable therapeutic target to reactivate IFN-γ responsiveness in cancer. In this article, we show that the polycomb repressive complex 2 (PRC2) components EZH2 and SUZ12, as well as the associated histone mark H3K27me3, are codetected at interenhancer regions across the CIITA locus. IFN-γ caused a BRG1-dependent reduction in H3K27me3, associated with nucleosome displacement. SUZ12 knockdown restored IFN-γ responsiveness in BRG1-null cells, and it mimicked the ability of BRG1 to induce active histone modifications (H3K27ac, H3K4me) at the -50-kb enhancer. Thus, PRC2 confers BRG1 dependency on the CIITA locus. Our data suggest that, in addition to its known roles in promoting stemness and proliferation, PRC2 may inhibit immune surveillance, and it could be targeted to reactivate CIITA expression in SWI/SNF deficient cancers. Copyright © 2015 by The American Association of Immunologists, Inc.

Long noncoding RNA PANDA and scaffold-attachment-factor SAFA control senescence entry and exit.

PubMed

Puvvula, Pavan Kumar; Desetty, Rohini Devi; Pineau, Pascal; Marchio, Agnés; Moon, Anne; Dejean, Anne; Bischof, Oliver

2014-11-19

Cellular senescence is a stable cell cycle arrest that limits the proliferation of pre-cancerous cells. Here we demonstrate that scaffold-attachment-factor A (SAFA) and the long noncoding RNA PANDA differentially interact with polycomb repressive complexes (PRC1 and PRC2) and the transcription factor NF-YA to either promote or suppress senescence. In proliferating cells, SAFA and PANDA recruit PRC complexes to repress the transcription of senescence-promoting genes. Conversely, the loss of SAFA-PANDA-PRC interactions allows expression of the senescence programme. Accordingly, we find that depleting either SAFA or PANDA in proliferating cells induces senescence. However, in senescent cells where PANDA sequesters transcription factor NF-YA and limits the expression of NF-YA-E2F-coregulated proliferation-promoting genes, PANDA depletion leads to an exit from senescence. Together, our results demonstrate that PANDA confines cells to their existing proliferative state and that modulating its level of expression can cause entry or exit from senescence.

Live-cell imaging reveals the dynamics of PRC2 and recruitment to chromatin by SUZ12-associated subunits.

PubMed

Youmans, Daniel T; Schmidt, Jens C; Cech, Thomas R

2018-06-01

Polycomb-repressive complex 2 (PRC2) is a histone methyltransferase that promotes epigenetic gene silencing, but the dynamics of its interactions with chromatin are largely unknown. Here we quantitatively measured the binding of PRC2 to chromatin in human cancer cells. Genome editing of a HaloTag into the endogenous EZH2 and SUZ12 loci and single-particle tracking revealed that ∼80% of PRC2 rapidly diffuses through the nucleus, while ∼20% is chromatin-bound. Short-term treatment with a small molecule inhibitor of the EED-H3K27me3 interaction had no immediate effect on the chromatin residence time of PRC2. In contrast, separation-of-function mutants of SUZ12, which still form the core PRC2 complex but cannot bind accessory proteins, revealed a major contribution of AEBP2 and PCL homolog proteins to chromatin binding. We therefore quantified the dynamics of this chromatin-modifying complex in living cells and separated the contributions of H3K27me3 histone marks and various PRC2 subunits to recruitment of PRC2 to chromatin. © 2018 Youmans et al.; Published by Cold Spring Harbor Laboratory Press.

Discovery of Peptidomimetic Ligands of EED as Allosteric Inhibitors of PRC2

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

Barnash, Kimberly D.; The, Juliana; Norris-Drouin, Jacqueline L.

The function of EED within polycomb repressive complex 2 (PRC2) is mediated by a complex network of protein–protein interactions. Allosteric activation of PRC2 by binding of methylated proteins to the embryonic ectoderm development (EED) aromatic cage is essential for full catalytic activity, but details of this regulation are not fully understood. EED’s recognition of the product of PRC2 activity, histone H3 lysine 27 trimethylation (H3K27me3), stimulates PRC2 methyltransferase activity at adjacent nucleosomes leading to H3K27me3 propagation and, ultimately, gene repression. By coupling combinatorial chemistry and structure-based design, we optimized a low-affinity methylated jumonji, AT-rich interactive domain 2 (Jarid2) peptide tomore » a smaller, more potent peptidomimetic ligand (K d = 1.14 ± 0.14 μM) of the aromatic cage of EED. Our strategy illustrates the effectiveness of applying combinatorial chemistry to achieve both ligand potency and property optimization. Furthermore, the resulting ligands, UNC5114 and UNC5115, demonstrate that targeted disruption of EED’s reader function can lead to allosteric inhibition of PRC2 catalytic activity.« less

The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex

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

He, Yupeng; Selvaraju, Sujatha; Curtin, Michael L.

Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2. Phenotypic effects observed inmore » vitro and in vivo are similar to those of known PRC2 enzymatic inhibitors; however, A-395 retains potent activity against cell lines resistant to the catalytic inhibitors. A-395 represents a first-in-class antagonist of PRC2 protein–protein interactions (PPI) for use as a chemical probe to investigate the roles of EED-containing protein complexes.« less

The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex.

PubMed

He, Yupeng; Selvaraju, Sujatha; Curtin, Michael L; Jakob, Clarissa G; Zhu, Haizhong; Comess, Kenneth M; Shaw, Bailin; The, Juliana; Lima-Fernandes, Evelyne; Szewczyk, Magdalena M; Cheng, Dong; Klinge, Kelly L; Li, Huan-Qiu; Pliushchev, Marina; Algire, Mikkel A; Maag, David; Guo, Jun; Dietrich, Justin; Panchal, Sanjay C; Petros, Andrew M; Sweis, Ramzi F; Torrent, Maricel; Bigelow, Lance J; Senisterra, Guillermo; Li, Fengling; Kennedy, Steven; Wu, Qin; Osterling, Donald J; Lindley, David J; Gao, Wenqing; Galasinski, Scott; Barsyte-Lovejoy, Dalia; Vedadi, Masoud; Buchanan, Fritz G; Arrowsmith, Cheryl H; Chiang, Gary G; Sun, Chaohong; Pappano, William N

2017-04-01

Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2. Phenotypic effects observed in vitro and in vivo are similar to those of known PRC2 enzymatic inhibitors; however, A-395 retains potent activity against cell lines resistant to the catalytic inhibitors. A-395 represents a first-in-class antagonist of PRC2 protein-protein interactions (PPI) for use as a chemical probe to investigate the roles of EED-containing protein complexes.

Polycomb repressive complex 2 epigenomic signature defines age-associated hypermethylation and gene expression changes

PubMed Central

Dozmorov, Mikhail G

2015-01-01

Although age-associated gene expression and methylation changes have been reported throughout the literature, the unifying epigenomic principles of aging remain poorly understood. Recent explosion in availability and resolution of functional/regulatory genome annotation data (epigenomic data), such as that provided by the ENCODE and Roadmap Epigenomics projects, provides an opportunity for the identification of epigenomic mechanisms potentially altered by age-associated differentially methylated regions (aDMRs) and regulatory signatures in the promoters of age-associated genes (aGENs). In this study we found that aDMRs and aGENs identified in multiple independent studies share a common Polycomb Repressive Complex 2 signature marked by EZH2, SUZ12, CTCF binding sites, repressive H3K27me3, and activating H3K4me1 histone modification marks, and a “poised promoter” chromatin state. This signature is depleted in RNA Polymerase II-associated transcription factor binding sites, activating H3K79me2, H3K36me3, H3K27ac marks, and an “active promoter” chromatin state. The PRC2 signature was shown to be generally stable across cell types. When considering the directionality of methylation changes, we found the PRC2 signature to be associated with aDMRs hypermethylated with age, while hypomethylated aDMRs were associated with enhancers. In contrast, aGENs were associated with the PRC2 signature independently of the directionality of gene expression changes. In this study we demonstrate that the PRC2 signature is the common epigenomic context of genomic regions associated with hypermethylation and gene expression changes in aging. PMID:25880792

Telobox motifs recruit CLF/SWN-PRC2 for H3K27me3 deposition via TRB factors in Arabidopsis.

PubMed

Zhou, Yue; Wang, Yuejun; Krause, Kristin; Yang, Tingting; Dongus, Joram A; Zhang, Yijing; Turck, Franziska

2018-05-01

Polycomb repressive complexes (PRCs) control organismic development in higher eukaryotes through epigenetic gene repression 1-4 . PRC proteins do not contain DNA-binding domains, thus prompting questions regarding how PRCs find their target loci 5 . Here we present genome-wide evidence of PRC2 recruitment by telomere-repeat-binding factors (TRBs) through telobox-related motifs in Arabidopsis. A triple trb1-2, trb2-1, and trb3-2 (trb1/2/3) mutant with a developmental phenotype and a transcriptome strikingly similar to those of strong PRC2 mutants showed redistribution of trimethyl histone H3 Lys27 (H3K27me3) marks and lower H3K27me3 levels, which were correlated with derepression of TRB1-target genes. TRB1-3 physically interacted with the PRC2 proteins CLF and SWN. A SEP3 reporter gene with a telobox mutation showed ectopic expression, which was correlated with H3K27me3 depletion, whereas tethering TRB1 to the mutated cis element partially restored repression. We propose that telobox-related motifs recruit PRC2 through the interaction between TRBs and CLF/SWN, a mechanism essential for H3K27me3 deposition at a subset of target genes.

Structure of a BMI-1-Ring1B Polycomb Group Ubiquitin Ligase Complex

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

Li,Z.; Cao, R.; Wang, M.

2006-01-01

Polycomb group (PcG) proteins Bmi-1 and Ring1B are core subunits of the PRC1 complex which plays important roles in the regulation of Hox gene expression, X-chromosome inactivation, tumorigenesis and stem cell self-renewal. The RING finger protein Ring1B is an E3 ligase that participates in the ubiquitination of lysine 119 of histone H2A, and the binding of Bmi-1 stimulates the E3 ligase activity. We have mapped the regions of Bmi-1 and Ring1B required for efficient ubiquitin transfer and determined a 2.5 Angstroms structure of the Bmi-1-Ring1B core domain complex. The structure reveals that Ring1B 'hugs' Bmi-1 through extensive RING domain contactsmore » and its N-terminal tail wraps around Bmi-1. The two regions of interaction have a synergistic effect on the E3 ligase activity. Our analyses suggest a model where the Bmi-1-Ring1B complex stabilizes the interaction between the E2 enzyme and the nucleosomal substrate to allow efficient ubiquitin transfer.« less

PRC2 Represses Hormone-Induced Somatic Embryogenesis in Vegetative Tissue of Arabidopsis thaliana

PubMed Central

Mozgová, Iva

2017-01-01

Many plant cells can be reprogrammed into a pluripotent state that allows ectopic organ development. Inducing totipotent states to stimulate somatic embryo (SE) development is, however, challenging due to insufficient understanding of molecular barriers that prevent somatic cell dedifferentiation. Here we show that Polycomb repressive complex 2 (PRC2)-activity imposes a barrier to hormone-mediated transcriptional reprogramming towards somatic embryogenesis in vegetative tissue of Arabidopsis thaliana. We identify factors that enable SE development in PRC2-depleted shoot and root tissue and demonstrate that the establishment of embryogenic potential is marked by ectopic co-activation of crucial developmental regulators that specify shoot, root and embryo identity. Using inducible activation of PRC2 in PRC2-depleted cells, we demonstrate that transient reduction of PRC2 activity is sufficient for SE formation. We suggest that modulation of PRC2 activity in plant vegetative tissue combined with targeted activation of developmental pathways will open possibilities for novel approaches to cell reprogramming. PMID:28095419

Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development

PubMed Central

Bar, Carmit; Tsai, Pai-Chi; Valdes, Victor J.; Cohen, Idan; Santoriello, Francis J.; Zhao, Dejian; Hsu, Ya-Chieh; Ezhkova, Elena

2016-01-01

An increasing amount of evidence indicates that developmental programs are tightly regulated by the complex interplay between signaling pathways, as well as transcriptional and epigenetic processes. Here, we have uncovered coordination between transcriptional and morphogen cues to specify Merkel cells, poorly understood skin cells that mediate light touch sensations. In murine dorsal skin, Merkel cells are part of touch domes, which are skin structures consisting of specialized keratinocytes, Merkel cells, and afferent neurons, and are located exclusively around primary hair follicles. We show that the developing primary hair follicle functions as a niche required for Merkel cell specification. We find that intraepidermal Sonic hedgehog (Shh) signaling, initiated by the production of Shh ligand in the developing hair follicles, is required for Merkel cell specification. The importance of Shh for Merkel cell formation is further reinforced by the fact that Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to primary, secondary, and tertiary hair follicles, raising the possibility that there are restrictive mechanisms that regulate Merkel cell specification exclusively around primary hair follicles. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2) in the epidermis results in the formation of ectopic Merkel cells that are associated with all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through the upregulation of key Merkel-differentiation genes, which are known PRC2 targets. Importantly, PRC2-mediated repression of the Merkel cell differentiation program requires inductive Shh signaling to form mature Merkel cells. Our study exemplifies how the interplay between epigenetic and morphogen cues regulates the complex patterning and formation of the mammalian skin structures. PMID:27414999

Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development.

PubMed

Perdigoto, Carolina N; Dauber, Katherine L; Bar, Carmit; Tsai, Pai-Chi; Valdes, Victor J; Cohen, Idan; Santoriello, Francis J; Zhao, Dejian; Zheng, Deyou; Hsu, Ya-Chieh; Ezhkova, Elena

2016-07-01

An increasing amount of evidence indicates that developmental programs are tightly regulated by the complex interplay between signaling pathways, as well as transcriptional and epigenetic processes. Here, we have uncovered coordination between transcriptional and morphogen cues to specify Merkel cells, poorly understood skin cells that mediate light touch sensations. In murine dorsal skin, Merkel cells are part of touch domes, which are skin structures consisting of specialized keratinocytes, Merkel cells, and afferent neurons, and are located exclusively around primary hair follicles. We show that the developing primary hair follicle functions as a niche required for Merkel cell specification. We find that intraepidermal Sonic hedgehog (Shh) signaling, initiated by the production of Shh ligand in the developing hair follicles, is required for Merkel cell specification. The importance of Shh for Merkel cell formation is further reinforced by the fact that Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to primary, secondary, and tertiary hair follicles, raising the possibility that there are restrictive mechanisms that regulate Merkel cell specification exclusively around primary hair follicles. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2) in the epidermis results in the formation of ectopic Merkel cells that are associated with all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through the upregulation of key Merkel-differentiation genes, which are known PRC2 targets. Importantly, PRC2-mediated repression of the Merkel cell differentiation program requires inductive Shh signaling to form mature Merkel cells. Our study exemplifies how the interplay between epigenetic and morphogen cues regulates the complex patterning and formation of the mammalian skin structures.

Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase

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

Lingel, Andreas; Sendzik, Martin; Huang, Ying

2017-01-12

PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 of histone H3, leading to chromatin compaction and repression of tumor suppressor genes. Inhibiting this activity by small molecules targeting EZH2 was shown to result in antitumor efficacy. Here, we describe the optimization of a chemical series representing a new class of PRC2 inhibitors which acts allosterically via the trimethyllysine pocket of the noncatalytic EED subunit. Deconstruction of a larger and complex screening hit to a simple fragment-sized molecule followed by structure-guided regrowth and careful propertymore » modulation were employed to yield compounds which achieve submicromolar inhibition in functional assays and cellular activity. The resulting molecules can serve as a simplified entry point for lead optimization and can be utilized to study this new mechanism of PRC2 inhibition and the associated biology in detail.« less

The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy.

PubMed

Wang, Zhihua; Zhang, Xiao-Jing; Ji, Yan-Xiao; Zhang, Peng; Deng, Ke-Qiong; Gong, Jun; Ren, Shuxun; Wang, Xinghua; Chen, Iris; Wang, He; Gao, Chen; Yokota, Tomohiro; Ang, Yen Sin; Li, Shen; Cass, Ashley; Vondriska, Thomas M; Li, Guangping; Deb, Arjun; Srivastava, Deepak; Yang, Huang-Tian; Xiao, Xinshu; Li, Hongliang; Wang, Yibin

2016-10-01

Epigenetic reprogramming is a critical process of pathological gene induction during cardiac hypertrophy and remodeling, but the underlying regulatory mechanisms remain to be elucidated. Here we identified a heart-enriched long noncoding (lnc)RNA, named cardiac-hypertrophy-associated epigenetic regulator (Chaer), which is necessary for the development of cardiac hypertrophy. Mechanistically, Chaer directly interacts with the catalytic subunit of polycomb repressor complex 2 (PRC2). This interaction, which is mediated by a 66-mer motif in Chaer, interferes with PRC2 targeting to genomic loci, thereby inhibiting histone H3 lysine 27 methylation at the promoter regions of genes involved in cardiac hypertrophy. The interaction between Chaer and PRC2 is transiently induced after hormone or stress stimulation in a process involving mammalian target of rapamycin complex 1, and this interaction is a prerequisite for epigenetic reprogramming and induction of genes involved in hypertrophy. Inhibition of Chaer expression in the heart before, but not after, the onset of pressure overload substantially attenuates cardiac hypertrophy and dysfunction. Our study reveals that stress-induced pathological gene activation in the heart requires a previously uncharacterized lncRNA-dependent epigenetic checkpoint.

VE-Cadherin–Mediated Epigenetic Regulation of Endothelial Gene Expression

PubMed Central

Morini, Marco F.; Giampietro, Costanza; Corada, Monica; Pisati, Federica; Lavarone, Elisa; Cunha, Sara I.; Conze, Lei L.; O’Reilly, Nicola; Joshi, Dhira; Kjaer, Svend; George, Roger; Nye, Emma; Ma, Anqi; Jin, Jian; Mitter, Richard; Lupia, Michela; Cavallaro, Ugo; Pasini, Diego; Calado, Dinis P.

2018-01-01

Rationale: The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumors, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular interendothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, VEC (vascular endothelial cadherin), upregulate genes with key roles in endothelial differentiation and stability. Objective: We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization. Methods and Results: We compared a VEC-null cell line with the same line reconstituted with VEC wild-type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and von Willebrand factor (vWf). Mechanistically, VEC exerts this effect by inhibiting polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 (Forkhead box protein O1) and β-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5, VE-PTP, and vWf. VEC/β-catenin complex also sequesters a core subunit of PRC2 (Ezh2 [enhancer of zeste homolog 2]) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VEC association increases Ezh2 recruitment to claudin-5, VE-PTP, and vWf promoters, causing gene downregulation. RNA sequencing comparison of VEC-null and VEC-positive cells suggested a more general role of VEC in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of claudin-5 and VE-PTP. Conclusions: These data extend the knowledge of polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the polycomb-mediated repression system. PMID:29233846

VE-Cadherin-Mediated Epigenetic Regulation of Endothelial Gene Expression.

PubMed

Morini, Marco F; Giampietro, Costanza; Corada, Monica; Pisati, Federica; Lavarone, Elisa; Cunha, Sara I; Conze, Lei L; O'Reilly, Nicola; Joshi, Dhira; Kjaer, Svend; George, Roger; Nye, Emma; Ma, Anqi; Jin, Jian; Mitter, Richard; Lupia, Michela; Cavallaro, Ugo; Pasini, Diego; Calado, Dinis P; Dejana, Elisabetta; Taddei, Andrea

2018-01-19

The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumors, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular interendothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, VEC (vascular endothelial cadherin), upregulate genes with key roles in endothelial differentiation and stability. We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization. We compared a VEC-null cell line with the same line reconstituted with VEC wild-type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5 , vascular endothelial-protein tyrosine phosphatase ( VE-PTP ), and von Willebrand factor ( vWf ). Mechanistically, VEC exerts this effect by inhibiting polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 (Forkhead box protein O1) and β-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5 , VE-PTP , and vWf . VEC/β-catenin complex also sequesters a core subunit of PRC2 (Ezh2 [enhancer of zeste homolog 2]) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VEC association increases Ezh2 recruitment to claudin-5 , VE-PTP , and vWf promoters, causing gene downregulation. RNA sequencing comparison of VEC-null and VEC-positive cells suggested a more general role of VEC in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of claudin-5 and VE-PTP. These data extend the knowledge of polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the polycomb-mediated repression system. © 2017 The Authors.

MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53.

PubMed

Wienken, Magdalena; Dickmanns, Antje; Nemajerova, Alice; Kramer, Daniela; Najafova, Zeynab; Weiss, Miriam; Karpiuk, Oleksandra; Kassem, Moustapha; Zhang, Yanping; Lozano, Guillermina; Johnsen, Steven A; Moll, Ute M; Zhang, Xin; Dobbelstein, Matthias

2016-01-07

The MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that MDM2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, MDM2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. MDM2 physically associated with EZH2 on chromatin, enhancing the trimethylation of histone 3 at lysine 27 and the ubiquitination of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, MDM2 supports the Polycomb-mediated repression of lineage-specific genes, independent of p53. Copyright © 2016 Elsevier Inc. All rights reserved.

PRC2 is required to maintain expression of the maternal Gtl2-Rian-Mirg locus by preventing de novo DNA methylation in mouse embryonic stem cells

PubMed Central

Das, Partha Pratim; Hendrix, David A.; Apostolou, Effie; Buchner, Alice H.; Canver, Matthew C.; Beyaz, Semir; Ljuboja, Damir; Kuintzle, Rachael; Kim, Woojin; Karnik, Rahul; Shao, Zhen; Xie, Huafeng; Xu, Jian; De Los Angeles, Alejandro; Zhang, Yingying; Choe, Junho; Jun, Don Leong Jia; Shen, Xiaohua; Gregory, Richard I.; Daley, George Q.; Meissner, Alexander; Kellis, Manolis; Hochedlinger, Konrad; Kim, Jonghwan; Orkin, Stuart H.

2017-01-01

SUMMARY Polycomb Repressive Complex 2 (PRC2) function and DNA methylation (DNAme) are typically correlated with the gene repression. Here, we show that PRC2 is required to maintain expression of maternal microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) from the Gtl2-Rian-Mirg locus, which is essential for full pluripotency of iPSCs. In the absence of PRC2 the entire locus becomes transcriptionally repressed due to gain of DNA methylation at the intergenic differentially methylated regions (IG-DMR). Furthermore, we demonstrate that the IG-DMR serves as an enhancer of the maternal Gtl2-Rian-Mirg locus. Mechanistic study reveals that PRC2 interacts physically with Dnmt3 methyltransferases and prevents their recruitment and subsequent DNAme at the IG-DMR, thereby allowing for proper expression of the maternal Gtl2-Rian-Mirg locus. Our observations provide a novel mechanism by which PRC2 counteracts the action of Dnmt3 methyltransferases at an imprinted locus required for full pluripotency. PMID:26299972

Epigenetic dysregulation of key developmental genes in radiation-induced rat mammary carcinomas.

PubMed

Daino, Kazuhiro; Nishimura, Mayumi; Imaoka, Tatsuhiko; Takabatake, Masaru; Morioka, Takamitsu; Nishimura, Yukiko; Shimada, Yoshiya; Kakinuma, Shizuko

2018-02-13

With the increase in the number of long-term cancer survivors worldwide, there is a growing concern about the risk of secondary cancers induced by radiotherapy. Epigenetic modifications of genes associated with carcinogenesis are attractive targets for the prevention of cancer owing to their reversible nature. To identify genes with possible changes in functionally relevant DNA methylation patterns in mammary carcinomas induced by radiation exposure, we performed microarray-based global DNA methylation and expression profiling in γ-ray-induced rat mammary carcinomas and normal mammary glands. The gene expression profiling identified dysregulation of developmentally related genes, including the downstream targets of polycomb repressive complex 2 (PRC2) and overexpression of enhancer of zeste homolog 2, a component of PRC2, in the carcinomas. By integrating expression and DNA methylation profiles, we identified ten hypermethylated and three hypomethylated genes that possibly act as tumor-suppressor genes and oncogenes dysregulated by aberrant DNA methylation; half of these genes encode developmental transcription factors. Bisulfite sequencing and quantitative PCR confirmed the dysregulation of the polycomb-regulated developmentally related transcription-factor genes Dmrt2, Hoxa7, Foxb1, Sox17, Lhx8, Gata3 and Runx1. Silencing of Hoxa7 was further verified by immunohistochemistry. These results suggest that, in radiation-induced mammary gland carcinomas, PRC2-mediated aberrant DNA methylation leads to dysregulation of developmentally related transcription-factor genes. Our findings provide clues to molecular mechanisms linking epigenetic regulation and radiation-induced breast carcinogenesis and underscore the potential of such epigenetic mechanisms as targets for cancer prevention. © 2018 UICC.

SETDB1 modulates PRC2 activity at developmental genes independently of H3K9 trimethylation in mouse ES cells

PubMed Central

Fei, Qi; Yang, Xiaoqin; Jiang, Hua; Wang, Qian; Yu, Yanyan; Yu, Yiling; Yi, Wei; Zhou, Shaolian; Chen, Taiping; Lu, Chris; Atadja, Peter; Liu, Xiaole Shirley; Li, En; Zhang, Yong; Shou, Jianyong

2015-01-01

SETDB1, a histone methyltransferase responsible for methylation of histone H3 lysine 9 (H3K9), is involved in maintenance of embryonic stem (ES) cells and early embryonic development of the mouse. However, how SETDB1 regulates gene expression during development is largely unknown. Here, we characterized genome-wide SETDB1 binding and H3K9 trimethylation (H3K9me3) profiles in mouse ES cells and uncovered two distinct classes of SETDB1 binding sites, termed solo and ensemble peaks. The solo peaks were devoid of H3K9me3 and enriched near developmental regulators while the ensemble peaks were associated with H3K9me3. A subset of the SETDB1 solo peaks, particularly those near neural development–related genes, was found to be associated with Polycomb Repressive Complex 2 (PRC2) as well as PRC2-interacting proteins JARID2 and MTF2. Genetic deletion of Setdb1 reduced EZH2 binding as well as histone 3 lysine 27 (H3K27) trimethylation level at SETDB1 solo peaks and facilitated neural differentiation. Furthermore, we found that H3K27me3 inhibits SETDB1 methyltransferase activity. The currently identified reciprocal action between SETDB1 and PRC2 reveals a novel mechanism underlying ES cell pluripotency and differentiation regulation. PMID:26160163

Structural Context of Disease-Associated Mutations and Putative Mechanism of Autoinhibition Revealed by X-Ray Crystallographic Analysis of the EZH2-SET Domain

PubMed Central

Antonysamy, Stephen; Condon, Bradley; Druzina, Zhanna; Bonanno, Jeffrey B.; Gheyi, Tarun; Zhang, Feiyu; MacEwan, Iain; Zhang, Aiping; Ashok, Sheela; Rodgers, Logan; Russell, Marijane; Gately Luz, John

2013-01-01

The enhancer-of-zeste homolog 2 (EZH2) gene product is an 87 kDa polycomb group (PcG) protein containing a C-terminal methyltransferase SET domain. EZH2, along with binding partners, i.e., EED and SUZ12, upon which it is dependent for activity forms the core of the polycomb repressive complex 2 (PRC2). PRC2 regulates gene silencing by catalyzing the methylation of histone H3 at lysine 27. Both overexpression and mutation of EZH2 are associated with the incidence and aggressiveness of various cancers. The novel crystal structure of the SET domain was determined in order to understand disease-associated EZH2 mutations and derive an explanation for its inactivity independent of complex formation. The 2.00 Å crystal structure reveals that, in its uncomplexed form, the EZH2 C-terminus folds back into the active site blocking engagement with substrate. Furthermore, the S-adenosyl-L-methionine (SAM) binding pocket observed in the crystal structure of homologous SET domains is notably absent. This suggests that a conformational change in the EZH2 SET domain, dependent upon complex formation, must take place for cofactor and substrate binding activities to be recapitulated. In addition, the data provide a structural context for clinically significant mutations found in the EZH2 SET domain. PMID:24367637

BCOR regulates myeloid cell proliferation and differentiation

PubMed Central

Cao, Qi; Gearhart, Micah D.; Gery, Sigal; Shojaee, Seyedmehdi; Yang, Henry; Sun, Haibo; Lin, De-chen; Bai, Jing-wen; Mead, Monica; Zhao, Zhiqiang; Chen, Qi; Chien, Wen-wen; Alkan, Serhan; Alpermann, Tamara; Haferlach, Torsten; Müschen, Markus; Bardwell, Vivian J.; Koeffler, H. Phillip

2016-01-01

BCOR is a component of a variant Polycomb group repressive complex 1 (PRC1). Recently, we and others reported recurrent somatic BCOR loss-of-function mutations in myelodysplastic syndrome and acute myelogenous leukaemia (AML). However, the role of BCOR in normal hematopoiesis is largely unknown. Here, we explored the function of BCOR in myeloid cells using myeloid murine models with Bcor conditional loss-of-function or overexpression alleles. Bcor mutant bone marrow cells showed significantly higher proliferation and differentiation rates with upregulated expression of Hox genes. Mutation of Bcor reduced protein levels of RING1B, an H2A ubiquitin ligase subunit of PRC1 family complexes and reduced H2AK119ub upstream of upregulated HoxA genes. Global RNA expression profiling in murine cells and AML patient samples with BCOR loss-of-function mutation suggested that loss of BCOR expression is associated with enhanced cell proliferation and myeloid differentiation. Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. PMID:26847029

EZH2 mutations and promoter hypermethylation in childhood acute lymphoblastic leukemia.

PubMed

Schäfer, Vivien; Ernst, Jana; Rinke, Jenny; Winkelmann, Nils; Beck, James F; Hochhaus, Andreas; Gruhn, Bernd; Ernst, Thomas

2016-07-01

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and young adults. The polycomb repressive complex 2 (PRC2) has been identified as one of the most frequently mutated epigenetic protein complexes in hematologic cancers. PRC2 acts as an epigenetic repressor through histone H3 lysine 27 trimethylation (H3K27me3), catalyzed by the histone methyltransferase enhancer of zeste homolog 2 protein (EZH2). To study the prevalence and clinical impact of PRC2 aberrations in an unselected childhood ALL cohort (n = 152), we performed PRC2 mutational screenings by Sanger sequencing and promoter methylation analyses by quantitative pyrosequencing for the three PRC2 core component genes EZH2, suppressor of zeste 12 (SUZ12), and embryonic ectoderm development (EED). Targeted deep next-generation sequencing of 30 frequently mutated genes in leukemia was performed to search for cooperating mutations in patients harboring PRC2 aberrations. Finally, the functional consequence of EZH2 promoter hypermethylation on H3K27me3 was studied by Western blot analyses of primary cells. Loss-of-function EZH2 mutations were detected in 2/152 (1.3 %) patients with common-ALL and early T-cell precursor (ETP)-ALL, respectively. In one patient, targeted deep sequencing identified cooperating mutations in ASXL1 and TET2. EZH2 promoter hypermethylation was found in one patient with ETP-ALL which led to reduced H3K27me3. In comparison with healthy children, the EZH2 promoter was significantly higher methylated in T-ALL patients. No mutations or promoter methylation changes were identified for SUZ12 or EED genes, respectively. Although PRC2 aberrations seem to be rare in childhood ALL, our findings indicate that EZH2 aberrations might contribute to the disease in specific cases. Hereby, EZH2 promoter hypermethylation might have functionally similar consequences as loss-of-function mutations.

Epigenetic modification of histone 3 lysine 27: mediator subunit MED25 is required for the dissociation of polycomb repressive complex 2 from the promoter of cytochrome P450 2C9.

PubMed

Englert, Neal A; Luo, George; Goldstein, Joyce A; Surapureddi, Sailesh

2015-01-23

The Mediator complex is vital for the transcriptional regulation of eukaryotic genes. Mediator binds to nuclear receptors at target response elements and recruits chromatin-modifying enzymes and RNA polymerase II. Here, we examine the involvement of Mediator subunit MED25 in the epigenetic regulation of human cytochrome P450 2C9 (CYP2C9). MED25 is recruited to the CYP2C9 promoter through association with liver-enriched HNF4α, and we show that MED25 influences the H3K27 status of the HNF4α binding region. This region was enriched for the activating marker H3K27ac and histone acetyltransferase CREBBP after MED25 overexpression but was trimethylated when MED25 expression was silenced. The epigenetic regulator Polycomb repressive complex (PRC2), which represses expression by methylating H3K27, plays an important role in target gene regulation. Silencing MED25 correlated with increased association of PRC2 not only with the promoter region chromatin but with HNF4α itself. We confirmed the involvement of MED25 for fully functional preinitiation complex recruitment and transcriptional output in vitro. Formaldehyde-assisted isolation of regulatory elements (FAIRE) revealed chromatin conformation changes that were reliant on MED25, indicating that MED25 induced a permissive chromatin state that reflected increases in CYP2C9 mRNA. For the first time, we showed evidence that a functionally relevant human gene is transcriptionally regulated by HNF4α via MED25 and PRC2. CYP2C9 is important for the metabolism of many exogenous chemicals including pharmaceutical drugs as well as endogenous substrates. Thus, MED25 is important for regulating the epigenetic landscape resulting in transcriptional activation of a highly inducible gene, CYP2C9. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

The PRC2-binding long non-coding RNAs in human and mouse genomes are associated with predictive sequence features

NASA Astrophysics Data System (ADS)

Tu, Shiqi; Yuan, Guo-Cheng; Shao, Zhen

2017-01-01

Recently, long non-coding RNAs (lncRNAs) have emerged as an important class of molecules involved in many cellular processes. One of their primary functions is to shape epigenetic landscape through interactions with chromatin modifying proteins. However, mechanisms contributing to the specificity of such interactions remain poorly understood. Here we took the human and mouse lncRNAs that were experimentally determined to have physical interactions with Polycomb repressive complex 2 (PRC2), and systematically investigated the sequence features of these lncRNAs by developing a new computational pipeline for sequences composition analysis, in which each sequence is considered as a series of transitions between adjacent nucleotides. Through that, PRC2-binding lncRNAs were found to be associated with a set of distinctive and evolutionarily conserved sequence features, which can be utilized to distinguish them from the others with considerable accuracy. We further identified fragments of PRC2-binding lncRNAs that are enriched with these sequence features, and found they show strong PRC2-binding signals and are more highly conserved across species than the other parts, implying their functional importance.

Stage- and subunit-specific functions of polycomb repressive complex 2 in bladder urothelial formation and regeneration

PubMed Central

Guo, Chunming; Balsara, Zarine R.

2017-01-01

ABSTRACT Urothelium is the protective lining of the urinary tract. The mechanisms underlying urothelial formation and maintenance are largely unknown. Here, we report the stage-specific roles of PRC2 epigenetic regulators in embryonic and adult urothelial progenitors. Without Eed, the obligatory subunit of PRC2, embryonic urothelial progenitors demonstrate reduced proliferation with concomitant dysregulation of genes including Cdkn2a (p16), Cdkn2b (p15) and Shh. These mutants display premature differentiation of keratin 5-positive (Krt5+) basal cells and ectopic expression of squamous-like differentiation markers. Deletion of Ezh2, the major enzymatic component of PRC2, causes upregulation of Upk3a+ superficial cells. Unexpectedly, Eed and Eed/Ezh2 double mutants exhibit delayed superficial cell differentiation. Furthermore, Eed regulates the proliferative and regenerative capacity of adult urothelial progenitors and prevents precocious differentiation. Collectively, these findings uncover the epigenetic mechanism by which PRC2 controls urothelial progenitor cell fate and the timing of differentiation, and further suggest an epigenetic basis of urothelial maintenance and regeneration. PMID:28049658

Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogaster.

PubMed

Tolhuis, Bas; de Wit, Elzo; Muijrers, Inhua; Teunissen, Hans; Talhout, Wendy; van Steensel, Bas; van Lohuizen, Maarten

2006-06-01

Polycomb group (PcG) proteins maintain transcriptional repression of developmentally important genes and have been implicated in cell proliferation and stem cell self-renewal. We used a genome-wide approach to map binding patterns of PcG proteins (Pc, esc and Sce) in Drosophila melanogaster Kc cells. We found that Pc associates with large genomic regions of up to approximately 150 kb in size, hereafter referred to as 'Pc domains'. Sce and esc accompany Pc in most of these domains. PcG-bound chromatin is trimethylated at histone H3 Lys27 and is generally transcriptionally silent. Furthermore, PcG proteins preferentially bind to developmental genes. Many of these encode transcriptional regulators and key components of signal transduction pathways, including Wingless, Hedgehog, Notch and Delta. We also identify several new putative functions of PcG proteins, such as in steroid hormone biosynthesis. These results highlight the extensive involvement of PcG proteins in the coordination of development through the formation of large repressive chromatin domains.

The histone H2A deubiquitinase Usp16 regulates hematopoiesis and hematopoietic stem cell function.

PubMed

Gu, Yue; Jones, Amanda E; Yang, Wei; Liu, Shanrun; Dai, Qian; Liu, Yudong; Swindle, C Scott; Zhou, Dewang; Zhang, Zhuo; Ryan, Thomas M; Townes, Tim M; Klug, Christopher A; Chen, Dongquan; Wang, Hengbin

2016-01-05

Epigenetic mechanisms play important regulatory roles in hematopoiesis and hematopoietic stem cell (HSC) function. Subunits of polycomb repressive complex 1 (PRC1), the major histone H2A ubiquitin ligase, are critical for both normal and pathological hematopoiesis; however, it is unclear which of the several counteracting H2A deubiquitinases functions along with PRC1 to control H2A ubiquitination (ubH2A) level and regulates hematopoiesis in vivo. Here we investigated the function of Usp16 in mouse hematopoiesis. Conditional deletion of Usp16 in bone marrow resulted in a significant increase of global ubH2A level and lethality. Usp16 deletion did not change HSC number but was associated with a dramatic reduction of mature and progenitor cell populations, revealing a role in governing HSC lineage commitment. ChIP- and RNA-sequencing studies in HSC and progenitor cells revealed that Usp16 bound to many important hematopoietic regulators and that Usp16 deletion altered the expression of genes in transcription/chromosome organization, immune response, hematopoietic/lymphoid organ development, and myeloid/leukocyte differentiation. The altered gene expression was partly rescued by knockdown of PRC1 subunits, suggesting that Usp16 and PRC1 counterbalance each other to regulate cellular ubH2A level and gene expression in the hematopoietic system. We further discovered that knocking down Cdkn1a (p21cip1), a Usp16 target and regulated gene, rescued the altered cell cycle profile and differentiation defect of Usp16-deleted HSCs. Collectively, these studies identified Usp16 as one of the histone H2A deubiquitinases, which coordinates with the H2A ubiquitin ligase PRC1 to regulate hematopoiesis, and revealed cell cycle regulation by Usp16 as key for HSC differentiation.

LHP1 Regulates H3K27me3 Spreading and Shapes the Three-Dimensional Conformation of the Arabidopsis Genome

PubMed Central

Ariel, Federico; Latrasse, David; Mariappan, Kiruthiga Gayathri; Kim, Soon-Kap; Crespi, Martin; Hirt, Heribert; Bergounioux, Catherine; Raynaud, Cécile; Benhamed, Moussa

2016-01-01

Precise expression patterns of genes in time and space are essential for proper development of multicellular organisms. Dynamic chromatin conformation and spatial organization of the genome constitute a major step in this regulation to modulate developmental outputs. Polycomb repressive complexes (PRCs) mediate stable or flexible gene repression in response to internal and environmental cues. In Arabidopsis thaliana, LHP1 co-localizes with H3K27me3 epigenetic marks throughout the genome and interacts with PRC1 and PRC2 members as well as with a long noncoding RNA. Here, we show that LHP1 is responsible for the spreading of H3K27me3 towards the 3’ end of the gene body. We also identified a subset of LHP1-activated genes and demonstrated that LHP1 shapes local chromatin topology in order to control transcriptional co-regulation. Our work reveals a general role of LHP1 from local to higher conformation levels of chromatin configuration to determine its accessibility to define gene expression patterns. PMID:27410265

Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia

PubMed Central

Ridinger-Saison, M; Evanno, E; Gallais, I; Rimmelé, P; Selimoglu-Buet, D; Sapharikas, E; Moreau-Gachelin, F; Guillouf, C

2013-01-01

Deregulation of transcriptional networks contributes to haematopoietic malignancies. The transcription factor Spi-1/PU.1 is a master regulator of haematopoiesis and its alteration leads to leukaemia. Spi-1 overexpression inhibits differentiation and promotes resistance to apoptosis in erythroleukaemia. Here, we show that Spi-1 inhibits mitochondrial apoptosis in vitro and in vivo through the transcriptional repression of Bim, a proapoptotic factor. BIM interacts with MCL-1 that behaves as a major player in the survival of the preleukaemic cells. The repression of BIM expression reduces the amount of BIM-MCL-1 complexes, thus increasing the fraction of potentially active antiapoptotic MCL-1. We then demonstrate that Spi-1 represses Bim transcription by binding to the Bim promoter and by promoting the trimethylation of histone 3 on lysine 27 (H3K27me3, a repressive histone mark) on the Bim promoter. The PRC2 repressive complex of Polycomb is directly responsible for the deposit of H3K27me3 mark at the Bim promoter. SUZ12 and the histone methyltransferase EZH2, two PRC2 subunits bind to the Bim promoter at the same location than H3K27me3, distinct of the Spi-1 DNA binding site. As Spi-1 interacts with SUZ12 and EZH2, these results indicate that Spi-1 modulates the activity of PRC2 without directly recruiting the complex to the site of its activity on the chromatin. Our results identify a new mechanism whereby Spi-1 represses transcription and provide mechanistic insights on the antiapoptotic function of a transcription factor mediated by the epigenetic control of gene expression. PMID:23852375

Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy.

PubMed

Wang, Lu; Zhao, Zibo; Ozark, Patrick A; Fantini, Damiano; Marshall, Stacy A; Rendleman, Emily J; Cozzolino, Kira A; Louis, Nundia; He, Xingyao; Morgan, Marc A; Takahashi, Yoh-Hei; Collings, Clayton K; Smith, Edwin R; Ntziachristos, Panagiotis; Savas, Jeffrey N; Zou, Lihua; Hashizume, Rintaro; Meeks, Joshua J; Shilatifard, Ali

2018-06-01

The lysine methyltransferase KMT2C (also known as MLL3), a subunit of the COMPASS complex, implements monomethylation of Lys4 on histone H3 (H3K4) at gene enhancers. KMT2C (hereafter referred to as MLL3) frequently incurs point mutations across a range of human tumor types, but precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within the region encoding its plant homeodomain (PHD) repeats and demonstrate that this domain mediates association of MLL3 with the histone H2A deubiquitinase and tumor suppressor BAP1. Cancer-associated mutations in the sequence encoding the MLL3 PHD repeats disrupt the interaction between MLL3 and BAP1 and correlate with poor patient survival. Cancer cells that had PHD-associated MLL3 mutations or lacked BAP1 showed reduced recruitment of MLL3 and the H3K27 demethylase KDM6A (also known as UTX) to gene enhancers. As a result, inhibition of the H3K27 methyltransferase activity of the Polycomb repressive complex 2 (PRC2) in tumor cells harboring BAP1 or MLL3 mutations restored normal gene expression patterns and impaired cell proliferation in vivo. This study provides mechanistic insight into the oncogenic effects of PHD-associated mutations in MLL3 and suggests that restoration of a balanced state of Polycomb-COMPASS activity may have therapeutic efficacy in tumors that bear mutations in the genes encoding these epigenetic factors.

An RNA matchmaker protein regulates the activity of the long noncoding RNA HOTAIR

PubMed Central

Meredith, Emily K.; Balas, Maggie M.; Sindy, Karla; Haislop, Krystal; Johnson, Aaron M.

2016-01-01

The human long noncoding RNA (lncRNA) HOTAIR acts in trans to recruit the Polycomb repressive complex 2 (PRC2) to the HOXD gene cluster and to promote gene silencing during development. In breast cancers, overexpression of HOTAIR increases metastatic potential via the repression of many additional genes. It has remained unclear what factors determine HOTAIR-dependent PRC2 activity at specific genomic loci, particularly when high levels of HOTAIR result in aberrant gene silencing. To identify additional proteins that contribute to the specific action of HOTAIR, we performed a quantitative proteomic analysis of the HOTAIR interactome. We found that the most specific interaction was between HOTAIR and the heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, a member of a family of proteins involved in nascent mRNA processing and RNA matchmaking. Our data suggest that A2/B1 are key contributors to HOTAIR-mediated chromatin regulation in breast cancer cells: A2/B1 knockdown reduces HOTAIR-dependent breast cancer cell invasion and decreases PRC2 activity at the majority of HOTAIR-dependent loci. We found that the B1 isoform, which differs from A2 by 12 additional amino acids, binds with highest specificity to HOTAIR. B1 also binds chromatin and associates preferentially with RNA transcripts of HOTAIR gene targets. We furthermore demonstrate a direct RNA–RNA interaction between HOTAIR and a target transcript that is enhanced by B1 binding. Together, these results suggest a model in which B1 matches HOTAIR with transcripts of target genes on chromatin, leading to repression by PRC2. PMID:27146324

Ezh1 and Ezh2 differentially regulate PSD-95 gene transcription in developing hippocampal neurons.

PubMed

Henriquez, Berta; Bustos, Fernando J; Aguilar, Rodrigo; Becerra, Alvaro; Simon, Felipe; Montecino, Martin; van Zundert, Brigitte

2013-11-01

Polycomb Repressive Complex 2 (PRC2) mediates transcriptional silencing by catalyzing histone H3 lysine 27 trimethylation (H3K27me3), but its role in the maturation of postmitotic mammalian neurons remains largely unknown. We report that the PRC2 paralogs Ezh1 and Ezh2 are differentially expressed during hippocampal development. We show that depletion of Ezh2 leads to increased expression of PSD-95, a critical plasticity gene, and that reduced PSD-95 gene transcription is correlated with enrichment of Ezh2 at the PSD-95 gene promoter; however, the H3K27me3 epigenetic mark is not present at the PSD-95 gene promoter, likely due to the antagonizing effects of the H3S28P and H3K27Ac marks and the activity of the H3K27 demethylases JMJD3 and UTX. In contrast, increased PSD-95 gene transcription is accompanied by the presence of Ezh1 and elongation-engaged RNA Polymerase II complexes at the PSD-95 gene promoter, while knock-down of Ezh1 reduces PSD-95 transcription. These results indicate that Ezh1 and Ezh2 have antagonistic roles in regulating PSD-95 transcription. © 2013.

The CpG island encompassing the promoter and first exon of human DNMT3L gene is a PcG/TrX response element (PRE).

PubMed

Basu, Amitava; Dasari, Vasanthi; Mishra, Rakesh K; Khosla, Sanjeev

2014-01-01

DNMT3L, a member of DNA methyltransferases family, is present only in mammals. As it provides specificity to the action of de novo methyltransferases, DNMT3A and DNMT3B and interacts with histone H3, DNMT3L has been invoked as the molecule that can read the histone code and translate it into DNA methylation. It plays an important role in the initiation of genomic imprints during gametogenesis and in nuclear reprogramming. With important functions attributed to it, it is imperative that the DNMT3L expression is tightly controlled. Previously, we had identified a CpG island within the human DNMT3L promoter and first exon that showed loss of DNA methylation in cancer samples. Here we show that this Differentially Methylated CpG island within DNMT3L (DNMT3L DMC) acts to repress transcription, is a Polycomb/Trithorax Response Element (PRE) and interacts with both PRC1 and PRC2 Polycomb repressive complexes. In addition, it adopts inactive chromatin conformation and is associated with other inactive chromatin-specific proteins like SUV39H1 and HP1. The presence of DNMT3L DMC also influences the adjacent promoter to adopt repressive histone post-translational modifications. Due to its association with multiple layers of repressive epigenetic modifications, we believe that PRE within the DNMT3L DMC is responsible for the tight regulation of DNMT3L expression and the aberrant epigenetic modifications of this region leading to DNMT3L overexpression could be the reason of nuclear programming during carcinogenesis.

A polycomb repressive complex 2 gene regulates apogamy and gives evolutionary insights into early land plant evolution.

PubMed

Okano, Yosuke; Aono, Naoki; Hiwatashi, Yuji; Murata, Takashi; Nishiyama, Tomoaki; Ishikawa, Takaaki; Kubo, Minoru; Hasebe, Mitsuyasu

2009-09-22

Land plants have distinct developmental programs in haploid (gametophyte) and diploid (sporophyte) generations. Although usually the two programs strictly alternate at fertilization and meiosis, one program can be induced during the other program. In a process called apogamy, cells of the gametophyte other than the egg cell initiate sporophyte development. Here, we report for the moss Physcomitrella patens that apogamy resulted from deletion of the gene orthologous to the Arabidopsis thaliana CURLY LEAF (PpCLF), which encodes a component of polycomb repressive complex 2 (PRC2). In the deletion lines, a gametophytic vegetative cell frequently gave rise to a sporophyte-like body. This body grew indeterminately from an apical cell with the character of a sporophytic pluripotent stem cell but did not form a sporangium. Furthermore, with continued culture, the sporophyte-like body branched. Sporophyte branching is almost unknown among extant bryophytes. When PpCLF was expressed in the deletion lines once the sporophyte-like bodies had formed, pluripotent stem cell activity was arrested and a sporangium-like organ formed. Supported by the observed pattern of PpCLF expression, these results demonstrate that, in the gametophyte, PpCLF represses initiation of a sporophytic pluripotent stem cell and, in the sporophyte, represses that stem cell activity and induces reproductive organ development. In land plants, branching, along with indeterminate apical growth and delayed initiation of spore-bearing reproductive organs, were conspicuous innovations for the evolution of a dominant sporophyte plant body. Our study provides insights into the role of PRC2 gene regulation for sustaining evolutionary innovation in land plants.

Menin regulates Inhbb expression through an Akt/Ezh2-mediated H3K27 histone modification.

PubMed

Gherardi, Samuele; Ripoche, Doriane; Mikaelian, Ivan; Chanal, Marie; Teinturier, Romain; Goehrig, Delphine; Cordier-Bussat, Martine; Zhang, Chang X; Hennino, Ana; Bertolino, Philippe

2017-04-01

Although Men1 is a well-known tumour suppressor gene, little is known about the functions of Menin, the protein it encodes for. Since few years, numerous publications support a major role of Menin in the control of epigenetics gene regulation. While Menin interaction with MLL complex favours transcriptional activation of target genes through H3K4me3 marks, Menin also represses gene expression via mechanisms involving the Polycomb repressing complex (PRC). Interestingly, Ezh2, the PRC-methyltransferase that catalyses H3K27me3 repressive marks and Menin have been shown to co-occupy a large number of promoters. However, lack of binding between Menin and Ezh2 suggests that another member of the PRC complex is mediating this indirect interaction. Having found that ActivinB - a TGFβ superfamily member encoded by the Inhbb gene - is upregulated in insulinoma tumours caused by Men1 invalidation, we hypothesize that Menin could directly participate in the epigenetic-repression of Inhbb gene expression. Using Animal model and cell lines, we report that loss of Menin is directly associated with ActivinB-induced expression both in vivo and in vitro. Our work further reveals that ActivinB expression is mediated through a direct modulation of H3K27me3 marks on the Inhbb locus in Menin-KO cell lines. More importantly, we show that Menin binds on the promoter of Inhbb gene where it favours the recruitment of Ezh2 via an indirect mechanism involving Akt-phosphorylation. Our data suggests therefore that Menin could take an important part to the Ezh2-epigenetic repressive landscape in many cells and tissues through its capacity to modulate Akt phosphorylation. Copyright © 2017 Elsevier B.V. All rights reserved.

Polycomb repressive complex 1 provides a molecular explanation for repeat copy number dependency in FSHD muscular dystrophy.

PubMed

Casa, Valentina; Runfola, Valeria; Micheloni, Stefano; Aziz, Arif; Dilworth, F Jeffrey; Gabellini, Davide

2017-02-15

Repression of repetitive elements is crucial to preserve genome integrity and has been traditionally ascribed to constitutive heterochromatin pathways. FacioScapuloHumeral Muscular Dystrophy (FSHD), one of the most common myopathies, is characterized by a complex interplay of genetic and epigenetic events. The main FSHD form is linked to a reduced copy number of the D4Z4 macrosatellite repeat on 4q35, causing loss of silencing and aberrant expression of the D4Z4-embedded DUX4 gene leading to disease. By an unknown mechanism, D4Z4 copy-number correlates with FSHD phenotype. Here we show that the DUX4 proximal promoter (DUX4p) is sufficient to nucleate the enrichment of both constitutive and facultative heterochromatin components and to mediate a copy-number dependent gene silencing. We found that both the CpG/GC dense DNA content and the repetitive nature of DUX4p arrays are important for their repressive ability. We showed that DUX4p mediates a copy number-dependent Polycomb Repressive Complex 1 (PRC1) recruitment, which is responsible for the copy-number dependent gene repression. Overall, we directly link genetic and epigenetic defects in FSHD by proposing a novel molecular explanation for the copy number-dependency in FSHD pathogenesis, and offer insight into the molecular functions of repeats in chromatin regulation. © The Author 2016. Published by Oxford University Press.

PRC2/EED-EZH2 Complex Is Up-Regulated in Breast Cancer Lymph Node Metastasis Compared to Primary Tumor and Correlates with Tumor Proliferation In Situ

PubMed Central

Yu, Hongxiang; Simons, Diana L.; Segall, Ilana; Carcamo-Cavazos, Valeria; Schwartz, Erich J.; Yan, Ning; Zuckerman, Neta S.; Dirbas, Frederick M.; Johnson, Denise L.; Holmes, Susan P.; Lee, Peter P.

2012-01-01

Background Lymph node metastasis is a key event in the progression of breast cancer. Therefore it is important to understand the underlying mechanisms which facilitate regional lymph node metastatic progression. Methodology/Principal Findings We performed gene expression profiling of purified tumor cells from human breast tumor and lymph node metastasis. By microarray network analysis, we found an increased expression of polycomb repression complex 2 (PRC2) core subunits EED and EZH2 in lymph node metastatic tumor cells over primary tumor cells which were validated through real-time PCR. Additionally, immunohistochemical (IHC) staining and quantitative image analysis of whole tissue sections showed a significant increase of EZH2 expressing tumor cells in lymph nodes over paired primary breast tumors, which strongly correlated with tumor cell proliferation in situ. We further explored the mechanisms of PRC2 gene up-regulation in metastatic tumor cells and found up-regulation of E2F genes, MYC targets and down-regulation of tumor suppressor gene E-cadherin targets in lymph node metastasis through GSEA analyses. Using IHC, the expression of potential EZH2 target, E-cadherin was examined in paired primary/lymph node samples and was found to be significantly decreased in lymph node metastases over paired primary tumors. Conclusions/Significance This study identified an over expression of the epigenetic silencing complex PRC2/EED-EZH2 in breast cancer lymph node metastasis as compared to primary tumor and its positive association with tumor cell proliferation in situ. Concurrently, PRC2 target protein E-cadherin was significant decreased in lymph node metastases, suggesting PRC2 promotes epithelial mesenchymal transition (EMT) in lymph node metastatic process through repression of E-cadherin. These results indicate that epigenetic regulation mediated by PRC2 proteins may provide additional advantage for the outgrowth of metastatic tumor cells in lymph nodes. This opens up epigenetic drug development possibilities for the treatment and prevention of lymph node metastasis in breast cancer. PMID:23251464

MUC1-C activates EZH2 expression and function in human cancer cells.

PubMed

Rajabi, Hasan; Hiraki, Masayuki; Tagde, Ashujit; Alam, Maroof; Bouillez, Audrey; Christensen, Camilla L; Samur, Mehmet; Wong, Kwok-Kin; Kufe, Donald

2017-08-07

The EZH2 histone methyltransferase is a member of the polycomb repressive complex 2 (PRC2) that is highly expressed in diverse human cancers and is associated with a poor prognosis. MUC1-C is an oncoprotein that is similarly overexpressed in carcinomas and has been linked to epigenetic regulation. A role for MUC1-C in regulating EZH2 and histone methylation is not known. Here, we demonstrate that targeting MUC1-C in diverse human carcinoma cells downregulates EZH2 and other PRC2 components. MUC1-C activates (i) the EZH2 promoter through induction of the pRB→E2F pathway, and (ii) an NF-κB p65 driven enhancer in exon 1. We also show that MUC1-C binds directly to the EZH2 CXC region adjacent to the catalytic SET domain and associates with EZH2 on the CDH1 and BRCA1 promoters. In concert with these results, targeting MUC1-C downregulates EZH2 function as evidenced by (i) global and promoter-specific decreases in H3K27 trimethylation (H3K27me3), and (ii) activation of tumor suppressor genes, including BRCA1. These findings highlight a previously unreported role for MUC1-C in activating EZH2 expression and function in cancer cells.

Regulation of T Cell Differentiation and Function by EZH2

PubMed Central

Karantanos, Theodoros; Christofides, Anthos; Bardhan, Kankana; Li, Lequn; Boussiotis, Vassiliki A.

2016-01-01

The enhancer of zeste homolog 2 (EZH2), one of the polycomb-group proteins, is the catalytic subunit of Polycomb-repressive complex 2 (PRC2) and induces the trimethylation of the histone H3 lysine 27 (H3K27me3) promoting epigenetic gene silencing. EZH2 contains a SET domain promoting the methyltransferase activity, while the three other protein components of PRC2, namely EED, SUZ12, and RpAp46/48, induce compaction of the chromatin permitting EZH2 enzymatic activity. Numerous studies highlight the role of this evolutionary conserved protein as a master regulator of differentiation in humans involved in the repression of the homeotic gene and the inactivation of X-chromosome. Through its effects in the epigenetic regulation of critical genes, EZH2 has been strongly linked to cell cycle progression, stem cell pluripotency, and cancer biology, being currently at the cutting edge of research. Most recently, EZH2 has been associated with hematopoietic stem cell proliferation and differentiation, thymopoiesis and lymphopoiesis. Several studies have evaluated the role of EZH2 in the regulation of T cell differentiation and plasticity as well as its implications in the development of autoimmune diseases and graft-versus-host disease (GVHD). The aim of this review is to summarize the current knowledge regarding the role of EZH2 in the regulation of the differentiation and function of T cells focusing on possible applications in various immune-mediated conditions, including autoimmune disorders and GVHD. PMID:27199994

EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia-telangiectasia

PubMed Central

Li, Jiali; Hart, Ronald P.; Mallimo, Elyse M.; Swerdel, Mavis R.; Kusnecov, Alexander; Herrup, Karl

2014-01-01

The symptoms of ataxia-telangiectasia (A-T) include a progressive neurodegeneration caused by ATM protein deficiency. We previously found that nuclear accumulation of histone deacetylase-4, HDAC4, contributes to this degeneration; we now report that increased histone H3K27 trimethylation (H3K27me3) mediated by polycomb repressive complex 2 (PRC2) also plays an important role in the A-T phenotype. Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is a new ATM kinase target, and ATM-mediated S734 phosphorylation of EZH2 reduces protein stability. Thus, PRC2 formation is elevated along with H3K27me3in ATM deficiency. ChIP-sequencing shows a significant increase in H3K27me3 ‘marks’ and a dramatic shift in their location. The change of H3K27me3 chromatin-binding pattern is directly related to cell cycle re-entry and cell death of ATM-deficient neurons. Lentiviral knockdown of EZH2 rescues Purkinje cell degeneration and behavioral abnormalities in Atm−/− mice, demonstrating that EZH2 hyperactivity is another key factor in A-T neurodegeneration. PMID:24162653

Hhex Regulates Hematopoietic Stem Cell Self-Renewal and Stress Hematopoiesis via Repression of Cdkn2a.

PubMed

Jackson, Jacob T; Shields, Benjamin J; Shi, Wei; Di Rago, Ladina; Metcalf, Donald; Nicola, Nicos A; McCormack, Matthew P

2017-08-01

The hematopoietically expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of common lymphoid progenitors (CLPs) to lymphoid lineages. Here, we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal. Moreover, Hhex-deleted mice show markedly impaired hematopoietic recovery following myeloablation, due to a failure of progenitor expansion. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature progenitors. Transcriptome analysis of Hhex-null Lin - Sca + Kit + cells showed that Hhex deletion leads to derepression of polycomb repressive complex 2 (PRC2) and PRC1 target genes, including the Cdkn2a locus encoding the tumor suppressors p16 Ink 4 a and p19 Arf . Indeed, loss of Cdkn2a restored the capacity of Hhex-null blast colonies to generate myeloid progenitors in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to promote PRC2-mediated Cdkn2a repression to enable continued self-renewal and response to hematopoietic stress. Stem Cells 2017;35:1948-1957. © 2017 AlphaMed Press.

Juxtaposed Polycomb complexes co-regulate vertebral identity.

PubMed

Kim, Se Young; Paylor, Suzanne W; Magnuson, Terry; Schumacher, Armin

2006-12-01

Best known as epigenetic repressors of developmental Hox gene transcription, Polycomb complexes alter chromatin structure by means of post-translational modification of histone tails. Depending on the cellular context, Polycomb complexes of diverse composition and function exhibit cooperative interaction or hierarchical interdependency at target loci. The present study interrogated the genetic, biochemical and molecular interaction of BMI1 and EED, pivotal constituents of heterologous Polycomb complexes, in the regulation of vertebral identity during mouse development. Despite a significant overlap in dosage-sensitive homeotic phenotypes and co-repression of a similar set of Hox genes, genetic analysis implicated eed and Bmi1 in parallel pathways, which converge at the level of Hox gene regulation. Whereas EED and BMI1 formed separate biochemical entities with EzH2 and Ring1B, respectively, in mid-gestation embryos, YY1 engaged in both Polycomb complexes. Strikingly, methylated lysine 27 of histone H3 (H3-K27), a mediator of Polycomb complex recruitment to target genes, stably associated with the EED complex during the maintenance phase of Hox gene repression. Juxtaposed EED and BMI1 complexes, along with YY1 and methylated H3-K27, were detected in upstream regulatory regions of Hoxc8 and Hoxa5. The combined data suggest a model wherein epigenetic and genetic elements cooperatively recruit and retain juxtaposed Polycomb complexes in mammalian Hox gene clusters toward co-regulation of vertebral identity.

Genetic and epigenetic profiling of CLL disease progression reveals limited somatic evolution and suggests a relationship to memory-cell development.

PubMed

Smith, E N; Ghia, E M; DeBoever, C M; Rassenti, L Z; Jepsen, K; Yoon, K-A; Matsui, H; Rozenzhak, S; Alakus, H; Shepard, P J; Dai, Y; Khosroheidari, M; Bina, M; Gunderson, K L; Messer, K; Muthuswamy, L; Hudson, T J; Harismendy, O; Barrett, C L; Jamieson, C H M; Carson, D A; Kipps, T J; Frazer, K A

2015-04-10

We examined genetic and epigenetic changes that occur during disease progression from indolent to aggressive forms of chronic lymphocytic leukemia (CLL) using serial samples from 27 patients. Analysis of DNA mutations grouped the leukemia cases into three categories: evolving (26%), expanding (26%) and static (47%). Thus, approximately three-quarters of the CLL cases had little to no genetic subclonal evolution. However, we identified significant recurrent DNA methylation changes during progression at 4752 CpGs enriched for regions near Polycomb 2 repressive complex (PRC2) targets. Progression-associated CpGs near the PRC2 targets undergo methylation changes in the same direction during disease progression as during normal development from naive to memory B cells. Our study shows that CLL progression does not typically occur via subclonal evolution, but that certain CpG sites undergo recurrent methylation changes. Our results suggest CLL progression may involve developmental processes shared in common with the generation of normal memory B cells.

Allele-specific DNA methylation and its interplay with repressive histone marks at promoter-mutant TERT genes

PubMed Central

Stern, Josh Lewis; Paucek, Richard D.; Huang, Franklin W.; Ghandi, Mahmoud; Nwumeh, Ronald; Costello, James C.; Cech, Thomas R.

2017-01-01

SUMMARY A mutation in the promoter of the Telomerase Reverse Transcriptase (TERT) gene is the most frequent noncoding mutation in cancer. The mutation drives unusual monoallelic expression of TERT, allowing immortalization. Here we find that DNA methylation of the TERT CpG Island (CGI) is also allele-specific in multiple cancers. The expressed allele is hypomethylated, which is opposite to cancers without TERT promoter mutations. The continued presence of Polycomb repressive complex 2 (PRC2) on the inactive allele suggests that histone marks of repressed chromatin may be causally linked to high DNA methylation. Consistent with this hypothesis, TERT promoter DNA containing 5-methyl-CpG has much increased affinity for PRC2 in vitro. Thus, CpG methylation and histone marks appear to collaborate to maintain the two TERT alleles in different epigenetic states in TERT promoter-mutant cancers. Finally, in several cancers DNA methylation levels at the TERT CGI correlate with altered patient survival. PMID:29281820

Dosage-Sensitive Function of RETINOBLASTOMA RELATED and Convergent Epigenetic Control Are Required during the Arabidopsis Life Cycle

PubMed Central

Johnston, Amal J.; Kirioukhova, Olga; Barrell, Philippa J.; Rutten, Twan; Moore, James M.; Baskar, Ramamurthy; Grossniklaus, Ueli; Gruissem, Wilhelm

2010-01-01

The plant life cycle alternates between two distinct multi-cellular generations, the reduced gametophytes and the dominant sporophyte. Little is known about how generation-specific cell fate, differentiation, and development are controlled by the core regulators of the cell cycle. In Arabidopsis, RETINOBLASTOMA RELATED (RBR), an evolutionarily ancient cell cycle regulator, controls cell proliferation, differentiation, and regulation of a subset of Polycomb Repressive Complex 2 (PRC2) genes and METHYLTRANSFERASE 1 (MET1) in the male and female gametophytes, as well as cell fate establishment in the male gametophyte. Here we demonstrate that RBR is also essential for cell fate determination in the female gametophyte, as revealed by loss of cell-specific marker expression in all the gametophytic cells that lack RBR. Maintenance of genome integrity also requires RBR, because diploid plants heterozygous for rbr (rbr/RBR) produce an abnormal portion of triploid offspring, likely due to gametic genome duplication. While the sporophyte of the diploid mutant plants phenocopied wild type due to the haplosufficiency of RBR, genetic analysis of tetraploid plants triplex for rbr (rbr/rbr/rbr/RBR) revealed that RBR has a dosage-dependent pleiotropic effect on sporophytic development, trichome differentiation, and regulation of PRC2 subunit genes CURLY LEAF (CLF) and VERNALIZATION 2 (VRN2), and MET1 in leaves. There were, however, no obvious cell cycle and cell proliferation defects in these plant tissues, suggesting that a single functional RBR copy in tetraploids is capable of maintaining normal cell division but is not sufficient for distinct differentiation and developmental processes. Conversely, in leaves of mutants in sporophytic PRC2 subunits, trichome differentiation was also affected and expression of RBR and MET1 was reduced, providing evidence for a RBR-PRC2-MET1 regulatory feedback loop involved in sporophyte development. Together, dosage-sensitive RBR function and its genetic interaction with PRC2 genes and MET1 must have been recruited during plant evolution to control distinct generation-specific cell fate, differentiation, and development. PMID:20585548

Rice Fertilization-Independent Endosperm1 Regulates Seed Size under Heat Stress by Controlling Early Endosperm Development1[W

PubMed Central

Folsom, Jing J.; Begcy, Kevin; Hao, Xiaojuan; Wang, Dong; Walia, Harkamal

2014-01-01

Although heat stress reduces seed size in rice (Oryza sativa), little is known about the molecular mechanisms underlying the observed reduction in seed size and yield. To elucidate the mechanistic basis of heat sensitivity and reduced seed size, we imposed a moderate (34°C) and a high (42°C) heat stress treatment on developing rice seeds during the postfertilization stage. Both stress treatments reduced the final seed size. At a cellular level, the moderate heat stress resulted in precocious endosperm cellularization, whereas severe heat-stressed seeds failed to cellularize. Initiation of endosperm cellularization is a critical developmental transition required for normal seed development, and it is controlled by Polycomb Repressive Complex2 (PRC2) in Arabidopsis (Arabidopsis thaliana). We observed that a member of PRC2 called Fertilization-Independent Endosperm1 (OsFIE1) was sensitive to temperature changes, and its expression was negatively correlated with the duration of the syncytial stage during heat stress. Seeds from plants overexpressing OsFIE1 had reduced seed size and exhibited precocious cellularization. The DNA methylation status and a repressive histone modification of OsFIE1 were observed to be temperature sensitive. Our data suggested that the thermal sensitivity of seed enlargement could partly be caused by altered epigenetic regulation of endosperm development during the transition from the syncytial to the cellularized state. PMID:24590858

Incorporating genomic, transcriptomic and clinical data: a prognostic and stem cell-like MYC and PRC imbalance in high-risk neuroblastoma.

PubMed

Yang, Xinan Holly; Tang, Fangming; Shin, Jisu; Cunningham, John M

2017-10-03

Previous studies suggested that cancer cells possess traits reminiscent of the biological mechanisms ascribed to normal embryonic stem cells (ESCs) regulated by MYC and Polycomb repressive complex 2 (PRC2). Several poorly differentiated adult tumors showed preferentially high expression levels in targets of MYC, coincident with low expression levels in targets of PRC2. This paper will reveal this ESC-like cancer signature in high-risk neuroblastoma (HR-NB), the most common extracranial solid tumor in children. We systematically assembled genomic variants, gene expression changes, priori knowledge of gene functions, and clinical outcomes to identify prognostic multigene signatures. First, we assigned a new, individualized prognostic index using the relative expressions between the poor- and good-outcome signature genes. We then characterized HR-NB aggressiveness beyond these prognostic multigene signatures through the imbalanced effects of MYC and PRC2 signaling. We further analyzed Retinoic acid (RA)-induced HR-NB cells to model tumor cell differentiation. Finally, we performed in vitro validation on ZFHX3, a cell differentiation marker silenced by PRC2, and compared cell morphology changes before and after blocking PRC2 in HR-NB cells. A significant concurrence existed between exons with verified variants and genes showing MYCN-dependent expression in HR-NB. From these biomarker candidates, we identified two novel prognostic gene-set pairs with multi-scale oncogenic defects. Intriguingly, MYC targets over-represented an unfavorable component of the identified prognostic signatures while PRC2 targets over-represented a favorable component. The cell cycle arrest and neuronal differentiation marker ZFHX3 was identified as one of PRC2-silenced tumor suppressor candidates. Blocking PRC2 reduced tumor cell growth and increased the mRNA expression levels of ZFHX3 in an early treatment stage. This hypothesis-driven systems bioinformatics work offered novel insights into the PRC2-mediated tumor cell growth and differentiation in neuroblastoma, which may exert oncogenic effects together with MYC regulation. Our results propose a prognostic effect of imbalanced MYC and PRC2 moderations in pediatric HR-NB for the first time. This study demonstrates an incorporation of genomic landscapes and transcriptomic profiles into the hypothesis-driven precision prognosis and biomarker discovery. The application of this approach to neuroblastoma, as well as other cancer more broadly, could contribute to reduced relapse and mortality rates in the long term.

Architecture of epigenetic reprogramming following Twist1-mediated epithelial-mesenchymal transition

PubMed Central

2013-01-01

Background Epithelial-mesenchymal transition (EMT) is known to impart metastasis and stemness characteristics in breast cancer. To characterize the epigenetic reprogramming following Twist1-induced EMT, we characterized the epigenetic and transcriptome landscapes using whole-genome transcriptome analysis by RNA-seq, DNA methylation by digital restriction enzyme analysis of methylation (DREAM) and histone modifications by CHIP-seq of H3K4me3 and H3K27me3 in immortalized human mammary epithelial cells relative to cells induced to undergo EMT by Twist1. Results EMT is accompanied by focal hypermethylation and widespread global DNA hypomethylation, predominantly within transcriptionally repressed gene bodies. At the chromatin level, the number of gene promoters marked by H3K4me3 increases by more than one fifth; H3K27me3 undergoes dynamic genomic redistribution characterized by loss at half of gene promoters and overall reduction of peak size by almost half. This is paralleled by increased phosphorylation of EZH2 at serine 21. Among genes with highly altered mRNA expression, 23.1% switch between H3K4me3 and H3K27me3 marks, and those point to the master EMT targets and regulators CDH1, PDGFRα and ESRP1. Strikingly, Twist1 increases the number of bivalent genes by more than two fold. Inhibition of the H3K27 methyltransferases EZH2 and EZH1, which form part of the Polycomb repressive complex 2 (PRC2), blocks EMT and stemness properties. Conclusions Our findings demonstrate that the EMT program requires epigenetic remodeling by the Polycomb and Trithorax complexes leading to increased cellular plasticity. This suggests that inhibiting epigenetic remodeling and thus decrease plasticity will prevent EMT, and the associated breast cancer metastasis. PMID:24367927

B lymphoma Moloney murine leukemia virus insertion region 1: An oncogenic mediator in prostate cancer.

PubMed

Liu, Qipeng; Li, Qiaqia; Zhu, Sen; Yi, Yang; Cao, Qi

2018-06-01

B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known as a critical regulator in cellular physiology, BMI1 is essential in self-renewal and differentiation in different lineages of stem cells. BMI1 also plays a significant role in cancer etiology for its involvement in pathological progress such as epithelial-mesenchymal transition (EMT) and cancer stem cell maintenance, propagation, and differentiation. Importantly, overexpression of BMI1 is predictive for drug resistance, tumor recurrence, and eventual therapy failure of various cancer subtypes, which renders the pharmacological targeting at BMI1 as a novel and promising therapeutic approach. The study on prostate cancer, a prevalent hormone-related cancer among men, has promoted enormous research advancements in cancer genetics and epigenetics. This review summarizes the role of BMI1 as an oncogenic and epigenetic regulator in tumor initiation, progression, and relapse of prostate cancer.

MUC1-C activates BMI1 in human cancer cells.

PubMed

Hiraki, M; Maeda, T; Bouillez, A; Alam, M; Tagde, A; Hinohara, K; Suzuki, Y; Markert, T; Miyo, M; Komura, K; Ahmad, R; Rajabi, H; Kufe, D

2017-05-18

B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is a component of the polycomb repressive complex 1 (PRC1) complex that is overexpressed in breast and other cancers, and promotes self-renewal of cancer stem-like cells. The oncogenic mucin 1 (MUC1) C-terminal (MUC1-C) subunit is similarly overexpressed in human carcinoma cells and has been linked to their self-renewal. There is no known relationship between MUC1-C and BMI1 in cancer. The present studies demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism in breast and other cancer cells. In addition, we show that MUC1-C blocks miR-200c-mediated downregulation of BMI1 expression. The functional significance of this MUC1-C→︀BMI1 pathway is supported by the demonstration that targeting MUC1-C suppresses BMI1-induced ubiquitylation of H2A and thereby derepresses homeobox HOXC5 and HOXC13 gene expression. Notably, our results further show that MUC1-C binds directly to BMI1 and promotes occupancy of BMI1 on the CDKN2A promoter. In concert with BMI1-induced repression of the p16 INK4a tumor suppressor, we found that targeting MUC1-C is associated with induction of p16 INK4a expression. In support of these results, analysis of three gene expresssion data sets demonstrated highly significant correlations between MUC1-C and BMI1 in breast cancers. These findings uncover a previously unrecognized role for MUC1-C in driving BMI1 expression and in directly interacting with this stem cell factor, linking MUC1-C with function of the PRC1 in epigenetic gene silencing.

The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration.

PubMed

Cheng, Yating; Jutooru, Indira; Chadalapaka, Gayathri; Corton, J Christopher; Safe, Stephen

2015-05-10

HOTTIP is a long non-coding RNA (lncRNA) transcribed from the 5' tip of the HOXA locus and is associated with the polycomb repressor complex 2 (PRC2) and WD repeat containing protein 5 (WDR5)/mixed lineage leukemia 1 (MLL1) chromatin modifying complexes. HOTTIP is expressed in pancreatic cancer cell lines and knockdown of HOTTIP by RNA interference (siHOTTIP) in Panc1 pancreatic cancer cells decreased proliferation, induced apoptosis and decreased migration. In Panc1 cells transfected with siHOTTIP, there was a decrease in expression of 757 genes and increased expression of 514 genes, and a limited gene analysis indicated that HOTTIP regulation of genes is complex. For example, Aurora kinase A, an important regulator of cell growth, is coregulated by MLL and not WDR5 and, in contrast to previous studies in liver cancer cells, HOTTIP does not regulate HOXA13 but plays a role in regulation of several other HOX genes including HOXA10, HOXB2, HOXA11, HOXA9 and HOXA1. Although HOTTIP and the HOX-associated lncRNA HOTAIR have similar pro-oncogenic functions, they regulate strikingly different sets of genes in Panc1 cells and in pancreatic tumors.

Insights into GATA-1 Mediated Gene Activation versus Repression via Genome-wide Chromatin Occupancy Analysis

PubMed Central

Yu, Ming; Riva, Laura; Xie, Huafeng; Schindler, Yocheved; Moran, Tyler B.; Cheng, Yong; Yu, Duonan; Hardison, Ross; Weiss, Mitchell J; Orkin, Stuart H.; Bernstein, Bradley E.; Fraenkel, Ernest; Cantor, Alan B.

2009-01-01

Summary The transcription factor GATA-1 is required for terminal erythroid maturation and functions as an activator or repressor depending on gene context. Yet its in vivo site selectivity and ability to distinguish between activated versus repressed genes remain incompletely understood. In this study, we performed GATA-1 ChIP-seq in erythroid cells and compared it to GATA-1 induced gene expression changes. Bound and differentially expressed genes contain a greater number of GATA binding motifs, a higher frequency of palindromic GATA sites, and closer occupancy to the transcriptional start site versus non-differentially expressed genes. Moreover, we show that the transcription factor Zbtb7a occupies GATA-1 bound regions of some direct GATA-1 target genes, that the presence of SCL/TAL1 helps distinguish transcriptional activation versus repression, and that Polycomb Repressive Complex 2 (PRC2) is involved in epigenetic silencing of a subset of GATA-1 repressed genes. These data provide insights into GATA-1 mediated gene regulation in vivo. PMID:19941827

Allele-Specific DNA Methylation and Its Interplay with Repressive Histone Marks at Promoter-Mutant TERT Genes.

PubMed

Stern, Josh Lewis; Paucek, Richard D; Huang, Franklin W; Ghandi, Mahmoud; Nwumeh, Ronald; Costello, James C; Cech, Thomas R

2017-12-26

A mutation in the promoter of the Telomerase Reverse Transcriptase (TERT) gene is the most frequent noncoding mutation in cancer. The mutation drives unusual monoallelic expression of TERT, allowing immortalization. Here, we find that DNA methylation of the TERT CpG island (CGI) is also allele-specific in multiple cancers. The expressed allele is hypomethylated, which is opposite to cancers without TERT promoter mutations. The continued presence of Polycomb repressive complex 2 (PRC2) on the inactive allele suggests that histone marks of repressed chromatin may be causally linked to high DNA methylation. Consistent with this hypothesis, TERT promoter DNA containing 5-methyl-CpG has much increased affinity for PRC2 in vitro. Thus, CpG methylation and histone marks appear to collaborate to maintain the two TERT alleles in different epigenetic states in TERT promoter mutant cancers. Finally, in several cancers, DNA methylation levels at the TERT CGI correlate with altered patient survival. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

A New lncRNA, APTR, Associates with and Represses the CDKN1A/p21 Promoter by Recruiting Polycomb Proteins

PubMed Central

Negishi, Masamitsu; Wongpalee, Somsakul P.; Sarkar, Sukumar; Park, Jonghoon; Lee, Kyung Yong; Shibata, Yoshiyuki; Reon, Brian J.; Abounader, Roger; Suzuki, Yutaka; Sugano, Sumio; Dutta, Anindya

2014-01-01

Long noncoding RNAs (lncRNAs) have emerged as a major regulator of cell physiology, but many of which have no known function. CDKN1A/p21 is an important inhibitor of the cell-cycle, regulator of the DNA damage response and effector of the tumor suppressor p53, playing a crucial role in tumor development and prevention. In order to identify a regulator for tumor progression, we performed an siRNA screen of human lncRNAs required for cell proliferation, and identified a novel lncRNA, APTR, that acts in trans to repress the CDKN1A/p21 promoter independent of p53 to promote cell proliferation. APTR associates with the promoter of CDKN1A/p21 and this association requires a complementary-Alu sequence encoded in APTR. A different module of APTR associates with and recruits the Polycomb repressive complex 2 (PRC2) to epigenetically repress the p21 promoter. A decrease in APTR is necessary for the induction of p21 after heat stress and DNA damage by doxorubicin, and the levels of APTR and p21 are anti-correlated in human glioblastomas. Our data identify a new regulator of the cell-cycle inhibitor CDKN1A/p21 that acts as a proliferative factor in cancer cell lines and in glioblastomas and demonstrate that Alu elements present in lncRNAs can contribute to targeting regulatory lncRNAs to promoters. PMID:24748121

Nucleotide substitutions revealing specific functions of Polycomb group genes.

PubMed

Bajusz, Izabella; Sipos, László; Pirity, Melinda K

2015-04-01

POLYCOMB group (PCG) proteins belong to the family of epigenetic regulators of genes playing important roles in differentiation and development. Mutants of PcG genes were isolated first in the fruit fly, Drosophila melanogaster, resulting in spectacular segmental transformations due to the ectopic expression of homeotic genes. Homologs of Drosophila PcG genes were also identified in plants and in vertebrates and subsequent experiments revealed the general role of PCG proteins in the maintenance of the repressed state of chromatin through cell divisions. The past decades of gene targeting experiments have allowed us to make significant strides towards understanding how the network of PCG proteins influences multiple aspects of cellular fate determination during development. Being involved in the transmission of specific expression profiles of different cell lineages, PCG proteins were found to control wide spectra of unrelated epigenetic processes in vertebrates, such as stem cell plasticity and renewal, genomic imprinting and inactivation of X-chromosome. PCG proteins also affect regulation of metabolic genes being important for switching programs between pluripotency and differentiation. Insight into the precise roles of PCG proteins in normal physiological processes has emerged from studies employing cell culture-based systems and genetically modified animals. Here we summarize the findings obtained from PcG mutant fruit flies and mice generated to date with a focus on PRC1 and PRC2 members altered by nucleotide substitutions resulting in specific alleles. We also include a compilation of lessons learned from these models about the in vivo functions of this complex protein family. With multiple knockout lines, sophisticated approaches to study the consequences of peculiar missense point mutations, and insights from complementary gain-of-function systems in hand, we are now in a unique position to significantly advance our understanding of the molecular basis of in vivo functions of PcG proteins. Copyright © 2015 Elsevier Inc. All rights reserved.

A methyltransferase required for proper timing of the vernalization response in Arabidopsis

DOE PAGES

Lee, Joohyun; Yun, Jae-Young; Zhao, Wei; ...

2015-01-20

Prolonged exposure to winter cold enables flowering in many plant species through a process called vernalization. In Arabidopsis, vernalization results from the epigenetic silencing of the floral repressor FLOWERING LOCUS C (FLC) via a Polycomb Repressive Complex 2 (PRC2)-mediated increase in the density of the epigenetic silencing mark H3K27me3 at FLC chromatin. During cold exposure, a gene encoding a unique, cold-specific PRC2 component, VERNALIZATION INSENSITIVE 3 (VIN3), which is necessary for PRC2-mediated silencing of FLC, is induced. In this paper, we show that SET DOMAIN GROUP 7 (SDG7) is required for proper timing of VIN3 induction and of the vernalizationmore » process. Loss of SDG7 results in a vernalization-hypersensitive phenotype, as well as more rapid cold-mediated up-regulation of VIN3. In the absence of cold, loss of SDG7 results in elevated levels of long noncoding RNAs, which are thought to participate in epigenetic repression of FLC. Furthermore, loss of SDG7 results in increased H3K27me3 deposition on FLC chromatin in the absence of cold exposure and enhanced H3K27me3 spreading during cold treatment. In conclusion, SDG7 is a negative regulator of vernalization, and loss of SDG7 creates a partially vernalized state without cold exposure.« less

Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2.

PubMed

Ler, Lian Dee; Ghosh, Sujoy; Chai, Xiaoran; Thike, Aye Aye; Heng, Hong Lee; Siew, Ee Yan; Dey, Sucharita; Koh, Liang Kai; Lim, Jing Quan; Lim, Weng Khong; Myint, Swe Swe; Loh, Jia Liang; Ong, Pauline; Sam, Xin Xiu; Huang, Dachuan; Lim, Tony; Tan, Puay Hoon; Nagarajan, Sanjanaa; Cheng, Christopher Wai Sam; Ho, Henry; Ng, Lay Guat; Yuen, John; Lin, Po-Hung; Chuang, Cheng-Keng; Chang, Ying-Hsu; Weng, Wen-Hui; Rozen, Steven G; Tan, Patrick; Creasy, Caretha L; Pang, See-Tong; McCabe, Michael T; Poon, Song Ling; Teh, Bin Tean

2017-02-22

Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, KDM6A (a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of KDM6A mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type. Further transcriptome analysis found multiple deregulated pathways, especially PRC2/EZH2, in KDM6A -mutated urothelial bladder carcinoma. Chromatin immunoprecipitation sequencing analysis revealed enrichment of H3K27me3 at specific loci in KDM6A -null cells, including PRC2/EZH2 and their downstream targets. Consequently, we targeted EZH2 (an H3K27 methylase) and demonstrated that KDM6A -null urothelial bladder carcinoma cell lines were sensitive to EZH2 inhibition. Loss- and gain-of-function assays confirmed that cells with loss of KDM6A are vulnerable to EZH2. IGFBP3, a direct KDM6A/EZH2/H3K27me3 target, was up-regulated by EZH2 inhibition and contributed to the observed EZH2-dependent growth suppression in KDM6A -null cell lines. EZH2 inhibition delayed tumor onset in KDM6A -null cells and caused regression of KDM6A -null bladder tumors in both patient-derived and cell line xenograft models. In summary, our study demonstrates that inactivating mutations of KDM6A , which are common in urothelial bladder carcinoma, are potentially targetable by inhibiting EZH2. Copyright © 2017, American Association for the Advancement of Science.

The Histone Modification H3K27me3 Is Retained after Gene Duplication and Correlates with Conserved Noncoding Sequences in Arabidopsis

PubMed Central

Berke, Lidija; Snel, Berend

2014-01-01

The histone modification H3K27me3 is involved in repression of transcription and plays a crucial role in developmental transitions in both animals and plants. It is deposited by PRC2 (Polycomb repressive complex 2), a conserved protein complex. In Arabidopsis thaliana, H3K27me3 is found at 15% of all genes. These tend to encode transcription factors and other regulators important for development. However, it is not known how PRC2 is recruited to target loci nor how this set of target genes arose during Arabidopsis evolution. To resolve the latter, we integrated A. thaliana gene families with five independent genome-wide H3K27me3 data sets. Gene families were either significantly enriched or depleted of H3K27me3, showing a strong impact of shared ancestry to H3K27me3 distribution. To quantify this, we performed ancestral state reconstruction of H3K27me3 on phylogenetic trees of gene families. The set of H3K27me3-marked genes changed less than expected by chance, suggesting that H3K27me3 was retained after gene duplication. This retention suggests that the PRC2-recruiting signal could be encoded in the DNA and also conserved among certain duplicated genes. Indeed, H3K27me3-marked genes were overrepresented among paralogs sharing conserved noncoding sequences (CNSs) that are enriched with transcription factor binding sites. The association of upstream CNSs with H3K27me3-marked genes represents the first genome-wide connection between H3K27me3 and potential regulatory elements in plants. Thus, we propose that CNSs likely function as part of the PRC2 recruitment in plants. PMID:24567304

CBX7 regulates stem cell-like properties of gastric cancer cells via p16 and AKT-NF-κB-miR-21 pathways.

PubMed

Ni, Su-Jie; Zhao, Li-Qin; Wang, Xiao-Feng; Wu, Zhen-Hua; Hua, Rui-Xi; Wan, Chun-Hua; Zhang, Jie-Yun; Zhang, Xiao-Wei; Huang, Ming-Zhu; Gan, Lu; Sun, Hua-Lin; Dimri, Goberdhan P; Guo, Wei-Jian

2018-02-08

Chromobox protein homolog 7 (CBX7), a member of the polycomb group (PcG) family of proteins, is involved in the regulation of cell proliferation and cancer progression. PcG family members, such as BMI, Mel-18, and EZH2, are integral constituents of the polycomb repressive complexes (PRCs) and have been known to regulate cancer stem cell (CSC) phenotype. However, the role of other PRCs' constituents such as CBX7 in the regulation of CSC phenotype remains largely elusive. This study was to investigate the role of CBX7 in regulating stem cell-like properties of gastric cancer and the underlying mechanisms. Firstly, the role of CBX7 in regulating stem cell-like properties of gastric cancer was investigated using sphere formation, Western blot, and xenograft tumor assays. Next, RNA interference and ectopic CBX7 expression were employed to determine the impact of CBX7 on the expression of CSC marker proteins and CSC characteristics. The expression of CBX7, its downstream targets, and stem cell markers were analyzed in gastric stem cell spheres, common cancer cells, and gastric cancer tissues. Finally, the pathways by which CBX7 regulates stem cell-like properties of gastric cancer were explored. We found that CBX7, a constituent of the polycomb repressive complex 1 (PRC1), plays an important role in maintaining stem cell-like characteristics of gastric cancer cells via the activation of AKT pathway and the downregulation of p16. Spearman rank correlation analysis showed positive correlations among the expression of CBX7 and phospho-AKT (pAKT), stem cell markers OCT-4, and CD133 in gastric cancer tissues. In addition, CBX7 was found to upregulate microRNA-21 (miR-21) via the activation of AKT-NF-κB pathway, and miR-21 contributes to CBX7-mediated CSC characteristics. CBX7 positively regulates stem cell-like characteristics of gastric cancer cells by inhibiting p16 and activating AKT-NF-κB-miR-21 pathway.

Braveheart, a long non-coding RNA required for cardiovascular lineage commitment

PubMed Central

Klattenhoff, Carla; Scheuermann, Johanna C.; Surface, Lauren E.; Bradley, Robert K.; Fields, Paul A.; Steinhauser, Matthew L.; Ding, Huiming; Butty, Vincent L.; Torrey, Lillian; Haas, Simon; Abo, Ryan; Tabebordbar, Mohammadsharif; Lee, Richard T.; Burge, Christopher B.; Boyer, Laurie A.

2013-01-01

Summary Long noncoding RNAs (lncRNAs) are often expressed in a development-specific manner, yet little is known about their roles in lineage commitment. Here, we identified Braveheart (Bvht), a heart-associated lncRNA in mouse. Using multiple embryonic stem cell (ESC) differentiation strategies, we show that Bvht is required for progression of nascent mesoderm towards a cardiac fate. We find that Bvht is necessary for activation of a core cardiovascular gene network and functions upstream of MesP1 (mesoderm posterior 1), a master regulator of a common multipotent cardiovascular progenitor. We also show that Bvht interacts with SUZ12, a component of Polycomb Repressive Complex 2 (PRC2), during cardiomyocyte differentiation suggesting that Bvht mediates epigenetic regulation of cardiac commitment. Finally, we demonstrate a role for Bvht in maintaining cardiac fate in neonatal cardiomyocytes. Together, our work provides evidence for a long noncoding RNA with critical roles in the establishment of the cardiovascular lineage during mammalian development. PMID:23352431

The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration

PubMed Central

Cheng, Yating; Jutooru, Indira; Chadalapaka, Gayathri; Corton, J. Christopher; Safe, Stephen

2015-01-01

HOTTIP is a long non-coding RNA (lncRNA) transcribed from the 5′ tip of the HOXA locus and is associated with the polycomb repressor complex 2 (PRC2) and WD repeat containing protein 5 (WDR5)/mixed lineage leukemia 1 (MLL1) chromatin modifying complexes. HOTTIP is expressed in pancreatic cancer cell lines and knockdown of HOTTIP by RNA interference (siHOTTIP) in Panc1 pancreatic cancer cells decreased proliferation, induced apoptosis and decreased migration. In Panc1 cells transfected with siHOTTIP, there was a decrease in expression of 757 genes and increased expression of 514 genes, and a limited gene analysis indicated that HOTTIP regulation of genes is complex. For example, Aurora kinase A, an important regulator of cell growth, is coregulated by MLL and not WDR5 and, in contrast to previous studies in liver cancer cells, HOTTIP does not regulate HOXA13 but plays a role in regulation of several other HOX genes including HOXA10, HOXB2, HOXA11, HOXA9 and HOXA1. Although HOTTIP and the HOX-associated lncRNA HOTAIR have similar pro-oncogenic functions, they regulate strikingly different sets of genes in Panc1 cells and in pancreatic tumors. PMID:25912306

Reduced H3K27me3 expression in Merkel cell polyoma virus-positive tumors.

PubMed

Busam, Klaus J; Pulitzer, Melissa P; Coit, Daniel C; Arcila, Maria; Leng, Danielle; Jungbluth, Achim A; Wiesner, Thomas

2017-06-01

Merkel cell carcinoma is a primary cutaneous neuroendocrine carcinoma, which once metastatic is difficult to treat. Recent mutation analyses of Merkel cell carcinoma revealed a low number of mutations in Merkel cell polyomavirus-associated tumors, and a high number of mutations in virus-negative combined squamous cell and neuroendocrine carcinomas of chronically sun-damaged skin. We speculated that the paucity of mutations in virus-positive Merkel cell carcinoma may reflect a pathomechanism that depends on derangements of chromatin without alterations in the DNA sequence (epigenetic dysregulation). One central epigenetic regulator is the Polycomb repressive complex 2 (PRC2), which silences genomic regions by trimethylating (me3) lysine (K) 27 of histone H3, and thereby establishes the histone mark H3K27me3. Recent experimental research data demonstrated that PRC2 loss in mice skin results in the formation of Merkel cells. Prompted by these findings, we explored a possible contribution of PRC2 loss in human Merkel cell carcinoma. We examined the immunohistochemical expression of H3K27me3 in 35 Merkel cell carcinomas with pure histological features (22 primary and 13 metastatic lesions) and in 5 combined squamous and neuroendocrine carcinomas of the skin. We found a strong reduction of H3K27me3 staining in tumors with pure histologic features and virus-positive Merkel cell carcinomas. Combined neuroendocrine carcinomas had no or only minimal loss of H3K27me3 labeling. Our findings suggest that a PRC2-mediated epigenetic deregulation may play a role in the pathogenesis of virus-positive Merkel cell carcinomas and in tumors with pure histologic features.

Chromatin isolation by RNA purification (ChIRP).

PubMed

Chu, Ci; Quinn, Jeffrey; Chang, Howard Y

2012-03-25

Long noncoding RNAs are key regulators of chromatin states for important biological processes such as dosage compensation, imprinting, and developmental gene expression (1,2,3,4,5,6,7). The recent discovery of thousands of lncRNAs in association with specific chromatin modification complexes, such as Polycomb Repressive Complex 2 (PRC2) that mediates histone H3 lysine 27 trimethylation (H3K27me3), suggests broad roles for numerous lncRNAs in managing chromatin states in a gene-specific fashion (8,9). While some lncRNAs are thought to work in cis on neighboring genes, other lncRNAs work in trans to regulate distantly located genes. For instance, Drosophila lncRNAs roX1 and roX2 bind numerous regions on the X chromosome of male cells, and are critical for dosage compensation (10,11). However, the exact locations of their binding sites are not known at high resolution. Similarly, human lncRNA HOTAIR can affect PRC2 occupancy on hundreds of genes genome-wide( 3,12,13), but how specificity is achieved is unclear. LncRNAs can also serve as modular scaffolds to recruit the assembly of multiple protein complexes. The classic trans-acting RNA scaffold is the TERC RNA that serves as the template and scaffold for the telomerase complex (14); HOTAIR can also serve as a scaffold for PRC2 and a H3K4 demethylase complex (13). Prior studies mapping RNA occupancy at chromatin have revealed substantial insights (15,16), but only at a single gene locus at a time. The occupancy sites of most lncRNAs are not known, and the roles of lncRNAs in chromatin regulation have been mostly inferred from the indirect effects of lncRNA perturbation. Just as chromatin immunoprecipitation followed by microarray or deep sequencing (ChIP-chip or ChIP-seq, respectively) has greatly improved our understanding of protein-DNA interactions on a genomic scale, here we illustrate a recently published strategy to map long RNA occupancy genome-wide at high resolution (17). This method, Chromatin Isolation by RNA Purification (ChIRP) (Figure 1), is based on affinity capture of target lncRNA:chromatin complex by tiling antisense-oligos, which then generates a map of genomic binding sites at a resolution of several hundred bases with high sensitivity and low background. ChIRP is applicable to many lncRNAs because the design of affinity-probes is straightforward given the RNA sequence and requires no knowledge of the RNA's structure or functional domains.

S6K1ing to ResTOR Adipogenesis with Polycomb.

PubMed

Juan, Aster H; Sartorelli, Vittorio

2016-05-05

Signal-directed chromatin recruitment of mammalian Polycomb complexes is a fundamental component of epigenetic regulation. In this issue, Yi et al. (2016) reveal how mTORC1 activation deploys the ribosomal serine/threonine kinase S6K1 and Polycomb proteins at genomic regulatory regions to repress expression of anti-adipogenic developmental regulators. Copyright © 2016 Elsevier Inc. All rights reserved.

Dynamics of H3K27me3 methylation and demethylation in plant development

PubMed Central

Gan, Eng-Seng; Xu, Yifeng; Ito, Toshiro

2015-01-01

Epigenetic regulation controls multiple aspects of the plant development. The N-terminal tail of histone can be differently modified to regulate various chromatin activities. One of them, the trimethylation of histone H3 lysine 27 (H3K27me3) confers a repressive chromatin state with gene silencing. H3K27me3 is dynamically deposited and removed throughout development. While components of the H3K27me3 writer, Polycomb repressive complex 2 (PRC2), have been reported for almost 2 decades, it is only recently that JUMONJI (JMJ) proteins are reported as H3K27me3 demethylases, affirming the dynamic nature of histone modifications. This review highlights recent progress in plant epigenetic research, focusing on the H3K27me3 demethylases. PMID:26313233

The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells

PubMed Central

Mayr, Christian; Wagner, Andrej; Loeffelberger, Magdalena; Bruckner, Daniela; Jakab, Martin; Berr, Frieder; Di Fazio, Pietro; Ocker, Matthias; Neureiter, Daniel; Pichler, Martin; Kiesslich, Tobias

2016-01-01

BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and is up-regulated in biliary tract cancer (BTC), contributing to aggressive clinical features. In this study we investigated the cytotoxic effects of PTC-209, a recently developed inhibitor of BMI1, in BTC cells. PTC-209 reduced overall viability in BTC cell lines in a dose-dependent fashion (0.04 - 20 μM). Treatment with PTC-209 led to slightly enhanced caspase activity and stop of cell proliferation. Cell cycle analysis revealed that PTC-209 caused cell cycle arrest at the G1/S checkpoint. A comprehensive investigation of expression changes of cell cycle-related genes showed that PTC-209 caused significant down-regulation of cell cycle-promoting genes as well as of genes that contribute to DNA synthesis initiation and DNA repair, respectively. This was accompanied by significantly elevated mRNA levels of cell cycle inhibitors. In addition, PTC-209 reduced sphere formation and, in a cell line-dependent manner, aldehyde dehydrogease-1 positive cells. We conclude that PTC-209 might be a promising drug for future in vitro and in vivo studies in BTC. PMID:26623561

GRHL3/GET1 and Trithorax Group Members Collaborate to Activate the Epidermal Progenitor Differentiation Program

PubMed Central

Hopkin, Amelia Soto; Gordon, William; Klein, Rachel Herndon; Espitia, Francisco; Daily, Kenneth; Zeller, Michael; Baldi, Pierre; Andersen, Bogi

2012-01-01

The antagonistic actions of Polycomb and Trithorax are responsible for proper cell fate determination in mammalian tissues. In the epidermis, a self-renewing epithelium, previous work has shown that release from Polycomb repression only partially explains differentiation gene activation. We now show that Trithorax is also a key regulator of epidermal differentiation, not only through activation of genes repressed by Polycomb in progenitor cells, but also through activation of genes independent of regulation by Polycomb. The differentiation associated transcription factor GRHL3/GET1 recruits the ubiquitously expressed Trithorax complex to a subset of differentiation genes. PMID:22829784

Pho dynamically interacts with Spt5 to facilitate transcriptional switches at the hsp70 locus.

PubMed

Pereira, Allwyn; Paro, Renato

2017-12-06

Numerous target genes of the Polycomb group (PcG) are transiently activated by a stimulus and subsequently repressed. However, mechanisms by which PcG proteins regulate such target genes remain elusive. We employed the heat shock-responsive hsp70 locus in Drosophila to study the chromatin dynamics of PRC1 and its interplay with known regulators of the locus before, during and after heat shock. We detected mutually exclusive binding patterns for HSF and PRC1 at the hsp70 locus. We found that Pleiohomeotic (Pho), a DNA-binding PcG member, dynamically interacts with Spt5, an elongation factor. The dynamic interaction switch between Pho and Spt5 is triggered by the recruitment of HSF to chromatin. Mutation in the protein-protein interaction domain (REPO domain) of Pho interferes with the dynamics of its interaction with Spt5. The transcriptional kinetics of the heat shock response is negatively affected by a mutation in the REPO domain of Pho. We propose that a dynamic interaction switch between PcG proteins and an elongation factor enables stress-inducible genes to efficiently switch between ON/OFF states in the presence/absence of the activating stimulus.

A PML/Slit Axis Controls Physiological Cell Migration and Cancer Invasion in the CNS.

PubMed

Amodeo, Valeria; A, Deli; Betts, Joanne; Bartesaghi, Stefano; Zhang, Ying; Richard-Londt, Angela; Ellis, Matthew; Roshani, Rozita; Vouri, Mikaella; Galavotti, Sara; Oberndorfer, Sarah; Leite, Ana Paula; Mackay, Alan; Lampada, Aikaterini; Stratford, Eva Wessel; Li, Ningning; Dinsdale, David; Grimwade, David; Jones, Chris; Nicotera, Pierluigi; Michod, David; Brandner, Sebastian; Salomoni, Paolo

2017-07-11

Cell migration through the brain parenchyma underpins neurogenesis and glioblastoma (GBM) development. Since GBM cells and neuroblasts use the same migratory routes, mechanisms underlying migration during neurogenesis and brain cancer pathogenesis may be similar. Here, we identify a common pathway controlling cell migration in normal and neoplastic cells in the CNS. The nuclear scaffold protein promyelocytic leukemia (PML), a regulator of forebrain development, promotes neural progenitor/stem cell (NPC) and neuroblast migration in the adult mouse brain. The PML pro-migratory role is active also in transformed mouse NPCs and in human primary GBM cells. In both normal and neoplastic settings, PML controls cell migration via Polycomb repressive complex 2 (PRC2)-mediated repression of Slits, key regulators of axon guidance. Finally, a PML/SLIT1 axis regulates sensitivity to the PML-targeting drug arsenic trioxide in primary GBM cells. Taken together, these findings uncover a drug-targetable molecular axis controlling cell migration in both normal and neoplastic cells. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2

PubMed Central

Chen, Liying; Dharia, Neekesh V.; Ross, Linda; Iniguez, Amanda Balboni; Conway, Amy Saur; Wang, Emily Jue; Veschi, Veronica; Lam, Norris; Gustafson, W. Clay; Nasholm, Nicole; Vazquez, Francisca; Weir, Barbara A.; Ali, Levi D.; Pantel, Sasha; Jiang, Guozhi; Harrington, William F.; Lee, Yenarae; Goodale, Amy; Lubonja, Rakela; Krill-Burger, John M.; Meyers, Robin M.; Root, David E.; Bradner, James E.; Golub, Todd R.; Roberts, Charles W.M.; Hahn, William C.; Weiss, William A.; Thiele, Carol J.

2017-01-01

Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood cancer neuroblastoma, amplification of the oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening of MYCN-amplified neuroblastoma and found a preferential dependency on genes encoding the polycomb repressive complex 2 (PRC2) components EZH2, EED, and SUZ12. Genetic and pharmacological suppression of EZH2 inhibited neuroblastoma growth in vitro and in vivo. Moreover, compared with neuroblastomas without MYCN amplification, MYCN-amplified neuroblastomas expressed higher levels of EZH2. ChIP analysis showed that MYCN binds at the EZH2 promoter, thereby directly driving expression. Transcriptomic and epigenetic analysis, as well as genetic rescue experiments, revealed that EZH2 represses neuronal differentiation in neuroblastoma in a PRC2-dependent manner. Moreover, MYCN-amplified and high-risk primary tumors from patients with neuroblastoma exhibited strong repression of EZH2-regulated genes. Additionally, overexpression of IGFBP3, a direct EZH2 target, suppressed neuroblastoma growth in vitro and in vivo. We further observed strong synergy between histone deacetylase inhibitors and EZH2 inhibitors. Together, these observations demonstrate that MYCN upregulates EZH2, leading to inactivation of a tumor suppressor program in neuroblastoma, and support testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma. PMID:29202477

CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2.

PubMed

Chen, Liying; Alexe, Gabriela; Dharia, Neekesh V; Ross, Linda; Iniguez, Amanda Balboni; Conway, Amy Saur; Wang, Emily Jue; Veschi, Veronica; Lam, Norris; Qi, Jun; Gustafson, W Clay; Nasholm, Nicole; Vazquez, Francisca; Weir, Barbara A; Cowley, Glenn S; Ali, Levi D; Pantel, Sasha; Jiang, Guozhi; Harrington, William F; Lee, Yenarae; Goodale, Amy; Lubonja, Rakela; Krill-Burger, John M; Meyers, Robin M; Tsherniak, Aviad; Root, David E; Bradner, James E; Golub, Todd R; Roberts, Charles Wm; Hahn, William C; Weiss, William A; Thiele, Carol J; Stegmaier, Kimberly

2018-01-02

Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood cancer neuroblastoma, amplification of the oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening of MYCN-amplified neuroblastoma and found a preferential dependency on genes encoding the polycomb repressive complex 2 (PRC2) components EZH2, EED, and SUZ12. Genetic and pharmacological suppression of EZH2 inhibited neuroblastoma growth in vitro and in vivo. Moreover, compared with neuroblastomas without MYCN amplification, MYCN-amplified neuroblastomas expressed higher levels of EZH2. ChIP analysis showed that MYCN binds at the EZH2 promoter, thereby directly driving expression. Transcriptomic and epigenetic analysis, as well as genetic rescue experiments, revealed that EZH2 represses neuronal differentiation in neuroblastoma in a PRC2-dependent manner. Moreover, MYCN-amplified and high-risk primary tumors from patients with neuroblastoma exhibited strong repression of EZH2-regulated genes. Additionally, overexpression of IGFBP3, a direct EZH2 target, suppressed neuroblastoma growth in vitro and in vivo. We further observed strong synergy between histone deacetylase inhibitors and EZH2 inhibitors. Together, these observations demonstrate that MYCN upregulates EZH2, leading to inactivation of a tumor suppressor program in neuroblastoma, and support testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.

Polycomb Group Repression Reduces DNA Accessibility

PubMed Central

Fitzgerald, Daniel P.; Bender, Welcome

2001-01-01

The Polycomb group proteins are responsible for long-term repression of a number of genes in Drosophila melanogaster, including the homeotic genes of the bithorax complex. The Polycomb protein is thought to alter the chromatin structure of its target genes, but there has been little direct evidence for this model. In this study, the chromatin structure of the bithorax complex was probed with three separate assays for DNA accessibility: (i) activation of polymerase II (Pol II) transcription by Gal4, (ii) transcription by the bacteriophage T7 RNA polymerase (T7RNAP), and (iii) FLP-mediated site-specific recombination. All three processes are restricted or blocked in Polycomb-repressed segments. In contrast, control test sites outside of the bithorax complex permitted Gal4, T7RNAP, and FLP activities throughout the embryo. Several P insertions in the bithorax complex were tested, providing evidence that the Polycomb-induced effect is widespread over target genes. This accessibility effect is similar to that seen for SIR silencing in Saccharomyces cerevisiae. In contrast to SIR silencing, however, episomes excised from Polycomb-repressed chromosomal sites do not show an altered superhelix density. PMID:11533246

Altered epigenetic regulation of homeobox genes in human oral squamous cell carcinoma cells

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

Marcinkiewicz, Katarzyna M.; Gudas, Lorraine J., E-mail: ljgudas@med.cornell.edu

To gain insight into oral squamous cell carcinogenesis, we performed deep sequencing (RNAseq) of non-tumorigenic human OKF6-TERT1R and tumorigenic SCC-9 cells. Numerous homeobox genes are differentially expressed between OKF6-TERT1R and SCC-9 cells. Data from Oncomine, a cancer microarray database, also show that homeobox (HOX) genes are dysregulated in oral SCC patients. The activity of Polycomb repressive complexes (PRC), which causes epigenetic modifications, and retinoic acid (RA) signaling can control HOX gene transcription. HOXB7, HOXC10, HOXC13, and HOXD8 transcripts are higher in SCC-9 than in OKF6-TERT1R cells; using ChIP (chromatin immunoprecipitation) we detected PRC2 protein SUZ12 and the epigenetic H3K27me3 markmore » on histone H3 at these genes in OKF6-TERT1R, but not in SCC-9 cells. In contrast, IRX1, IRX4, SIX2 and TSHZ3 transcripts are lower in SCC-9 than in OKF6-TERT1R cells. We detected SUZ12 and the H3K27me3 mark at these genes in SCC-9, but not in OKF6-TERT1R cells. SUZ12 depletion increased HOXB7, HOXC10, HOXC13, and HOXD8 transcript levels and decreased the proliferation of OKF6-TERT1R cells. Transcriptional responses to RA are attenuated in SCC-9 versus OKF6-TERT1R cells. SUZ12 and H3K27me3 levels were not altered by RA at these HOX genes in SCC-9 and OKF6-TERT1R cells. We conclude that altered activity of PRC2 is associated with dysregulation of homeobox gene expression in human SCC cells, and that this dysregulation potentially plays a role in the neoplastic transformation of oral keratinocytes. - Highlights: • RNAseq elucidates differences between non-tumorigenic and tumorigenic oral keratinocytes. • Changes in HOX mRNA in SCC-9 vs. OKF6-TERT1R cells are a result of altered epigenetic regulation. • RNAseq shows that retinoic acid (RA) influences gene expression in both OKF6-TERT1R and SCC-9 cells.« less

Convergent evolution of chromatin modification by structurally distinct enzymes: comparative enzymology of histone H3 Lys²⁷ methylation by human polycomb repressive complex 2 and vSET.

PubMed

Swalm, Brooke M; Hallenbeck, Kenneth K; Majer, Christina R; Jin, Lei; Scott, Margaret Porter; Moyer, Mikel P; Copeland, Robert A; Wigle, Tim J

2013-07-15

H3K27 (histone H3 Lys27) methylation is an important epigenetic modification that regulates gene transcription. In humans, EZH (enhancer of zeste homologue) 1 and EZH2 are the only enzymes capable of catalysing methylation of H3K27. There is great interest in understanding structure-function relationships for EZH2, as genetic alterations in this enzyme are thought to play a causal role in a number of human cancers. EZH2 is challenging to study because it is only active in the context of the multi-subunit PRC2 (polycomb repressive complex 2). vSET is a viral lysine methyltransferase that represents the smallest protein unit capable of catalysing H3K27 methylation. The crystal structure of this minimal catalytic protein has been solved and researchers have suggested that vSET might prove useful as an EZH2 surrogate for the development of active site-directed inhibitors. To test this proposition, we conducted comparative enzymatic analysis of human EZH2 and vSET and report that, although both enzymes share similar preferences for methylation of H3K27, they diverge in terms of their permissiveness for catalysing methylation of alternative histone lysine sites, their relative preferences for utilization of multimeric macromolecular substrates, their active site primary sequences and, most importantly, their sensitivity to inhibition by drug-like small molecules. The cumulative data led us to suggest that EZH2 and vSET have very distinct active site structures, despite the commonality of the reaction catalysed by the two enzymes. Hence, the EZH2 and vSET pair of enzymes represent an example of convergent evolution in which distinct structural solutions have developed to solve a common catalytic need.

The Roles and Regulation of Polycomb Complexes in Neural Development

PubMed Central

Corley, Matthew; Kroll, Kristen L.

2014-01-01

In the developing mammalian nervous system, common progenitors integrate both cell extrinsic and intrinsic regulatory programs to produce distinct neuronal and glial cell types as development proceeds. This spatiotemporal restriction of neural progenitor differentiation is enforced, in part, by the dynamic reorganization of chromatin into repressive domains by Polycomb Repressive Complexes, effectively limiting the expression of fate-determining genes. Here, we review distinct roles that the Polycomb Repressive Complexes play during neurogenesis and gliogenesis, while also highlighting recent work describing the molecular mechanisms that govern their dynamic activity in neural development. Further investigation of how Polycomb complexes are regulated in neural development will enable more precise manipulation of neural progenitor differentiation, facilitating the efficient generation of specific neuronal and glial cell types for many biological applications. PMID:25367430

Stuxnet Recruits the Proteasome to Take Down Polycomb.

PubMed

Karch, François

2016-06-20

In this issue of Developmental Cell, Du et al. (2016) describe a gene named stuxnet that regulates Polycomb protein stability, thereby influencing the activity of the Polycomb-group repressive chromatin complexes. Copyright © 2016 Elsevier Inc. All rights reserved.

Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis.

PubMed

Wassef, Michel; Rodilla, Veronica; Teissandier, Aurélie; Zeitouni, Bruno; Gruel, Nadege; Sadacca, Benjamin; Irondelle, Marie; Charruel, Margaux; Ducos, Bertrand; Michaud, Audrey; Caron, Matthieu; Marangoni, Elisabetta; Chavrier, Philippe; Le Tourneau, Christophe; Kamal, Maud; Pasmant, Eric; Vidaud, Michel; Servant, Nicolas; Reyal, Fabien; Meseure, Dider; Vincent-Salomon, Anne; Fre, Silvia; Margueron, Raphaël

2015-12-15

Alterations of chromatin modifiers are frequent in cancer, but their functional consequences often remain unclear. Focusing on the Polycomb protein EZH2 that deposits the H3K27me3 (trimethylation of Lys27 of histone H3) mark, we showed that its high expression in solid tumors is a consequence, not a cause, of tumorigenesis. In mouse and human models, EZH2 is dispensable for prostate cancer development and restrains breast tumorigenesis. High EZH2 expression in tumors results from a tight coupling to proliferation to ensure H3K27me3 homeostasis. However, this process malfunctions in breast cancer. Low EZH2 expression relative to proliferation and mutations in Polycomb genes actually indicate poor prognosis and occur in metastases. We show that while altered EZH2 activity consistently modulates a subset of its target genes, it promotes a wider transcriptional instability. Importantly, transcriptional changes that are consequences of EZH2 loss are predominantly irreversible. Our study provides an unexpected understanding of EZH2's contribution to solid tumors with important therapeutic implications. © 2015 Wassef et al.; Published by Cold Spring Harbor Laboratory Press.

Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis

PubMed Central

Wassef, Michel; Rodilla, Veronica; Teissandier, Aurélie; Zeitouni, Bruno; Gruel, Nadege; Sadacca, Benjamin; Irondelle, Marie; Charruel, Margaux; Ducos, Bertrand; Michaud, Audrey; Caron, Matthieu; Marangoni, Elisabetta; Chavrier, Philippe; Le Tourneau, Christophe; Kamal, Maud; Pasmant, Eric; Vidaud, Michel; Servant, Nicolas; Reyal, Fabien; Meseure, Dider; Vincent-Salomon, Anne; Fre, Silvia; Margueron, Raphaël

2015-01-01

Alterations of chromatin modifiers are frequent in cancer, but their functional consequences often remain unclear. Focusing on the Polycomb protein EZH2 that deposits the H3K27me3 (trimethylation of Lys27 of histone H3) mark, we showed that its high expression in solid tumors is a consequence, not a cause, of tumorigenesis. In mouse and human models, EZH2 is dispensable for prostate cancer development and restrains breast tumorigenesis. High EZH2 expression in tumors results from a tight coupling to proliferation to ensure H3K27me3 homeostasis. However, this process malfunctions in breast cancer. Low EZH2 expression relative to proliferation and mutations in Polycomb genes actually indicate poor prognosis and occur in metastases. We show that while altered EZH2 activity consistently modulates a subset of its target genes, it promotes a wider transcriptional instability. Importantly, transcriptional changes that are consequences of EZH2 loss are predominantly irreversible. Our study provides an unexpected understanding of EZH2's contribution to solid tumors with important therapeutic implications. PMID:26637281

RING1 is associated with the polycomb group protein complex and acts as a transcriptional repressor.

PubMed

Satijn, D P; Gunster, M J; van der Vlag, J; Hamer, K M; Schul, W; Alkema, M J; Saurin, A J; Freemont, P S; van Driel, R; Otte, A P

1997-07-01

The Polycomb (Pc) protein is a component of a multimeric, chromatin-associated Polycomb group (PcG) protein complex, which is involved in stable repression of gene activity. The identities of components of the PcG protein complex are largely unknown. In a two-hybrid screen with a vertebrate Pc homolog as a target, we identify the human RING1 protein as interacting with Pc. RING1 is a protein that contains the RING finger motif, a specific zinc-binding domain, which is found in many regulatory proteins. So far, the function of the RING1 protein has remained enigmatic. Here, we show that RING1 coimmunoprecipitates with a human Pc homolog, the vertebrate PcG protein BMI1, and HPH1, a human homolog of the PcG protein Polyhomeotic (Ph). Also, RING1 colocalizes with these vertebrate PcG proteins in nuclear domains of SW480 human colorectal adenocarcinoma and Saos-2 human osteosarcoma cells. Finally, we show that RING1, like Pc, is able to repress gene activity when targeted to a reporter gene. Our findings indicate that RING1 is associated with the human PcG protein complex and that RING1, like PcG proteins, can act as a transcriptional repressor.

Systems Level Analysis of Histone H3 Post-translational Modifications (PTMs) Reveals Features of PTM Crosstalk in Chromatin Regulation*

PubMed Central

Schwämmle, Veit; Sidoli, Simone; Ruminowicz, Chrystian; Wu, Xudong; Lee, Chung-Fan; Helin, Kristian; Jensen, Ole N.

2016-01-01

Histones are abundant chromatin constituents carrying numerous post-translational modifications (PTMs). Such PTMs mediate a variety of biological functions, including recruitment of enzymatic readers, writers and erasers that modulate DNA replication, transcription and repair. Individual histone molecules contain multiple coexisting PTMs, some of which exhibit crosstalk, i.e. coordinated or mutually exclusive activities. Here, we present an integrated experimental and computational systems level molecular characterization of histone PTMs and PTM crosstalk. Using wild type and engineered mouse embryonic stem cells (mESCs) knocked out in components of the Polycomb Repressive Complex 2 (PRC2, Suz12−/−), PRC1 (Ring1A/B−/−) and (Dnmt1/3a/3b−/−) we performed comprehensive PTM analysis of histone H3 tails (50 aa) by utilizing quantitative middle-down proteome analysis by tandem mass spectrometry. We characterized combinatorial PTM features across the four mESC lines and then applied statistical data analysis to predict crosstalk between histone H3 PTMs. We detected an overrepresentation of positive crosstalk (codependent marks) between adjacent mono-methylated and acetylated marks, and negative crosstalk (mutually exclusive marks) among most of the seven characterized di- and tri-methylated lysine residues in the H3 tails. We report novel features of PTM interplay involving hitherto poorly characterized arginine methylation and lysine methylation sites, including H3R2me, H3R8me and H3K37me. Integration of the H3 data with RNAseq data by coabundance clustering analysis of histone PTMs and histone modifying enzymes revealed correlations between PTM and enzyme levels. We conclude that middle-down proteomics is a powerful tool to determine conserved or dynamic interdependencies between histone marks, which paves the way for detailed investigations of the histone code. Histone H3 PTM data is publicly available in the CrossTalkDB repository at http://crosstalkdb.bmb.sdu.dk. PMID:27302890

Polycomb purification by in vivo biotinylation tagging reveals cohesin and Trithorax group proteins as interaction partners

PubMed Central

Strübbe, Gero; Popp, Christian; Schmidt, Alexander; Pauli, Andrea; Ringrose, Leonie; Beisel, Christian; Paro, Renato

2011-01-01

The maintenance of specific gene expression patterns during cellular proliferation is crucial for the identity of every cell type and the development of tissues in multicellular organisms. Such a cellular memory function is conveyed by the complex interplay of the Polycomb and Trithorax groups of proteins (PcG/TrxG). These proteins exert their function at the level of chromatin by establishing and maintaining repressed (PcG) and active (TrxG) chromatin domains. Past studies indicated that a core PcG protein complex is potentially associated with cell type or even cell stage-specific sets of accessory proteins. In order to better understand the dynamic aspects underlying PcG composition and function we have established an inducible version of the biotinylation tagging approach to purify Polycomb and associated factors from Drosophila embryos. This system enabled fast and efficient isolation of Polycomb containing complexes under near physiological conditions, thereby preserving substoichiometric interactions. Novel interacting proteins were identified by highly sensitive mass spectrometric analysis. We found many TrxG related proteins, suggesting a previously unrecognized extent of molecular interaction of the two counteracting chromatin regulatory protein groups. Furthermore, our analysis revealed an association of PcG protein complexes with the cohesin complex and showed that Polycomb-dependent silencing of a transgenic reporter depends on cohesin function. PMID:21415365

The role of enhancer of zeste homolog 2: From viral epigenetics to the carcinogenesis of hepatocellular carcinoma.

PubMed

Sanna, Luca; Marchesi, Irene; Melone, Mariarosa A B; Bagella, Luigi

2018-03-25

Nowadays, epigenetics covers a crucial role in different fields of science. The enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), is a big proponent of how epigenetic changes can affect the initiation and progression of several diseases. Through its catalytic activity, responsible for the tri-methylation of lysine 27 of the histone H3 (H3K27me3), EZH2 is a good target for both diagnosis and therapy of different pathologies. A large number of studies have demonstrated its crucial role in cancer initiation and progression. Nevertheless, only recently its function in virus diseases has been uncovered; therefore, EZH2 can be an important promoter of viral carcinogenesis. This review explores the role of EZH2 in viral epigenetics based on recent progress that demonstrated the role of this protein in virus environment. In particular, the review focuses on EZH2 behavior in Hepatitis B Virus, analyzing its role in the rise of Hepatocellular Carcinoma. © 2018 Wiley Periodicals, Inc.

Sjögren's syndrome X-chromosome dose effect: An epigenetic perspective.

PubMed

Mougeot, J-Lc; Noll, B D; Bahrani Mougeot, F K

2018-01-09

Sjögren's syndrome (SS) is a chronic autoimmune disease affecting exocrine glands leading to mouth and eyes dryness. The extent to which epigenetic DNA methylation changes are responsible for an X-chromosome dose effect has yet to be determined. Our objectives were to (i) describe how epigenetic DNA methylation changes could explain an X-chromosome dose effect in SS for women with normal 46,XX genotype and (ii) determine the relevant relationships to this dose effect, between X-linked genes, genes controlling X-chromosome inactivation (XCI) and genes encoding associated transcription factors, all of which are differentially expressed and/or differentially methylated in the salivary glands of patients with SS. We identified 58 upregulated X-chromosome genes, including 22 genes previously shown to escape XCI, based on the analysis of SS patient salivary gland GEO2R gene expression datasets. Moreover, we found XIST and its cis regulators RLIM, FTX, and CHIC1, and polycomb repressor genes of the PRC1/2 complexes to be upregulated. Many of the X-chromosome genes implicated in SS pathogenesis can be regulated by transcription factors which we found to be overexpressed and/or differentially methylated in patients with SS. Determination of the mechanisms underlying methylation-dependent gene expression and impaired XCI is needed to further elucidate the etiopathogenesis of SS. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.

Dynamic regulation of EZH2 from HPSc to hepatocyte-like cell fate

PubMed Central

Helsen, Nicky; Vanhove, Jolien; Boon, Ruben; Xu, Zhuofei; Ordovas, Laura; Verfaillie, Catherine M.

2017-01-01

Currently, drug metabolization and toxicity studies rely on the use of primary human hepatocytes and hepatoma cell lines, which both have conceivable limitations. Human pluripotent stem cell (hPSC)—derived hepatocyte-like cells (HLCs) are an alternative and valuable source of hepatocytes that can overcome these limitations. EZH2 (enhancer of zeste homolog 2), a transcriptional repressor of the polycomb repressive complex 2 (PRC2), may play an important role in hepatocyte development, but its role during in vitro hPSC-HLC differentiation has not yet been assessed. We here demonstrate dynamic regulation of EZH2 during hepatic differentiation of hPSC. To enhance EZH2 expression, we inducibly overexpressed EZH2 between d0 and d8, demonstrating a significant improvement in definitive endoderm formation, and improved generation of HLCs. Despite induction of EZH2 overexpression until d8, EZH2 transcript and protein levels decreased from d4 onwards, which might be caused by expression of microRNAs predicted to inhibit EZH2 expression. In conclusion, our studies demonstrate that EZH2 plays a role in endoderm formation and hepatocyte differentiation, but its expression is tightly post-transcriptionally regulated during this process. PMID:29091973

EZH2: a pivotal regulator in controlling cell differentiation.

PubMed

Chen, Ya-Huey; Hung, Mien-Chie; Li, Long-Yuan

2012-01-01

Epigenetic regulation plays an important role in stem cell self-renewal, maintenance and lineage differentiation. The epigenetic profiles of stem cells are related to their transcriptional signature. Enhancer of Zeste homlog 2 (EZH2), a catalytic subunit of epigenetic regulator Polycomb repressive complex 2 (PRC2), has been shown to be a key regulator in controlling cellular differentiation. EZH2 is a histone methyltransferase that not only methylates histone H3 on Lys 27 (H3K27me3) but also interacts with and recruits DNA methyltransferases to methylate CpG at certain EZH2 target genes to establish firm repressive chromatin structures, contributing to tumor progression and the regulation of development and lineage commitment both in embryonic stem cells (ESCs) and adult stem cells. In addition to its well-recognized epigenetic gene silencing function, EZH2 also directly methylates nonhistone targets such as the cardiac transcription factor, GATA4, resulting in attenuated GATA4 transcriptional activity and gene repression. This review addresses recent progress toward the understanding of the biological functions and regulatory mechanisms of EZH2 and its targets as well as their roles in stem cell maintenance and cell differentiation.

Development and validation of reagents and assays for EZH2 peptide and nucleosome high-throughput screens.

PubMed

Diaz, Elsie; Machutta, Carl A; Chen, Stephanie; Jiang, Yong; Nixon, Christopher; Hofmann, Glenn; Key, Danielle; Sweitzer, Sharon; Patel, Mehul; Wu, Zining; Creasy, Caretha L; Kruger, Ryan G; LaFrance, Louis; Verma, Sharad K; Pappalardi, Melissa B; Le, Baochau; Van Aller, Glenn S; McCabe, Michael T; Tummino, Peter J; Pope, Andrew J; Thrall, Sara H; Schwartz, Benjamin; Brandt, Martin

2012-12-01

Histone methyltransferases (HMT) catalyze the methylation of histone tail lysines, resulting in changes in gene transcription. Misregulation of these enzymes has been associated with various forms of cancer, making this target class a potential new area for the development of novel chemotherapeutics. EZH2 is the catalytic component of the polycomb group repressive complex (PRC2), which selectively methylates histone H3 lysine 27 (H3K27). EZH2 is overexpressed in prostate, breast, bladder, brain, and other tumor types and is recognized as a molecular marker for cancer progression and aggressiveness. Several new reagents and assays were developed to aid in the identification of EZH2 inhibitors, and these were used to execute two high-throughput screening campaigns. Activity assays using either an H3K27 peptide or nucleosomes as substrates for methylation are described. The strategy to screen EZH2 with either a surrogate peptide or a natural substrate led to the identification of the same tractable series. Compounds from this series are reversible, are [(3)H]-S-adenosyl-L-methionine competitive, and display biochemical inhibition of H3K27 methylation.

A noncoding RNA transcribed from the AGAMOUS (AG) second intron binds to CURLY LEAF and represses AG expression in leaves.

PubMed

Wu, Hui-Wen; Deng, Shulin; Xu, Haiying; Mao, Hui-Zhu; Liu, Jun; Niu, Qi-Wen; Wang, Huan; Chua, Nam-Hai

2018-06-04

Dispersed H3K27 trimethylation (H3K27me3) of the AGAMOUS (AG) genomic locus is mediated by CURLY LEAF (CLF), a component of the Polycomb Repressive Complex (PRC) 2. Previous reports have shown that the AG second intron, which confers AG tissue-specific expression, harbors sequences targeted by several positive and negative regulators. Using RACE reverse transcription polymerase chain reaction, we found that the AG intron 2 encodes several noncoding RNAs. RNAi experiment showed that incRNA4 is needed for CLF repressive activity. AG-incRNA4RNAi lines showed increased leaf AG mRNA levels associated with a decrease of H3K27me3 levels; these plants displayed AG overexpression phenotypes. Genetic and biochemical analyses demonstrated that the AG-incRNA4 can associate with CLF to repress AG expression in leaf tissues through H3K27me3-mediated repression and to autoregulate its own expression level. The mechanism of AG-incRNA4-mediated repression may be relevant to investigations on tissue-specific expression of Arabidopsis MADS-box genes. © 2018 The Authors New Phytologist © 2018 New Phytologist Trust.

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.

The SAND domain protein ULTRAPETALA1 acts as a trithorax group factor to regulate cell fate in plants

USDA-ARS?s Scientific Manuscript database

During development, trithorax group (trxG) chromatin remodeling complexes counteract repression by Polycomb group (PcG) complexes to sustain active expression of key regulatory genes. Although PcG complexes are well characterized in plants, little is known about trxG activities. Here we demonstrate ...

A Novel Role of Silibinin as a Putative Epigenetic Modulator in Human Prostate Carcinoma.

PubMed

Anestopoulos, Ioannis; Sfakianos, Aristeidis P; Franco, Rodrigo; Chlichlia, Katerina; Panayiotidis, Mihalis I; Kroll, David J; Pappa, Aglaia

2016-12-31

Silibinin, extracted from milk thistle ( Silybum marianum L.), has exhibited considerable preclinical activity against prostate carcinoma. Its antitumor and chemopreventive activities have been associated with diverse effects on cell cycle, apoptosis, and receptor-dependent mitogenic signaling pathways. Here we hypothesized that silibinin's pleiotropic effects may reflect its interference with epigenetic mechanisms in human prostate cancer cells. More specifically, we have demonstrated that silibinin reduces gene expression levels of the Polycomb Repressive Complex 2 (PRC2) members Enhancer of Zeste Homolog 2 (EZH2), Suppressor of Zeste Homolog 12 (SUZ12), and Embryonic Ectoderm Development (EED) in DU145 and PC3 human prostate cancer cells, as evidenced by Real Time Polymerase Chain Reaction (RT-PCR). Furthermore immunoblot and immunofluorescence analysis revealed that silibinin-mediated reduction of EZH2 levels was accompanied by an increase in trimethylation of histone H3 on lysine (Κ)-27 residue (H3K27me3) levels and that such response was, in part, dependent on decreased expression levels of phosphorylated Akt (ser473) (pAkt) and phosphorylated EZH2 (ser21) (pEZH2). Additionally silibinin exerted other epigenetic effects involving an increase in total DNA methyltransferase (DNMT) activity while it decreased histone deacetylases 1-2 (HDACs1-2) expression levels. We conclude that silibinin induces epigenetic alterations in human prostate cancer cells, suggesting that subsequent disruptions of central processes in chromatin conformation may account for some of its diverse anticancer effects.

Biochemical and Functional Interactions of Human Papillomavirus Proteins with Polycomb Group Proteins

PubMed Central

McLaughlin-Drubin, Margaret E.; Munger, Karl

2013-01-01

The role of enzymes involved in polycomb repression of gene transcription has been studied extensively in human cancer. Polycomb repressive complexes mediate oncogene-induced senescence, a principal innate cell-intrinsic tumor suppressor pathway that thwarts expansion of cells that have suffered oncogenic hits. Infections with human cancer viruses including human papillomaviruses (HPVs) and Epstein-Barr virus can trigger oncogene-induced senescence, and the viruses have evolved strategies to abrogate this response in order to establish an infection and reprogram their host cells to establish a long-term persistent infection. As a consequence of inhibiting polycomb repression and evading oncogene induced-senescence, HPV infected cells have an altered epigenetic program as evidenced by aberrant homeobox gene expression. Similar alterations are frequently observed in non-virus associated human cancers and may be harnessed for diagnosis and therapy. PMID:23673719

A functionally conserved Polycomb response element from mouse HoxD complex responds to heterochromatin factors

NASA Astrophysics Data System (ADS)

Vasanthi, Dasari; Nagabhushan, A.; Matharu, Navneet Kaur; Mishra, Rakesh K.

2013-10-01

Anterior-posterior body axis in all bilaterians is determined by the Hox gene clusters that are activated in a spatio-temporal order. This expression pattern of Hox genes is established and maintained by regulatory mechanisms that involve higher order chromatin structure and Polycomb group (PcG) and trithorax group (trxG) proteins. We identified earlier a Polycomb response element (PRE) in the mouse HoxD complex that is functionally conserved in flies. We analyzed the molecular and genetic interactions of mouse PRE using Drosophila melanogaster and vertebrate cell culture as the model systems. We demonstrate that the repressive activity of this PRE depends on PcG/trxG genes as well as the heterochromatin components. Our findings indicate that a wide range of factors interact with the HoxD PRE that can contribute to establishing the expression pattern of homeotic genes in the complex early during development and maintain that pattern at subsequent stages.

CTCF Binding Sites in the Herpes Simplex Virus 1 Genome Display Site-Specific CTCF Occupation, Protein Recruitment, and Insulator Function.

PubMed

Washington, Shannan D; Musarrat, Farhana; Ertel, Monica K; Backes, Gregory L; Neumann, Donna M

2018-04-15

There are seven conserved CTCF binding domains in the herpes simplex virus 1 (HSV-1) genome. These binding sites individually flank the latency-associated transcript (LAT) and the immediate early (IE) gene regions, suggesting that CTCF insulators differentially control transcriptional domains in HSV-1 latency. In this work, we show that two CTCF binding motifs in HSV-1 display enhancer blocking in a cell-type-specific manner. We found that CTCF binding to the latent HSV-1 genome was LAT dependent and that the quantity of bound CTCF was site specific. Following reactivation, CTCF eviction was dynamic, suggesting that each CTCF site was independently regulated. We explored whether CTCF sites recruit the polycomb-repressive complex 2 (PRC2) to establish repressive domains through a CTCF-Suz12 interaction and found that Suz12 colocalized to the CTCF insulators flanking the ICP0 and ICP4 regions and, conversely, was removed at early times postreactivation. Collectively, these data support the idea that CTCF sites in HSV-1 are independently regulated and may contribute to lytic-latent HSV-1 control in a site-specific manner. IMPORTANCE The role of chromatin insulators in DNA viruses is an area of interest. It has been shown in several beta- and gammaherpesviruses that insulators likely control the lytic transcriptional profile through protein recruitment and through the formation of three-dimensional (3D) chromatin loops. The ability of insulators to regulate alphaherpesviruses has been understudied to date. The alphaherpesvirus HSV-1 has seven conserved insulator binding motifs that flank regions of the genome known to contribute to the establishment of latency. Our work presented here contributes to the understanding of how insulators control transcription of HSV-1. Copyright © 2018 American Society for Microbiology.

Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B

PubMed Central

Santofimia-Castaño, Patricia; Rizzuti, Bruno; Pey, Ángel L.; Soubeyran, Philippe; Vidal, Miguel; Urrutia, Raúl; Iovanna, Juan L.; Neira, José L.

2017-01-01

Intrinsically disordered proteins (IDPs) are ubiquitous in eukaryotes, and they are often associated with diseases in humans. The protein NUPR1 is a multifunctional IDP involved in chromatin remodeling and in the development and progression of pancreatic cancer; however, the details of such functions are unknown. Polycomb proteins are involved in specific transcriptional cascades and gene silencing. One of the proteins of the Polycomb complex is the Ring finger protein 1 (RING1). RING1 is related to aggressive tumor features in multiple cancer types. In this work we characterized the interaction between NUPR1 and the paralogue RING1B in vitro, in silico, and in cellulo. The interaction occurred through the C-terminal region of RING1B (C-RING1B), with an affinity in the low micromolar range (∼10 μM). The binding region of NUPR1, mapped by NMR, was a hydrophobic polypeptide patch at the 30s region of its sequence, as pinpointed by computational results and site-directed mutagenesis at Ala33. The association between C-RING1B and wild-type NUPR1 also occurred in cellulo as tested by protein ligation assays; this interaction is inhibited by trifluoperazine, a drug known to hamper binding of wild-type NUPR1 with other proteins. Furthermore, the Thr68Gln and Ala33Gln/Thr68Gln mutants had a reduction in the binding toward C-RING1B as shown by in vitro, in silico, and in cellulo studies. This is an example of a well-folded partner of NUPR1, because its other interacting proteins are also unfolded. We hypothesize that NUPR1 plays an active role in chromatin remodeling and carcinogenesis, together with Polycomb proteins. PMID:28720707

Live Cell Imaging of the Nascent Inactive X Chromosome during the Early Differentiation Process of Naive ES Cells towards Epiblast Stem Cells

PubMed Central

Guyochin, Aurélia; Maenner, Sylvain; Chu, Erin Tsi-Jia; Hentati, Asma; Attia, Mikael; Avner, Philip; Clerc, Philippe

2014-01-01

Random X-chromosome inactivation ensures dosage compensation in mammals through the transcriptional silencing of one of the two X chromosomes present in each female cell. Silencing is initiated in the differentiating epiblast of the mouse female embryos through coating of the nascent inactive X chromosome by the non-coding RNA Xist, which subsequently recruits the Polycomb Complex PRC2 leading to histone H3-K27 methylation. Here we examined in mouse ES cells the early steps of the transition from naive ES cells towards epiblast stem cells as a model for inducing X chromosome inactivation in vitro. We show that these conditions efficiently induce random XCI. Importantly, in a transient phase of this differentiation pathway, both X chromosomes are coated with Xist RNA in up to 15% of the XX cells. In an attempt to determine the dynamics of this process, we designed a strategy aimed at visualizing the nascent inactive X-chromosome in live cells. We generated transgenic female XX ES cells expressing the PRC2 component Ezh2 fused to the fluorescent protein Venus. The fluorescent fusion protein was expressed at sub-physiological levels and located in nuclei of ES cells. Upon differentiation of ES cell towards epiblast stem cell fate, Venus-fluorescent territories appearing in interphase nuclei were identified as nascent inactive X chromosomes by their association with Xist RNA. Imaging of Ezh2-Venus for up to 24 hours during the differentiation process showed survival of some cells with two fluorescent domains and a surprising dynamics of the fluorescent territories across cell division and in the course of the differentiation process. Our data reveal a strategy for visualizing the nascent inactive X chromosome and suggests the possibility for a large plasticity of the nascent inactive X chromosome. PMID:25546018

A Combinatorial Platform for the Optimization of Peptidomimetic Methyl-Lysine Reader Antagonists

NASA Astrophysics Data System (ADS)

Barnash, Kimberly D.

Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.

SUZ12 is a novel putative oncogene promoting tumorigenesis in head and neck squamous cell carcinoma.

PubMed

Wu, Yaping; Hu, Huijun; Zhang, Wei; Li, Zhongwu; Diao, Pengfei; Wang, Dongmiao; Zhang, Wei; Wang, Yanling; Yang, Jianrong; Cheng, Jie

2018-04-18

The suppressor of zest 12 (SUZ12), one of the core polycomb repressive complex 2 (PRC2) components, has increasingly appreciated as a key mediator during human tumorigenesis. However, its expression pattern and oncogenic roles in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored yet. Here, we sought to determine its expression pattern, clinicopathological significance and biological roles in HNSCC. Through data mining and interrogation from multiple publicly available databases, our bioinformatics analyses revealed that SUZ12 mRNA was significantly overexpressed in multiple HNSCC patient cohorts. Moreover, SUZ12 protein was markedly up-regulated in primary HNSCC samples from our patient cohort as assessed by immunohistochemical staining and its overexpression significantly associated with cervical node metastasis and reduced overall and disease-free survival. In the 4-nitroquinoline 1-oxide (4NQO)-induced HNSCC mouse model, increased SUZ12 immunostaining was observed along with disease progression from epithelial hyperplasia to squamous cell carcinoma in tongue. Furthermore, shRNA-mediated SUZ12 knock-down significantly inhibited cell proliferation, migration and invasion in HNSCC cells, and resulted in compromised tumour growth in vivo. Collectively, our data reveal that SUZ12 might serve as a putative oncogene by promoting cell proliferation, migration and invasion, and also a novel biomarker with diagnostic and prognostic significance for HNSCC. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Brg1 modulates enhancer activation in mesoderm lineage commitment

DOE PAGES

Alexander, Jeffrey M.; Hota, Swetansu K.; He, Daniel; ...

2015-03-26

The interplay between different levels of gene regulation in modulating developmental transcriptional programs, such as histone modifications and chromatin remodeling, is not well understood. Here, we show that the chromatin remodeling factor Brg1 is required for enhancer activation in mesoderm induction. In an embryonic stem cell-based directed differentiation assay, the absence of Brg1 results in a failure of cardiomyocyte differentiation and broad deregulation of lineage-specific gene expression during mesoderm induction. We find that Brg1 co-localizes with H3K27ac at distal enhancers and is required for robust H3K27 acetylation at distal enhancers that are activated during mesoderm induction. Brg1 is also requiredmore » to maintain Polycomb-mediated repression of non-mesodermal developmental regulators, suggesting cooperativity between Brg1 and Polycomb complexes. Thus, Brg1 is essential for modulating active and repressive chromatin states during mesoderm lineage commitment, in particular the activation of developmentally important enhancers. In conclusion, these findings demonstrate interplay between chromatin remodeling complexes and histone modifications that, together, ensure robust and broad gene regulation during crucial lineage commitment decisions.« less

A Clinicopathologic Study of Head and Neck Malignant Peripheral Nerve Sheath Tumors.

PubMed

Owosho, Adepitan A; Estilo, Cherry L; Huryn, Joseph M; Chi, Ping; Antonescu, Cristina R

2018-06-01

Head and neck high grade malignant peripheral nerve sheath tumors (HN-MPNSTs) are rare highly aggressive soft tissue sarcomas that show overlapping morphologic and immunophenotypic features with melanoma and other high grade sarcomas, resulting in diagnostic challenges, particularly in sporadic settings. Recent discoveries have implicated loss of function mutations in the polycomb repressive complex 2 (PRC2) components, including EED or SUZ12 genes, as one of the leading pathogenetic mechanisms in high grade MPNST. MPNSTs with PRC2 loss are associated with complete loss of trimethylation at lysine 27 of histone H3 (H3K27me3), which emerged as a reliable immunohistochemical marker in the diagnosis of sporadic and radiation induced MPNST. As the diagnosis of MPNST in the HN is particularly challenging to distinguish from melanoma and other sarcoma types, we carried out a clinicopathologic analysis on HN-MPNST patients managed at our institution over a 20-year period (1997-2016), using the latest diagnostic criteria including H3K27me3 staining and other molecular investigations. The overall survival of HN-MPNST was compared with other HN soft tissue sarcomas. The diagnosis of HN-MPNST was confirmed in 13 patients (seven males and six females), with a mean age of 31 years; with 3 (23%) patients being of pediatric age. The most common site was the neck soft tissue (77%). Two-thirds of patients (n = 9) had stigmata of NF1, three had prior radiotherapy and only one developed a de novo MPNST. All except one tumor (86%) tested showed loss of H3K27me3 expression, including all non-NF1 patients. The 2 and 5-year DSS rates were 50 and 30%. The 2-year DFS rate was 21%. Adverse predictors on DSS included adult age (p = 0.011), prior-history of RT (p = 0.003) and recurrence (p = 0.003). Compared to other molecularly confirmed subsets of HN sarcomas (Ewing and Ewing-like sarcoma, rhabdomyosarcoma and synovial sarcoma), HN-MPNST had the worst overall survival (p < 0.0001). We conclude that HN-MPNSTs are highly aggressive sarcomas associated with an unfavorable outcome and the utility of H3K27me3 IHC stains in the evaluation of MPNST is a reliable ancillary diagnostic adjunct.

Lineage specific expression of Polycomb Group Proteins in human embryonic stem cells in vitro.

PubMed

Pethe, Prasad; Pursani, Varsha; Bhartiya, Deepa

2015-05-01

Human embryonic (hES) stem cells are an excellent model to study lineage specification and differentiation into various cell types. Differentiation necessitates repression of specific genes not required for a particular lineage. Polycomb Group (PcG) proteins are key histone modifiers, whose primary function is gene repression. PcG proteins form complexes called Polycomb Repressive Complexes (PRCs), which catalyze histone modifications such as H2AK119ub1, H3K27me3, and H3K9me3. PcG proteins play a crucial role during differentiation of stem cells. The expression of PcG transcripts during differentiation of hES cells into endoderm, mesoderm, and ectoderm lineage is yet to be shown. In-house derived hES cell line KIND1 was differentiated into endoderm, mesoderm, and ectoderm lineages; followed by characterization using RT-PCR for HNF4A, CDX2, MEF2C, TBX5, SOX1, and MAP2. qRT-PCR and western blotting was performed to compare expression of PcG transcripts and proteins across all the three lineages. We observed that cells differentiated into endoderm showed upregulation of RING1B, BMI1, EZH2, and EED transcripts. Mesoderm differentiation was characterized by significant downregulation of all PcG transcripts during later stages. BMI1 and RING1B were upregulated while EZH2, SUZ12, and EED remained low during ectoderm differentiation. Western blotting also showed distinct expression of BMI1 and EZH2 during differentiation into three germ layers. Our study shows that hES cells differentiating into endoderm, mesoderm, and ectoderm lineages show distinct PcG expression profile at transcript and protein level. © 2015 International Federation for Cell Biology.

batman Interacts with polycomb and trithorax group genes and encodes a BTB/POZ protein that is included in a complex containing GAGA factor.

PubMed

Faucheux, M; Roignant, J-Y; Netter, S; Charollais, J; Antoniewski, C; Théodore, L

2003-02-01

Polycomb and trithorax group genes maintain the appropriate repressed or activated state of homeotic gene expression throughout Drosophila melanogaster development. We have previously identified the batman gene as a Polycomb group candidate since its function is necessary for the repression of Sex combs reduced. However, our present genetic analysis indicates functions of batman in both activation and repression of homeotic genes. The 127-amino-acid Batman protein is almost reduced to a BTB/POZ domain, an evolutionary conserved protein-protein interaction domain found in a large protein family. We show that this domain is involved in the interaction between Batman and the DNA binding GAGA factor encoded by the Trithorax-like gene. The GAGA factor and Batman codistribute on polytene chromosomes, coimmunoprecipitate from nuclear embryonic and larval extracts, and interact in the yeast two-hybrid assay. Batman, together with the GAGA factor, binds to MHS-70, a 70-bp fragment of the bithoraxoid Polycomb response element. This binding, like that of the GAGA factor, requires the presence of d(GA)n sequences. Together, our results suggest that batman belongs to a subset of the Polycomb/trithorax group of genes that includes Trithorax-like, whose products are involved in both activation and repression of homeotic genes.

batman Interacts with Polycomb and trithorax Group Genes and Encodes a BTB/POZ Protein That Is Included in a Complex Containing GAGA Factor

PubMed Central

Faucheux, M.; Roignant, J.-Y.; Netter, S.; Charollais, J.; Antoniewski, C.; Théodore, L.

2003-01-01

Polycomb and trithorax group genes maintain the appropriate repressed or activated state of homeotic gene expression throughout Drosophila melanogaster development. We have previously identified the batman gene as a Polycomb group candidate since its function is necessary for the repression of Sex combs reduced. However, our present genetic analysis indicates functions of batman in both activation and repression of homeotic genes. The 127-amino-acid Batman protein is almost reduced to a BTB/POZ domain, an evolutionary conserved protein-protein interaction domain found in a large protein family. We show that this domain is involved in the interaction between Batman and the DNA binding GAGA factor encoded by the Trithorax-like gene. The GAGA factor and Batman codistribute on polytene chromosomes, coimmunoprecipitate from nuclear embryonic and larval extracts, and interact in the yeast two-hybrid assay. Batman, together with the GAGA factor, binds to MHS-70, a 70-bp fragment of the bithoraxoid Polycomb response element. This binding, like that of the GAGA factor, requires the presence of d(GA)n sequences. Together, our results suggest that batman belongs to a subset of the Polycomb/trithorax group of genes that includes Trithorax-like, whose products are involved in both activation and repression of homeotic genes. PMID:12556479

EED and KDM6B Coordinate the First Mammalian Cell Lineage Commitment To Ensure Embryo Implantation

PubMed Central

Saha, Biswarup; Home, Pratik; Ray, Soma; Larson, Melissa; Paul, Arindam; Rajendran, Ganeshkumar; Behr, Barry

2013-01-01

The first mammalian cell lineage commitment is the formation of the trophectoderm (TE) and the inner cell mass (ICM) lineages during preimplantation development. Proper development of the TE and ICM lineages is dependent upon establishment of specific transcriptional programs. However, the epigenetic mechanisms that functionally contribute to establish TE- and ICM-specific transcriptional programs are poorly understood. Here, we show that proper development of the TE and ICM lineages is coordinated via combinatorial regulation of embryonic ectoderm development (EED) and lysine-specific demethylase 6B (KDM6B). During blastocyst formation, the relative levels of EED and KDM6B expression determine altered polycomb repressor 2 (PRC2) complex recruitment and incorporation of the repressive histone H3 lysine 27 trimethylation (H3K27Me3) mark at the chromatin domains of TE-specific master regulators CDX2 and GATA3, leading to their activation in the TE lineage and repression in the ICM lineage. Furthermore, ectopic gain of EED along with depletion of KDM6B in preimplantation mouse embryos abrogates CDX2 and GATA3 expression in the nascent TE lineage. The loss of CDX2 and GATA3 in the nascent TE lineage results in improper TE development, leading to failure in embryo implantation to the uterus. Our study delineates a novel epigenetic mechanism that orchestrates proper development of the first mammalian cell lineages. PMID:23671187

The Human Polycomb Group Complex Associates with Pericentromeric Heterochromatin to Form a Novel Nuclear Domain

PubMed Central

Saurin, Andrew J.; Shiels, Carol; Williamson, Jill; Satijn, David P.E.; Otte, Arie P.; Sheer, Denise; Freemont, Paul S.

1998-01-01

The Polycomb group (PcG) complex is a chromatin-associated multiprotein complex, involved in the stable repression of homeotic gene activity in Drosophila. Recently, a mammalian PcG complex has been identified with several PcG proteins implicated in the regulation of Hox gene expression. Although the mammalian PcG complex appears analogous to the complex in Drosophila, the molecular mechanisms and functions for the mammalian PcG complex remain unknown. Here we describe a detailed characterization of the human PcG complex in terms of cellular localization and chromosomal association. By using antibodies that specifically recognize three human PcG proteins— RING1, BMI1, and hPc2—we demonstrate in a number of human cell lines that the PcG complex forms a unique discrete nuclear structure that we term PcG bodies. PcG bodies are prominent novel nuclear structures with the larger PcG foci generally localized near the centromeres, as visualized with a kinetochore antibody marker. In both normal fetal and adult fibroblasts, PcG bodies are not randomly dispersed, but appear clustered into defined areas within the nucleus. We show in three different human cell lines that the PcG complex can tightly associate with large pericentromeric heterochromatin regions (1q12) on chromosome 1, and with related pericentromeric sequences on different chromosomes, providing evidence for a mammalian PcG–heterochromatin association. Furthermore, these heterochromatin-bound PcG complexes remain stably associated throughout mitosis, thereby allowing the potential inheritance of the PcG complex through successive cell divisions. We discuss these results in terms of the known function of the PcG complex as a transcriptional repression complex. PMID:9722603

Polycomb group protein complexes exchange rapidly in living Drosophila.

PubMed

Ficz, Gabriella; Heintzmann, Rainer; Arndt-Jovin, Donna J

2005-09-01

Fluorescence recovery after photobleaching (FRAP) microscopy was used to determine the kinetic properties of Polycomb group (PcG) proteins in whole living Drosophila organisms (embryos) and tissues (wing imaginal discs and salivary glands). PcG genes are essential genes in higher eukaryotes responsible for the maintenance of the spatially distinct repression of developmentally important regulators such as the homeotic genes. Their absence, as well as overexpression, causes transformations in the axial organization of the body. Although protein complexes have been isolated in vitro, little is known about their stability or exact mechanism of repression in vivo. We determined the translational diffusion constants of PcG proteins, dissociation constants and residence times for complexes in vivo at different developmental stages. In polytene nuclei, the rate constants suggest heterogeneity of the complexes. Computer simulations with new models for spatially distributed protein complexes were performed in systems showing both diffusion and binding equilibria, and the results compared with our experimental data. We were able to determine forward and reverse rate constants for complex formation. Complexes exchanged within a period of 1-10 minutes, more than an order of magnitude faster than the cell cycle time, ruling out models of repression in which access of transcription activators to the chromatin is limited and demonstrating that long-term repression primarily reflects mass-action chemical equilibria.

Polycomb group (PcG) proteins and Pax6 cooperate to inhibit in vivo reprogramming of the developing Drosophila eye.

PubMed

Zhu, Jinjin; Ordway, Alison J; Weber, Lena; Buddika, Kasun; Kumar, Justin P

2018-04-04

How different cells and tissues commit to and determine their fates has been a central question in developmental biology since the seminal embryological experiments conducted by Wilhelm Roux and Hans Driesch in sea urchins and frogs. Here, we demonstrate that Polycomb group (PcG) proteins maintain Drosophila eye specification by suppressing the activation of alternative fate choices. The loss of PcG in the developing eye results in a cellular reprogramming event in which the eye is redirected to a wing fate. This fate transformation occurs with either the individual loss of Polycomb proteins or the simultaneous reduction of the Pleiohomeotic repressive complex and Pax6. Interestingly, the requirement for retinal selector genes is limited to Pax6, as the removal of more downstream members does not lead to the eye-wing transformation. We also show that distinct PcG complexes are required during different developmental windows throughout eye formation. These findings build on earlier observations that the eye can be reprogrammed to initiate head epidermis, antennal and leg development. © 2018. Published by The Company of Biologists Ltd.

PGC-1-related coactivator (PRC) negatively regulates endothelial adhesion of monocytes via inhibition of NF κB activity

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

Chengye, Zhan; Daixing, Zhou, E-mail: dxzhou7246@hotmail.com; Qiang, Zhong

2013-09-13

Highlights: •First time to display that LPS downregulate the expression of PRC. •First time to show that PRC inhibits the induction of VCAM-1 and E-selectin. •First time to show that PRC inhibit monocytes attachment to endothelial cells. •First time to display that PRC inhibits transcriptional activity of NF-κB. •PRC protects the respiration rate and suppresses the glycolysis rate against LPS. -- Abstract: PGC-1-related coactivator (PRC) is a growth-regulated transcriptional cofactor known to activate many of the nuclear genes specifying mitochondrial respiratory function. Endothelial dysfunction is a prominent feature found in many inflammatory diseases. Adhesion molecules, such as VCAM-1, mediate themore » attachment of monocytes to endothelial cells, thereby playing an important role in endothelial inflammation. The effects of PRC in regards to endothelial inflammation remain unknown. In this study, our findings show that PRC can be inhibited by the inflammatory cytokine LPS in cultured human umbilical vein endothelial cells (HUVECs). In the presence of LPS, the expression of endothelial cell adhesion molecular, such as VCAM1 and E-selectin, is found to be increased. These effects can be negated by overexpression of PRC. Importantly, monocyte adhesion to endothelial cells caused by LPS is significantly attenuated by PRC. In addition, overexpression of PRC protects mitochondrial metabolic function and suppresses the rate of glycolysis against LPS. It is also found that overexpression of PRC decreases the transcriptional activity of NF-κB. These findings suggest that PRC is a negative regulator of endothelial inflammation.« less

Prenatal alcohol exposure and cellular differentiation: a role for Polycomb and Trithorax group proteins in FAS phenotypes?

PubMed

Veazey, Kylee J; Muller, Daria; Golding, Michael C

2013-01-01

Exposure to alcohol significantly alters the developmental trajectory of progenitor cells and fundamentally compromises tissue formation (i.e., histogenesis). Emerging research suggests that ethanol can impair mammalian development by interfering with the execution of molecular programs governing differentiation. For example, ethanol exposure disrupts cellular migration, changes cell-cell interactions, and alters growth factor signaling pathways. Additionally, ethanol can alter epigenetic mechanisms controlling gene expression. Normally, lineage-specific regulatory factors (i.e., transcription factors) establish the transcriptional networks of each new cell type; the cell's identity then is maintained through epigenetic alterations in the way in which the DNA encoding each gene becomes packaged within the chromatin. Ethanol exposure can induce epigenetic changes that do not induce genetic mutations but nonetheless alter the course of fetal development and result in a large array of patterning defects. Two crucial enzyme complexes--the Polycomb and Trithorax proteins--are central to the epigenetic programs controlling the intricate balance between self-renewal and the execution of cellular differentiation, with diametrically opposed functions. Prenatal ethanol exposure may disrupt the functions of these two enzyme complexes, altering a crucial aspect of mammalian differentiation. Characterizing the involvement of Polycomb and Trithorax group complexes in the etiology of fetal alcohol spectrum disorders will undoubtedly enhance understanding of the role that epigenetic programming plays in this complex disorder.

Near-atomic cryo-EM structure of PRC1 bound to the microtubule.

PubMed

Kellogg, Elizabeth H; Howes, Stuart; Ti, Shih-Chieh; Ramírez-Aportela, Erney; Kapoor, Tarun M; Chacón, Pablo; Nogales, Eva

2016-08-23

Proteins that associate with microtubules (MTs) are crucial to generate MT arrays and establish different cellular architectures. One example is PRC1 (protein regulator of cytokinesis 1), which cross-links antiparallel MTs and is essential for the completion of mitosis and cytokinesis. Here we describe a 4-Å-resolution cryo-EM structure of monomeric PRC1 bound to MTs. Residues in the spectrin domain of PRC1 contacting the MT are highly conserved and interact with the same pocket recognized by kinesin. We additionally found that PRC1 promotes MT assembly even in the presence of the MT stabilizer taxol. Interestingly, the angle of the spectrin domain on the MT surface corresponds to the previously observed cross-bridge angle between MTs cross-linked by full-length, dimeric PRC1. This finding, together with molecular dynamic simulations describing the intrinsic flexibility of PRC1, suggests that the MT-spectrin domain interface determines the geometry of the MT arrays cross-linked by PRC1.

Near-atomic cryo-EM structure of PRC1 bound to the microtubule

PubMed Central

Kellogg, Elizabeth H.; Howes, Stuart; Ti, Shih-Chieh; Ramírez-Aportela, Erney; Kapoor, Tarun M.; Chacón, Pablo; Nogales, Eva

2016-01-01

Proteins that associate with microtubules (MTs) are crucial to generate MT arrays and establish different cellular architectures. One example is PRC1 (protein regulator of cytokinesis 1), which cross-links antiparallel MTs and is essential for the completion of mitosis and cytokinesis. Here we describe a 4-Å–resolution cryo-EM structure of monomeric PRC1 bound to MTs. Residues in the spectrin domain of PRC1 contacting the MT are highly conserved and interact with the same pocket recognized by kinesin. We additionally found that PRC1 promotes MT assembly even in the presence of the MT stabilizer taxol. Interestingly, the angle of the spectrin domain on the MT surface corresponds to the previously observed cross-bridge angle between MTs cross-linked by full-length, dimeric PRC1. This finding, together with molecular dynamic simulations describing the intrinsic flexibility of PRC1, suggests that the MT–spectrin domain interface determines the geometry of the MT arrays cross-linked by PRC1. PMID:27493215

Protein regulator of cytokinesis-1 expression: prognostic value in lung squamous cell carcinoma patients

PubMed Central

Zhan, Ping; Xi, Guang-Min; Liu, Hong-Bing; Liu, Ya-Fang; Xu, Wu-Jian; Zhu, Qingqing; Zhou, Ze-Jun; Miao, Ying-Ying; Wang, Xiao-Xia; Jin, Jia-Jia

2017-01-01

Background Protein regulator of cytokinesis-1 (PRC1) has been shown to participate in the completion of cytokinesis, and it is dysregulated in cancer processes. However, its relevance in lung squamous cell carcinoma (SCC) remained largely unknown. We aimed to study the expression pattern of PRC1 and assess its clinical significance in lung SCC. Methods PRC1 protein expression in human lung SCC and adjacent normal lung tissues was detected by immunohistochemistry. PRC1 expression was assessed in association with clinicopathological features and clinical outcomes of lung SCC patients. Results In lung SCC tissues, PRC1 protein expression was significantly higher than those in paired normal lung tissues. The lung SCC patients with PRC1 overexpression had an advanced pathological stage (TNM stage), positive lymph node metastasis, and a shorter overall survival (OS) time more frequently than patients with low PRC1 expression. Additional, PRC1 expression was also shown to be poor as a prognostic factor for OS in patients with lung SCC. Conclusions Our study indicated that aberrant expression of PRC1 may point to biochemical recurrence in lung SCC. This highlights its potential as a valuable prognostic marker for lung SCC. PMID:28840006

Human phase response curve to a 1 h pulse of bright white light

PubMed Central

St Hilaire, Melissa A; Gooley, Joshua J; Khalsa, Sat Bir S; Kronauer, Richard E; Czeisler, Charles A; Lockley, Steven W

2012-01-01

The phase resetting response of the human circadian pacemaker to light depends on the timing of exposure and is described by a phase response curve (PRC). The current study aimed to construct a PRC for a 1 h exposure to bright white light (∼8000 lux) and to compare this PRC to a <3 lux dim background light PRC. These data were also compared to a previously completed 6.7 h bright white light PRC and a <15 lux dim background light PRC constructed under similar conditions. Participants were randomized for exposure to 1 h of either bright white light (n= 18) or <3 lux dim background light (n= 18) scheduled at 1 of 18 circadian phases. Participants completed constant routine (CR) procedures in dim light (<3 lux) before and after the light exposure to assess circadian phase. Phase shifts were calculated as the difference in timing of dim light melatonin onset (DLMO) during pre- and post-stimulus CRs. Exposure to 1 h of bright white light induced a Type 1 PRC with a fitted peak-to-trough amplitude of 2.20 h. No discernible PRC was observed in the <3 lux dim background light PRC. The fitted peak-to-trough amplitude of the 1 h bright light PRC was ∼40% of that for the 6.7 h PRC despite representing only 15% of the light exposure duration, consistent with previous studies showing a non-linear duration–response function for the effects of light on circadian resetting. PMID:22547633

Human phase response curve to a 1 h pulse of bright white light.

PubMed

St Hilaire, Melissa A; Gooley, Joshua J; Khalsa, Sat Bir S; Kronauer, Richard E; Czeisler, Charles A; Lockley, Steven W

2012-07-01

The phase resetting response of the human circadian pacemaker to light depends on the timing of exposure and is described by a phase response curve (PRC). The current study aimed to construct a PRC for a 1 h exposure to bright white light (∼8000 lux) and to compare this PRC to a <3 lux dim background light PRC. These data were also compared to a previously completed 6.7 h bright white light PRC and a <15 lux dim background light PRC constructed under similar conditions. Participants were randomized for exposure to 1 h of either bright white light (n=18) or <3 lux dim background light (n=18) scheduled at 1 of 18 circadian phases. Participants completed constant routine (CR) procedures in dim light (<3 lux) before and after the light exposure to assess circadian phase. Phase shifts were calculated as the difference in timing of dim light melatonin onset (DLMO) during pre- and post-stimulus CRs. Exposure to 1 h of bright white light induced a Type 1 PRC with a fitted peak-to-trough amplitude of 2.20 h. No discernible PRC was observed in the <3 lux dim background light PRC. The fitted peak-to-trough amplitude of the 1 h bright light PRC was ∼40% of that for the 6.7 h PRC despite representing only 15% of the light exposure duration, consistent with previous studies showing a non-linear duration–response function for the effects of light on circadian resetting.

Regulation of gene transcription by Polycomb proteins

PubMed Central

Aranda, Sergi; Mas, Gloria; Di Croce, Luciano

2015-01-01

The Polycomb group (PcG) of proteins defines a subset of factors that physically associate and function to maintain the positional identity of cells from the embryo to adult stages. PcG has long been considered a paradigmatic model for epigenetic maintenance of gene transcription programs. Despite intensive research efforts to unveil the molecular mechanisms of action of PcG proteins, several fundamental questions remain unresolved: How many different PcG complexes exist in mammalian cells? How are PcG complexes targeted to specific loci? How does PcG regulate transcription? In this review, we discuss the diversity of PcG complexes in mammalian cells, examine newly identified modes of recruitment to chromatin, and highlight the latest insights into the molecular mechanisms underlying the function of PcGs in transcription regulation and three-dimensional chromatin conformation. PMID:26665172

Genome-wide analysis of Polycomb targets in Drosophila

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

Schwartz, Yuri B.; Kahn, Tatyana G.; Nix, David A.

2006-04-01

Polycomb Group (PcG) complexes are multiprotein assemblages that bind to chromatin and establish chromatin states leading to epigenetic silencing. PcG proteins regulate homeotic genes in flies and vertebrates but little is known about other PcG targets and the role of the PcG in development, differentiation and disease. We have determined the distribution of the PcG proteins PC, E(Z) and PSC and of histone H3K27 trimethylation in the Drosophila genome. At more than 200 PcG target genes, binding sites for the three PcG proteins colocalize to presumptive Polycomb Response Elements (PREs). In contrast, H3 me3K27 forms broad domains including the entiremore » transcription unit and regulatory regions. PcG targets are highly enriched in genes encoding transcription factors but receptors, signaling proteins, morphogens and regulators representing all major developmental pathways are also included.« less

Distinct neuroanatomical bases of episodic and semantic memory performance in Alzheimer's disease.

PubMed

Hirni, Daniela I; Kivisaari, Sasa L; Monsch, Andreas U; Taylor, Kirsten I

2013-04-01

Alzheimer's disease (AD) neurofibrillary pathology begins in the medial perirhinal cortex (mPRC) before spreading to the entorhinal cortex (ERC) and hippocampus (HP) in anterior medial temporal lobe (aMTL). While the role of the ERC/HP complex in episodic memory formation is well-established, recent research suggests that the PRC is required to form semantic memories of individual objects. We aimed to test whether commonly used clinical measures of episodic and semantic memory are distinctly associated with ERC/HP and mPRC integrity, respectively, in healthy mature individuals and very early AD patients. One hundred thirty normal controls, 32 amnestic mild cognitive impairment patients, some of whom are in the earliest (i.e., preclinical) stages of AD, and ten early-stage AD patients received neuropsychological testing and high-resolution anatomic and diffusion MRI. Voxel-based regression analyses tested for regions where episodic memory (delayed recall scores on the California Verbal Learning and Rey Osterrieth Complex Figure Tests) and semantic memory (Boston Naming Test, category fluency) performance correlated with gray matter (GM) regions of interest and whole-brain fractional anisotropy (FA) voxel values. When controlling for the opposing memory performance, poorer episodic memory performance was associated with reduced bilateral ERC/HP GM volume and related white matter integrity, but not with mPRC GM volume. Poor semantic memory performance was associated with both reduced left mPRC and ERC/HP GM volume, as well as reduced FA values in white matter tracts leading to the PRC. These results indicate a partial division of labor within the aMTL and suggest that mPRC damage in very early AD may be detectable with common clinical tests of semantic memory if episodic memory performance is controlled. Copyright © 2013 Elsevier Ltd. All rights reserved.

Long Noncoding RNA MEG3 Is an Epigenetic Determinant of Oncogenic Signaling in Functional Pancreatic Neuroendocrine Tumor Cells

PubMed Central

Iyer, Sucharitha; Modali, Sita D.

2017-01-01

ABSTRACT The long noncoding RNA (lncRNA) MEG3 is significantly downregulated in pancreatic neuroendocrine tumors (PNETs). MEG3 loss corresponds with aberrant upregulation of the oncogenic hepatocyte growth factor (HGF) receptor c-MET in PNETs. Meg3 overexpression in a mouse insulin-secreting PNET cell line, MIN6, downregulates c-Met expression. However, the molecular mechanism by which MEG3 regulates c-MET is not known. Using chromatin isolation by RNA purification and sequencing (ChIRP-Seq), we identified Meg3 binding to unique genomic regions in and around the c-Met gene. In the absence of Meg3, these c-Met regions displayed distinctive enhancer-signature histone modifications. Furthermore, Meg3 relied on functional enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), to inhibit c-Met expression. Another mechanism of lncRNA-mediated regulation of gene expression utilized triplex-forming GA-GT rich sequences. Transfection of such motifs from Meg3 RNA, termed triplex-forming oligonucleotides (TFOs), in MIN6 cells suppressed c-Met expression and enhanced cell proliferation, perhaps by modulating other targets. This study comprehensively establishes epigenetic mechanisms underlying Meg3 control of c-Met and the oncogenic consequences of Meg3 loss or c-Met gain. These findings have clinical relevance for targeting c-MET in PNETs. There is also the potential for pancreatic islet β-cell expansion through c-MET regulation to ameliorate β-cell loss in diabetes. PMID:28847847

Activation of a PGC-1-related Coactivator (PRC)-dependent Inflammatory Stress Program Linked to Apoptosis and Premature Senescence*

PubMed Central

Gleyzer, Natalie; Scarpulla, Richard C.

2013-01-01

PGC-1-related coactivator (PRC), a growth-regulated member of the PGC-1 coactivator family, contributes to the expression of the mitochondrial respiratory apparatus. PRC also orchestrates a robust response to metabolic stress by promoting the expression of multiple genes specifying inflammation, proliferation, and metabolic reprogramming. Here, we demonstrate that this PRC-dependent stress program is activated during apoptosis and senescence, two major protective mechanisms against cellular dysfunction. Both PRC and its targets (IL1α, SPRR2D, and SPRR2F) were rapidly induced by menadione, an agent that promotes apoptosis through the generation of intracellular oxidants. Menadione-induced apoptosis and the PRC stress program were blocked by the antioxidant N-acetylcysteine. The PRC stress response was also activated by the topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN-38), an inducer of premature senescence in tumor cells. Cells treated with SN-38 displayed morphological characteristics of senescence and express senescence-associated β-galactosidase activity. In contrast to menadione, the SN-38 induction of the PRC program occurred over an extended time course and was antioxidant-insensitive. The potential adaptive function of the PRC stress response was investigated by treating cells with meclizine, a drug that promotes glycolytic energy metabolism and has been linked to cardio- and neuroprotection against ischemia-reperfusion injury. Meclizine increased lactate production and was a potent inducer of the PRC stress program, suggesting that PRC may contribute to the protective effects of meclizine. Finally, c-MYC and PRC were coordinately induced under all conditions tested, implicating c-MYC in the biological response to metabolic stress. The results suggest a general role for PRC in the adaptive response to cellular dysfunction. PMID:23364789

Evidence for Alteration of EZH2, BMI1, and KDM6A and Epigenetic Reprogramming in Human Papillomavirus Type 16 E6/E7-Expressing Keratinocytes ▿

PubMed Central

Hyland, Paula L.; McDade, Simon S.; McCloskey, Rachel; Dickson, Glenda J.; Arthur, Ken; McCance, Dennis J.; Patel, Daksha

2011-01-01

A number of epigenetic alterations occur in both the virus and host cellular genomes during human papillomavirus (HPV)-associated carcinogenesis, and investigations of such alterations, including changes in chromatin proteins and histone modifications, have the potential to lead to therapeutic epigenetic reversion. We report here that transformed HPV16 E6/E7-expressing primary human foreskin keratinocytes (HFKs) (E6/E7 cells) demonstrate increased expression of the PRC2 methyltransferase EZH2 at both the mRNA and protein levels but do not exhibit the expected increase in trimethylated H3K27 (H3K27me3) compared to normal keratinocytes. In contrast, these cells show a reduction in global H3K27me3 levels in vitro, as well as upregulation of the KDM6A demethylase. We further show for the first time that transformation with the HPV16 E6 and E7 oncogenes also results in an increase in phosphorylated EZH2 serine 21 (P-EZH2-Ser21), mediated by active Akt, and in a downregulation of the PRC1 protein BMI1 in these cells. High-grade squamous cervical intraepithelial lesions also showed a loss of H3K27me3 in the presence of increased expression of EZH2. Correlating with the loss of H3K27me3, E6/E7 cells exhibited derepression of specific EZH2-, KMD6A-, and BMI1-targeted HOX genes. These results suggest that the observed reduction in H3K27me3 may be due to a combination of reduced activities/levels of specific polycomb proteins and increases in demethylases. The dysregulation of multiple chromatin proteins resulting in the loss of global H3K27me3 and the transcriptional reprogramming in HPV16 E6/E7-infected cells could provide an epigenetic signature associated with risk and/or progression of HPV16-associated cancers, as well as the potential for epigenetic reversion in the future. PMID:21865393

Evidence for alteration of EZH2, BMI1, and KDM6A and epigenetic reprogramming in human papillomavirus type 16 E6/E7-expressing keratinocytes.

PubMed

Hyland, Paula L; McDade, Simon S; McCloskey, Rachel; Dickson, Glenda J; Arthur, Ken; McCance, Dennis J; Patel, Daksha

2011-11-01

A number of epigenetic alterations occur in both the virus and host cellular genomes during human papillomavirus (HPV)-associated carcinogenesis, and investigations of such alterations, including changes in chromatin proteins and histone modifications, have the potential to lead to therapeutic epigenetic reversion. We report here that transformed HPV16 E6/E7-expressing primary human foreskin keratinocytes (HFKs) (E6/E7 cells) demonstrate increased expression of the PRC2 methyltransferase EZH2 at both the mRNA and protein levels but do not exhibit the expected increase in trimethylated H3K27 (H3K27me3) compared to normal keratinocytes. In contrast, these cells show a reduction in global H3K27me3 levels in vitro, as well as upregulation of the KDM6A demethylase. We further show for the first time that transformation with the HPV16 E6 and E7 oncogenes also results in an increase in phosphorylated EZH2 serine 21 (P-EZH2-Ser21), mediated by active Akt, and in a downregulation of the PRC1 protein BMI1 in these cells. High-grade squamous cervical intraepithelial lesions also showed a loss of H3K27me3 in the presence of increased expression of EZH2. Correlating with the loss of H3K27me3, E6/E7 cells exhibited derepression of specific EZH2-, KMD6A-, and BMI1-targeted HOX genes. These results suggest that the observed reduction in H3K27me3 may be due to a combination of reduced activities/levels of specific polycomb proteins and increases in demethylases. The dysregulation of multiple chromatin proteins resulting in the loss of global H3K27me3 and the transcriptional reprogramming in HPV16 E6/E7-infected cells could provide an epigenetic signature associated with risk and/or progression of HPV16-associated cancers, as well as the potential for epigenetic reversion in the future.

Interactions of Memory and Perception in Amnesia: The Figure–Ground Perspective

PubMed Central

Ngo, Joan K. W.; Hung, Lily H. T.; Peterson, Mary A.

2012-01-01

The medial temporal lobes (MTLs) have been thought to function exclusively in service of declarative memory. Recent research shows that damage to the perirhinal cortex (PRC) of the MTL impairs the discrimination of objects sharing many similar parts/features, leading to the hypothesis that the PRC contributes to the perception when the feature configurations, rather than the individual features, are required to solve the task. It remains uncertain, however, whether the previous research demands a slight extension of PRC function to include working memory or a more dramatic extension to include perception. We present 2 experiments assessing the implicit effects of familiar configuration on figure assignment, an early and fundamental perceptual outcome. Unlike controls, PRC-damaged individuals failed to perceive the regions portraying familiar configurations, as figure more often, than the regions comprising the same parts rearranged into novel configurations. They were also impaired in identifying the familiar objects. In a third experiment, PRC-damaged individuals performed poorly when asked to choose a familiar object from pairs of familiar and novel objects comprising the same parts. Our results demonstrate that the PRC is involved in both implicit and explicit perceptual discriminations of novel and familiar configurations. These results reveal that complex object representations in the PRC subserve both perception and memory. PMID:22172579

Interactions of memory and perception in amnesia: the figure-ground perspective.

PubMed

Barense, Morgan D; Ngo, Joan K W; Hung, Lily H T; Peterson, Mary A

2012-11-01

The medial temporal lobes (MTLs) have been thought to function exclusively in service of declarative memory. Recent research shows that damage to the perirhinal cortex (PRC) of the MTL impairs the discrimination of objects sharing many similar parts/features, leading to the hypothesis that the PRC contributes to the perception when the feature configurations, rather than the individual features, are required to solve the task. It remains uncertain, however, whether the previous research demands a slight extension of PRC function to include working memory or a more dramatic extension to include perception. We present 2 experiments assessing the implicit effects of familiar configuration on figure assignment, an early and fundamental perceptual outcome. Unlike controls, PRC-damaged individuals failed to perceive the regions portraying familiar configurations, as figure more often, than the regions comprising the same parts rearranged into novel configurations. They were also impaired in identifying the familiar objects. In a third experiment, PRC-damaged individuals performed poorly when asked to choose a familiar object from pairs of familiar and novel objects comprising the same parts. Our results demonstrate that the PRC is involved in both implicit and explicit perceptual discriminations of novel and familiar configurations. These results reveal that complex object representations in the PRC subserve both perception and memory.

How to harvest solar energy with the photosynthetic reaction center

NASA Astrophysics Data System (ADS)

Balaeff, Alexander; Reyes, Justin

Photosynthetic reaction center (PRC) is a protein complex that performs a key step in photosynthesis: the electron-hole separation driven by photon absorbtion. The PRC has a great promise for applications in solar energy harvesting and photosensing. Such applications, however, are hampered by the difficulty in extracting the photogenerated electric charge from the PRC. To that end, it was proposed to attach the PRC to a molecular wire through which the charge could be collected. In order to find the attachment point for the wire that would maximize the rate of charge outflow from the PRC, we performed a computational study of the PRC from the R. virdis bacterium. An ensemble of PRC structures generated by a molecular dynamics simulation was used to calculate the rate of charge transport from the site of initial charge separation to several trial sites on the protein surface. The Pathways model was used to calculate the charge transfer rate in each step of the network of heme co-factors through which the charge transport was presumed to proceed. A simple kinetic model was then used to determine the overall rate of the multistep charge transport. The calculations revealed several candidate sites for the molecular wire attachment, recommended for experimental verification.

A Genetic Analysis of the Suppressor 2 of Zeste Complex of Drosophila Melanogaster

PubMed Central

Wu, C. T.; Howe, M.

1995-01-01

The zeste(1) (z(1)) mutation of Drosophila melanogaster produces a mutant yellow eye color instead of the wild-type red. Genetic and molecular data suggest that z(1) achieves this change by altering expression of the wild-type white gene in a manner that exhibits transvection effects. There exist suppressor and enhancer mutations that modify the z(1) eye color, and this paper summarizes our studies of those belonging to the Suppressor 2 of zeste complex [Su(z)2-C]. The Su(z)2-C consists of at least three subregions called Psc (Posterior sex combs), Su(z)2 and Su(z)2D (Distal). The products of these subregions are proposed to act at the level of chromatin. Complementation analyses predict that the products are functionally similar and interacting. The alleles of Psc define two overlapping phenotypic classes, the hopeful and hapless. The distinctions between these two classes and the intragenic complementation seen among some of the Psc alleles are consistent with a multidomain structure for the product of Psc. Psc is a member of the homeotic Polycomb group of genes. A general discussion of the Polycomb and trithorax group of genes, position-effect variegation, transvection, chromosome pairing and chromatin structure is presented. PMID:7635282

The nuclear receptor NR2E1/TLX controls senescence.

PubMed

O'Loghlen, Ana; Martin, Nadine; Krusche, Benjamin; Pemberton, Helen; Alonso, Marta M; Chandler, Hollie; Brookes, Sharon; Parrinello, Simona; Peters, Gordon; Gil, Jesús

2015-07-30

The nuclear receptor NR2E1 (also known as TLX or tailless) controls the self-renewal of neural stem cells (NSCs) and has been implied as an oncogene which initiates brain tumors including glioblastomas. Despite NR2E1 regulating targets like p21(CIP1) or PTEN we still lack a full explanation for its role in NSC self-renewal and tumorigenesis. We know that polycomb repressive complexes also control stem cell self-renewal and tumorigenesis, but so far, no formal connection has been established between NR2E1 and PRCs. In a screen for transcription factors regulating the expression of the polycomb protein CBX7, we identified NR2E1 as one of its more prominent regulators. NR2E1 binds at the CBX7 promoter, inducing its expression. Notably CBX7 represses NR2E1 as part of a regulatory loop. Ectopic NR2E1 expression inhibits cellular senescence, extending cellular lifespan in fibroblasts via CBX7-mediated regulation of p16(INK4a) and direct repression of p21(CIP1). In addition NR2E1 expression also counteracts oncogene-induced senescence. The importance of NR2E1 to restrain senescence is highlighted through the process of knocking down its expression, which causes premature senescence in human fibroblasts and epithelial cells. We also confirmed that NR2E1 regulates CBX7 and restrains senescence in NSCs. Finally, we observed that the expression of NR2E1 directly correlates with that of CBX7 in human glioblastoma multiforme. Overall we identified control of senescence and regulation of polycomb action as two possible mechanisms that can join those so far invoked to explain the role of NR2E1 in control of NSC self-renewal and cancer.

GSK126 (EZH2 inhibitor) interferes with ultraviolet A radiation-induced photoaging of human skin fibroblast cells

PubMed Central

Qin, Haiyan; Zhang, Guang; Zhang, Lianbo

2018-01-01

Polycomb group genes (PcG) encode chromatin modification proteins that are involved in the epigenetic regulation of cell differentiation, proliferation and the aging processes. The key subunit of the PcG complex, enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), has a central role in a variety of mechanisms, such as the formation of chromatin structure, gene expression regulation and DNA damage. In the present study, ultraviolet A (UVA) was used to radiate human dermal fibroblasts in order to construct a photo-aged cell model. Subsequently, the cell viability assay, Hoechst staining, apoptosis detection using flow cytometry, senescence-associated β-galactosidase (SA-β-gal) staining and erythrocyte exclusion experiments were performed. GSK126, a histone methylation enzyme inhibitor of EZH2, was used as an experimental factor. Results suggested that GSK126 downregulated the mRNA expression levels of EZH2 and upregulated the mRNA expression levels of BMI-1. Notably, GSK126 affected the transcription of various photoaging-related genes and thus protected against photoaging induced by UVA radiation. PMID:29545866

Sediment storage and transport in Pancho Rico Valley during and after the Pleistocene-Holocene transition, Coast Ranges of central California (Monterey County)

USGS Publications Warehouse

Garcia, A.F.; Mahan, S.A.

2009-01-01

Factors influencing sediment transport and storage within the 156??6 km2 drainage basin of Pancho Rico Creek (PRC), and sediment transport from the PRC drainage basin to its c. 11000 km2 mainstem drainage (Salinas River) are investigated. Numeric age estimates are determined by optically stimulated luminescence (OSL) dating on quartz grains from three sediment samples collected from a 'quaternary terrace a (Qta)' PRC terrace/PRC-tributary fan sequence, which consists dominantly of debris flow deposits overlying fluvial sediments. OSL dating results, morphometric analyses of topography, and field results indicate that the stormy climate of the Pleistocene-Holocene transition caused intense debris-flow erosion of PRC- tributary valleys. However, during that time, the PRC channel was backfilled by Qta sediment, which indicates that there was insufficient discharge in PRC to transport the sediment load produced by tributary-valley denudation. Locally, Salinas Valley alluvial stratigraphy lacks any record of hillslope erosion occurring during the Pleistocene-Holocene transition, in that the alluvial fan formed where PRC enters the Salinas Valley lacks lobes correlative to Qta. This indicates that sediment stripped from PRC tributaries was mostly trapped in Pancho Rico Valley despite the relatively moist climate of the Pleistocene-Holocene transition. Incision into Qta did not occur until PRC enlarged its drainage basin by c. 50% through capture of the upper part of San Lorenzo Creek, which occurred some time after the Pleistocene-Holocene transition. During the relatively dry Holocene, PRC incision through Qta and into bedrock, as well as delivery of sediment to the San Ardo Fan, were facilitated by the discharge increase associated with stream-capture. The influence of multiple mechanisms on sediment storage and transport in the Pancho Rico Valley-Salinas Valley system exemplifies the complexity that (in some instances) must be recognized in order to correctly interpret terrestrial sedimentary sequences in tectonically active areas. ?? 2009 John Wiley & Sons, Ltd.

Trithorax monomethylates histone H3K4 and interacts directly with CBP to promote H3K27 acetylation and antagonize Polycomb silencing

PubMed Central

Tie, Feng; Banerjee, Rakhee; Saiakhova, Alina R.; Howard, Benny; Monteith, Kelsey E.; Scacheri, Peter C.; Cosgrove, Michael S.; Harte, Peter J.

2014-01-01

Trithorax (TRX) antagonizes epigenetic silencing by Polycomb group (PcG) proteins, stimulates enhancer-dependent transcription, and establishes a ‘cellular memory’ of active transcription of PcG-regulated genes. The mechanisms underlying these TRX functions remain largely unknown, but are presumed to involve its histone H3K4 methyltransferase activity. We report that the SET domains of TRX and TRX-related (TRR) have robust histone H3K4 monomethyltransferase activity in vitro and that Tyr3701 of TRX and Tyr2404 of TRR prevent them from being trimethyltransferases. The trxZ11 missense mutation (G3601S), which abolishes H3K4 methyltransferase activity in vitro, reduces the H3K4me1 but not the H3K4me3 level in vivo. trxZ11 also suppresses the impaired silencing phenotypes of the Pc3 mutant, suggesting that H3K4me1 is involved in antagonizing Polycomb silencing. Polycomb silencing is also antagonized by TRX-dependent H3K27 acetylation by CREB-binding protein (CBP). We show that perturbation of Polycomb silencing by TRX overexpression requires CBP. We also show that TRX and TRR are each physically associated with CBP in vivo, that TRX binds directly to the CBP KIX domain, and that the chromatin binding patterns of TRX and TRR are highly correlated with CBP and H3K4me1 genome-wide. In vitro acetylation of H3K27 by CBP is enhanced on K4me1-containing H3 substrates, and independently altering the H3K4me1 level in vivo, via the H3K4 demethylase LSD1, produces concordant changes in H3K27ac. These data indicate that the catalytic activities of TRX and CBP are physically coupled and suggest that both activities play roles in antagonizing Polycomb silencing, stimulating enhancer activity and cellular memory. PMID:24550119

Structure of the ribosome post-recycling complex probed by chemical cross-linking and mass spectrometry

PubMed Central

Kiosze-Becker, Kristin; Ori, Alessandro; Gerovac, Milan; Heuer, André; Nürenberg-Goloub, Elina; Rashid, Umar Jan; Becker, Thomas; Beckmann, Roland; Beck, Martin; Tampé, Robert

2016-01-01

Ribosome recycling orchestrated by the ATP binding cassette (ABC) protein ABCE1 can be considered as the final—or the first—step within the cyclic process of protein synthesis, connecting translation termination and mRNA surveillance with re-initiation. An ATP-dependent tweezer-like motion of the nucleotide-binding domains in ABCE1 transfers mechanical energy to the ribosome and tears the ribosome subunits apart. The post-recycling complex (PRC) then re-initiates mRNA translation. Here, we probed the so far unknown architecture of the 1-MDa PRC (40S/30S·ABCE1) by chemical cross-linking and mass spectrometry (XL-MS). Our study reveals ABCE1 bound to the translational factor-binding (GTPase) site with multiple cross-link contacts of the helix–loop–helix motif to the S24e ribosomal protein. Cross-linking of the FeS cluster domain to the ribosomal protein S12 substantiates an extreme lever-arm movement of the FeS cluster domain during ribosome recycling. We were thus able to reconstitute and structurally analyse a key complex in the translational cycle, resembling the link between translation initiation and ribosome recycling. PMID:27824037

78 FR 24101 - Generator Requirements at the Transmission Interface

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-24

... (Transmission Vegetation Management), PRC-004- 2.1a (Analysis and Mitigation of Transmission and Generation Protection System Misoperations), and PRC-005-1.1b (Transmission and Generation Protection System Maintenance... (Transmission Vegetation Management), PRC-004- 2.1a (Analysis and Mitigation of Transmission and Generation...

[RESEARCH PROGRESS OF BIOMECHANICS OF PROXIMAL ROW CARPAL INSTABILITY].

PubMed

Guo, Jinhai; Huang, Fuguo

2015-01-01

To review the research progress of the biomechanics of proximal row carpal instability (IPRC). The related literature concerning IPRC was extensively reviewed. The biomechanical mechanism of the surrounding soft tissue in maintaining the stability of the proximal row carpal (PRC) was analyzed, and the methods to repair or reconstruct the stability and function of the PRC were summarized from two aspects including basic biomechanics and clinical biomechanics. The muscles and ligaments of the PRC are critical to its stability. Most scholars have reached a consensus about biomechanical mechanism of the PRC, but there are still controversial conclusions on the biomechanics mechanism of the surrounding soft tissue to stability of distal radioulnar joint when the triangular fibrocartilage complex are damaged and the biomechanics mechanism of the scapholunate ligament. At present, there is no unified standard about the methods to repair or reconstruct the stability and function of the PRC. So, it is difficult for clinical practice. Some strides have been made in the basic biomechanical study on muscle and ligament and clinical biomechanical study on the methods to repair or reconstruct the stability and function of PRC, but it will be needed to further study the morphology of carpal articular surface and the adjacent articular surface, the pressure of distal carpals to proximal carpal and so on.

High expression of Polycomb group protein EZH2 predicts poor survival in salivary gland adenoid cystic carcinoma.

PubMed

Vékony, H; Raaphorst, F M; Otte, A P; van Lohuizen, M; Leemans, C R; van der Waal, I; Bloemena, E

2008-06-01

The prognosis of adenoid cystic carcinoma (ACC), a malignant salivary gland tumour, depends on clinicopathological parameters. To decipher the biological behaviour of ACC, and to identify patients at risk of developing metastases, additional markers are needed. Expression of the cell cycle proteins p53, cyclin D1, p16(INK4a), E2F1 and Ki-67, together with the Polycomb group (PcG) proteins BMI-1, MEL-18, EZH2 and EED was investigated immunohistochemically 21 formalin-fixed, paraffin-embedded primary ACCs in relation to tumour characteristics. ACC revealed significantly increased expression of the cell cycle proteins compared to normal salivary tissue (n = 17). Members of the two PcG complexes displayed mutually exclusive expression in normal salivary gland tissue, with BMI-1 and MEL-18 being abundantly present. In ACC, this expression pattern was disturbed, with EZH2 and EED showing significantly increased expression levels. In univariate analysis, presence of recurrence, poor differentiation and high EZH2 levels (>25% immunopositivity) significantly correlated with unfavourable outcome. ACCs with high proliferative rate (>25% Ki-67 immunopositivity) significantly correlated with high levels of EZH2 and p16. Only the development of recurrence was an independent prognostic factor of survival in multivariate analysis. Expression of PcG complexes and of essential cell cycle proteins is highly deregulated in ACC. Also, EZH2 expression has prognostic relevance in this malignancy.

EZH2-mediated repression of GSK-3β and TP53 promotes Wnt/β-catenin signaling-dependent cell expansion in cervical carcinoma.

PubMed

Chen, Qian; Zheng, Peng-Sheng; Yang, Wen-Ting

2016-06-14

Enhancer of zeste homolog 2 (EZH2), a catalytic core component of the Polycomb repressive complex 2 (PRC2), stimulates the silencing of target genes through histone H3 lysine 27 trimethylation (H3K27me3). Recent findings have indicated EZH2 is involved in the development and progression of various human cancers. However, the exact mechanism of EZH2 in the promotion of cervical cancer is largely unknown. Here, we show that EZH2 expression gradually increases during the progression of cervical cancer. We identified a significant positive correlation between EZH2 expression and cell proliferation in vitro and tumor formation in vivo by the up-regulation or down-regulation of EZH2 using CRISPR-Cas9-mediated gene editing technology and shRNA in HeLa and SiHa cells. Further investigation indicated that EZH2 protein significantly accelerated the cell cycle transition from the G0/G1 to S phase. TOP/FOP-Flash reporter assay revealed that EZH2 significantly activated Wnt/β-catenin signaling and the target genes of Wnt/β-catenin pathway were up-regulated, including β-catenin, cyclin D1, and c-myc. Moreover, dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays confirmed that EZH2 inhibited the expression of glycogen synthase kinase-3β (GSK-3β) and TP53 through physically interacting with motifs in the promoters of the GSK-3β and TP53 genes. Additionally, blockage of the Wnt/β-catenin pathway resulted in significant inhibition of cell proliferation, and activation of the Wnt/β-catenin pathway resulted in significant enhancement of cell proliferation, as induced by EZH2. Taken together, our data demonstrate that EZH2 promotes cell proliferation and tumor formation in cervical cancer through activating the Wnt/β-catenin pathway by epigenetic silencing via GSK-3β and TP53.

EZH2-mediated repression of GSK-3β and TP53 promotes Wnt/β-catenin signaling-dependent cell expansion in cervical carcinoma

PubMed Central

Chen, Qian; Zheng, Peng-Sheng; Yang, Wen-Ting

2016-01-01

Enhancer of zeste homolog 2 (EZH2), a catalytic core component of the Polycomb repressive complex 2 (PRC2), stimulates the silencing of target genes through histone H3 lysine 27 trimethylation (H3K27me3). Recent findings have indicated EZH2 is involved in the development and progression of various human cancers. However, the exact mechanism of EZH2 in the promotion of cervical cancer is largely unknown. Here, we show that EZH2 expression gradually increases during the progression of cervical cancer. We identified a significant positive correlation between EZH2 expression and cell proliferation in vitro and tumor formation in vivo by the up-regulation or down-regulation of EZH2 using CRISPR-Cas9-mediated gene editing technology and shRNA in HeLa and SiHa cells. Further investigation indicated that EZH2 protein significantly accelerated the cell cycle transition from the G0/G1 to S phase. TOP/FOP-Flash reporter assay revealed that EZH2 significantly activated Wnt/β-catenin signaling and the target genes of Wnt/β-catenin pathway were up-regulated, including β-catenin, cyclin D1, and c-myc. Moreover, dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays confirmed that EZH2 inhibited the expression of glycogen synthase kinase-3β (GSK-3β) and TP53 through physically interacting with motifs in the promoters of the GSK-3β and TP53 genes. Additionally, blockage of the Wnt/β-catenin pathway resulted in significant inhibition of cell proliferation, and activation of the Wnt/β-catenin pathway resulted in significant enhancement of cell proliferation, as induced by EZH2. Taken together, our data demonstrate that EZH2 promotes cell proliferation and tumor formation in cervical cancer through activating the Wnt/β-catenin pathway by epigenetic silencing via GSK-3β and TP53. PMID:27092879

A simple ERP method for quantitative analysis of cognitive workload in myoelectric prosthesis control and human-machine interaction.

PubMed

Deeny, Sean; Chicoine, Caitlin; Hargrove, Levi; Parrish, Todd; Jayaraman, Arun

2014-01-01

Common goals in the development of human-machine interface (HMI) technology are to reduce cognitive workload and increase function. However, objective and quantitative outcome measures assessing cognitive workload have not been standardized for HMI research. The present study examines the efficacy of a simple event-related potential (ERP) measure of cortical effort during myoelectric control of a virtual limb for use as an outcome tool. Participants trained and tested on two methods of control, direct control (DC) and pattern recognition control (PRC), while electroencephalographic (EEG) activity was recorded. Eighteen healthy participants with intact limbs were tested using DC and PRC under three conditions: passive viewing, easy, and hard. Novel auditory probes were presented at random intervals during testing, and significant task-difficulty effects were observed in the P200, P300, and a late positive potential (LPP), supporting the efficacy of ERPs as a cognitive workload measure in HMI tasks. LPP amplitude distinguished DC from PRC in the hard condition with higher amplitude in PRC, consistent with lower cognitive workload in PRC relative to DC for complex movements. Participants completed trials faster in the easy condition using DC relative to PRC, but completed trials more slowly using DC relative to PRC in the hard condition. The results provide promising support for ERPs as an outcome measure for cognitive workload in HMI research such as prosthetics, exoskeletons, and other assistive devices, and can be used to evaluate and guide new technologies for more intuitive HMI control.

H3K27 methylation and H3S28 phosphorylation-dependent transcriptional regulation by INHAT subunit SET/TAF-Iβ.

PubMed

Kim, Ji-Young; Kim, Kee-Beom; Son, Hye-Ju; Chae, Yun-Cheol; Oh, Si-Taek; Kim, Dong-Wook; Pak, Jhang Ho; Seo, Sang-Beom

2012-09-21

Significant progress has been made in understanding the relationship between histone modifications and 'reader' molecules and their effects on transcriptional regulation. A previously identified INHAT complex subunit, SET/TAF-Iβ, binds to histones and inhibits histone acetylation. To investigate the binding specificities of SET/TAF-Iβ to various histone modifications, we employed modified histone tail peptide array analyses. SET/TAF-Iβ strongly recognized PRC2-mediated H3K27me1/2/3; however, the bindings were completely disrupted by H3S28 phosphorylation. We have demonstrated that SET/TAF-Iβ is sequentially recruited to the target gene promoter ATF3 after the PRC2 complex via H3K27me recognition and may offer additive effects in the repression of the target gene. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Noncoding RNAs of the Ultrabithorax Domain of the Drosophila Bithorax Complex

PubMed Central

Pease, Benjamin; Borges, Ana C.; Bender, Welcome

2013-01-01

RNA transcripts without obvious coding potential are widespread in many creatures, including the fruit fly, Drosophila melanogaster. Several noncoding RNAs have been identified within the Drosophila bithorax complex. These first appear in blastoderm stage embryos, and their expression patterns indicate that they are transcribed only from active domains of the bithorax complex. It has been suggested that these noncoding RNAs have a role in establishing active domains, perhaps by setting the state of Polycomb Response Elements A comprehensive survey across the proximal half of the bithorax complex has now revealed nine distinct noncoding RNA transcripts, including four within the Ultrabithorax transcription unit. At the blastoderm stage, the noncoding transcripts collectively span ∼75% of the 135 kb surveyed. Recombination-mediated cassette exchange was used to invert the promoter of one of the noncoding RNAs, a 23-kb transcript from the bxd domain of the bithorax complex. The resulting animals fail to make the normal bxd noncoding RNA and show no transcription across the bxd Polycomb Response Element in early embryos. The mutant flies look normal; the regulation of the bxd domain appears unaffected. Thus, the bxd noncoding RNA has no apparent function. PMID:24077301

Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas.

PubMed

Sneeringer, Christopher J; Scott, Margaret Porter; Kuntz, Kevin W; Knutson, Sarah K; Pollock, Roy M; Richon, Victoria M; Copeland, Robert A

2010-12-07

EZH2, the catalytic subunit of the PRC2 complex, catalyzes the mono- through trimethylation of lysine 27 on histone H3 (H3K27). Histone H3K27 trimethylation is a mechanism for suppressing transcription of specific genes that are proximal to the site of histone modification. Point mutations of the EZH2 gene (Tyr641) have been reported to be linked to subsets of human B-cell lymphoma. The mutant allele is always found associated with a wild-type allele (heterozygous) in disease cells, and the mutations were reported to ablate the enzymatic activity of the PRC2 complex for methylating an unmodified peptide substrate. Here we demonstrate that the WT enzyme displays greatest catalytic efficiency (k(cat)/K) for the zero to monomethylation reaction of H3K27 and diminished efficiency for subsequent (mono- to di- and di- to trimethylation) reactions. In stark contrast, the disease-associated Y641 mutations display very limited ability to perform the first methylation reaction, but have enhanced catalytic efficiency for the subsequent reactions, relative to the WT enzyme. These results imply that the malignant phenotype of disease requires the combined activities of a H3K27 monomethylating enzyme (PRC2 containing WT EZH2 or EZH1) together with the mutant PRC2s for augmented conversion of H3K27 to the trimethylated form. To our knowledge, this is the first example of a human disease that is dependent on the coordinated activities of normal and disease-associated mutant enzymatic function.

Memory-guided drawing training increases Granger causal influences from the perirhinal cortex to V1 in the blind.

PubMed

Cacciamani, Laura; Likova, Lora T

2017-05-01

The perirhinal cortex (PRC) is a medial temporal lobe structure that has been implicated in not only visual memory in the sighted, but also tactile memory in the blind (Cacciamani & Likova, 2016). It has been proposed that, in the blind, the PRC may contribute to modulation of tactile memory responses that emerge in low-level "visual" area V1 as a result of training-induced cortical reorganization (Likova, 2012, 2015). While some studies in the sighted have indicated that the PRC is indeed structurally and functionally connected to the visual cortex (Clavagnier, Falchier, & Kennedy, 2004; Peterson, Cacciamani, Barense, & Scalf, 2012), the PRC's direct modulation of V1 is unknown-particularly in those who lack the visual input that typically stimulates this region. In the present study, we tested Likova's PRC modulation hypothesis; specifically, we used fMRI to assess the PRC's Granger causal influence on V1 activation in the blind during a tactile memory task. To do so, we trained congenital and acquired blind participants on a unique memory-guided drawing technique previously shown to result in V1 reorganization towards tactile memory representations (Likova, 2012). The tasks (20s each) included: tactile exploration of raised line drawings of faces and objects, tactile memory retrieval via drawing, and a scribble motor/memory control. FMRI before and after a week of the Cognitive-Kinesthetic training on these tasks revealed a significant increase in PRC-to-V1 Granger causality from pre- to post-training during the memory drawing task, but not during the motor/memory control. This increase in causal connectivity indicates that the training strengthened the top-down modulation of visual cortex from the PRC. This is the first study to demonstrate enhanced directed functional connectivity from the PRC to the visual cortex in the blind, implicating the PRC as a potential source of the reorganization towards tactile representations that occurs in V1 in the blind brain (Likova, 2012). Copyright © 2017 Elsevier Inc. All rights reserved.

Involvement of Two Plasmids in the Degradation of Carbaryl by Arthrobacter sp. Strain RC100

PubMed Central

Hayatsu, Masahito; Hirano, Motoko; Nagata, Tadahiro

1999-01-01

A bacterium capable of utilizing carbaryl (1-naphthyl N-methylcarbamate) as the sole carbon source was isolated from carbaryl-treated soil. This bacterium was characterized taxonomically as Arthrobacter and was designated strain RC100. RC100 hydrolyzes the N-methylcarbamate linkage to 1-naphthol, which was further metabolized via salicylate and gentisate. Strain RC100 harbored three plasmids (designated pRC1, pRC2, and pRC3). Mutants unable to degrade carbaryl arose at a high frequency after treating the culture with mitomycin C. All carbaryl-hydrolysis-deficient mutants (Cah−) lacked pRC1, and all 1-naphthol-utilization-deficient mutants (Nat−) lacked pRC2. The plasmid-free strain RC107 grew on gentisate as a carbon source. These two plasmids could be transferred to Cah− mutants or Nat− mutants by conjugation, resulting in the restoration of the Cah and Nah phenotypes. PMID:10049857

How Polycomb-Mediated Cell Memory Deals With a Changing Environment: Variations in PcG complexes and proteins assortment convey plasticity to epigenetic regulation as a response to environment.

PubMed

Marasca, Federica; Bodega, Beatrice; Orlando, Valerio

2018-04-01

Cells and tissues are continuously exposed to a changing microenvironment, hence the necessity of a flexible modulation of gene expression that in complex organism have been achieved through specialized chromatin mechanisms. Chromatin-based cell memory enables cells to maintain their identity by fixing lineage specific transcriptional programs, ensuring their faithful transmission through cell division; in particular PcG-based memory system evolved to maintain the silenced state of developmental and cell cycle genes. In evolution the complexity of this system have increased, particularly in vertebrates, indicating combinatorial and dynamic properties of Polycomb proteins, in some cases even overflowing outside the cell nucleus. Therefore, their function may not be limited to the imposition of rigid states of genetic programs, but on the ability to recognize signals and allow plastic transcriptional changes in response to different stimuli. Here, we discuss the most novel PcG mediated memory functions in facing and responding to the challenges posed by a fluctuating environment. © 2018 The Authors. BioEssays Published by WILEY Periodicals, Inc.

Calretinin and parvalbumin immunoreactive interneurons in the retrosplenial cortex of the rat brain: Qualitative and quantitative analyses.

PubMed

Salaj, Martin; Druga, Rastislav; Cerman, Jiří; Kubová, Hana; Barinka, Filip

2015-11-19

The retrosplenial cortex (RSC) is a mesocortical region broadly involved with memory and navigation. It shares many characteristics with the perirhinal cortex (PRC), both of which appear to be significantly involved in the spreading of epileptic activity. We hypothesized that RSC possesses an interneuronal composition similar to that of PRC. To prove the hypothesis we studied the general pattern of calretinin (CR) and parvalbumin (PV) immunoreactivity in the RSC of the rat brain, its optical density as well as the morphological features and density of CR- and PV-immunoreactive (CR+ and PV+) interneurons. We also analyzed the overall neuronal density on Nissl-stained sections in RSC. Finally, we compared our results with our earlier analysis of PRC (Barinka et al., 2012). Compared to PRC, RSC was observed to have a higher intensity of PV staining and lower intensity of CR staining of neuropil. Vertically-oriented bipolar neurons were the most common morphological type among CR+ neurons. The staining pattern did not allow for a similarly detailed analysis of somatodendritic morphology of PV+ neurons. RSC possessed lower absolute (i.e., neurons/mm(3)) and relative (i.e., percentage of the overall neuronal population) densities of CR+ neurons and similar absolute and lower relative densities of PV+ neurons relative to PRC. CR: PV neuronal ratio in RSC (1:2 in area 29 and 1:2.2 in area 30) differed from PRC (1:1.2 in area 35 and 1:1.7 in area 36). In conclusion, RSC, although similar in many aspects to PRC, differs strikingly in the interneuronal composition relative to PRC. Copyright © 2015 Elsevier B.V. All rights reserved.

Comparative methylome analysis in solid tumors reveals aberrant methylation at chromosome 6p in nasopharyngeal carcinoma.

PubMed

Dai, Wei; Cheung, Arthur Kwok Leung; Ko, Josephine Mun Yee; Cheng, Yue; Zheng, Hong; Ngan, Roger Kai Cheong; Ng, Wai Tong; Lee, Anne Wing Mui; Yau, Chun Chung; Lee, Victor Ho Fu; Lung, Maria Li

2015-07-01

Altered patterns of DNA methylation are key features of cancer. Nasopharyngeal carcinoma (NPC) has the highest incidence in Southern China. Aberrant methylation at the promoter region of tumor suppressors is frequently reported in NPC; however, genome-wide methylation changes have not been comprehensively investigated. Therefore, we systematically analyzed methylome data in 25 primary NPC tumors and nontumor counterparts using a high-throughput approach with the Illumina HumanMethylation450 BeadChip. Comparatively, we examined the methylome data of 11 types of solid tumors collected by The Cancer Genome Atlas (TCGA). In NPC, the hypermethylation pattern was more dominant than hypomethylation and the majority of de novo methylated loci were within or close to CpG islands in tumors. The comparative methylome analysis reveals hypermethylation at chromosome 6p21.3 frequently occurred in NPC (false discovery rate; FDR=1.33 × 10(-9) ), but was less obvious in other types of solid tumors except for prostate and Epstein-Barr virus (EBV)-positive gastric cancer (FDR<10(-3) ). Bisulfite pyrosequencing results further confirmed the aberrant methylation at 6p in an additional patient cohort. Evident enrichment of the repressive mark H3K27me3 and active mark H3K4me3 derived from human embryonic stem cells were found at these regions, indicating both DNA methylation and histone modification function together, leading to epigenetic deregulation in NPC. Our study highlights the importance of epigenetic deregulation in NPC. Polycomb Complex 2 (PRC2), responsible for H3K27 trimethylation, is a promising therapeutic target. A key genomic region on 6p with aberrant methylation was identified. This region contains several important genes having potential use as biomarkers for NPC detection. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Alterations in Seed Development Gene Expression Affect Size and Oil Content of Arabidopsis Seeds1[C][W][OPEN

PubMed Central

Fatihi, Abdelhak; Zbierzak, Anna Maria; Dörmann, Peter

2013-01-01

Seed endosperm development in Arabidopsis (Arabidopsis thaliana) is under control of the polycomb group complex, which includes Fertilization Independent Endosperm (FIE). The polycomb group complex regulates downstream factors, e.g. Pheres1 (PHE1), by genomic imprinting. In heterozygous fie mutants, an endosperm develops in ovules carrying a maternal fie allele without fertilization, finally leading to abortion. Another endosperm development pathway depends on MINISEED3 (a WRKY10 transcription factor) and HAIKU2 (a leucine-rich repeat kinase). While the role of seed development genes in the embryo and endosperm establishment has been studied in detail, their impact on metabolism and oil accumulation remained unclear. Analysis of oil, protein, and sucrose accumulation in mutants and overexpression plants of the four seed development genes revealed that (1) seeds carrying a maternal fie allele accumulate low oil with an altered composition of triacylglycerol molecular species; (2) homozygous mutant seeds of phe1, mini3, and iku2, which are smaller, accumulate less oil and slightly less protein, and starch, which accumulates early during seed development, remains elevated in mutant seeds; (3) embryo-specific overexpression of FIE, PHE1, and MINI3 has no influence on seed size and weight, nor on oil, protein, or sucrose content; and (4) overexpression of IKU2 results in seeds with increased size and weight, and oil content of overexpressed IKU2 seeds is increased by 35%. Thus, IKU2 overexpression represents a novel strategy for the genetic manipulation of the oil content in seeds. PMID:24014578

77 FR 27574 - Automatic Underfrequency Load Shedding and Load Shedding Plans Reliability Standards

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-11

... Requirement R8 and the ``Medium'' VRF for Requirement R5 of PRC-006-1. 11. In response to the NOPR, comments... Requirement R8 and the ``Medium'' VRF for Requirement R5 of PRC-006-1. Regarding the last issue, the Commission directs NERC to modify the ``Lower VSL'' for Requirement R8 of PRC-0061 and the ``Medium'' VRF for...

Identification of Novel Targets for Lung Cancer Therapy Using an Induced Pluripotent Stem Cell Model.

PubMed

Shukla, Vivek; Rao, Mahadev; Zhang, Hongen; Beers, Jeanette; Wangsa, Darawalee; Wangsa, Danny; Buishand, Floryne O; Wang, Yonghong; Yu, Zhiya; Stevenson, Holly; Reardon, Emily; McLoughlin, Kaitlin C; Kaufman, Andrew; Payabyab, Eden; Hong, Julie A; Zhang, Mary; Davis, Sean R; Edelman, Daniel C; Chen, Guokai; Miettinen, Markku; Restifo, Nicholas; Ried, Thomas; Meltzer, Paul S; Schrump, David S

2018-04-01

Despite extensive studies, the genetic and epigenetic mechanisms that mediate initiation and progression of lung cancers have not been fully elucidated. Previously, we have demonstrated that via complementary mechanisms, including DNA methylation, polycomb repressive complexes, and noncoding RNAs, cigarette smoke induces stem-like phenotypes that coincide with progression to malignancy in normal respiratory epithelia as well as enhanced growth and metastatic potential of lung cancer cells. To further investigate epigenetic mechanisms contributing to stemness/pluripotency in lung cancers and potentially identify novel therapeutic targets in these malignancies, induced pluripotent stem cells were generated from normal human small airway epithelial cells. Lung induced pluripotent stem cells were generated by lentiviral transduction of small airway epithelial cells of OSKM (Yamanaka) factors (octamer-binding transcription factor 4 [Oct4], sex-determining region Y box 2 [SOX2], Kruppel-like factor 4 [KLF4], and MYC proto-oncogene, bHLH transcription factor [MYC]). Western blot, real-time polymerase chain reaction, and chromatin immunoprecipitation sequencing analysis were performed. The lung induced pluripotent stem cells exhibited hallmarks of pluripotency, including morphology, surface antigen and stem cell gene expression, in vitro proliferation, and teratoma formation. In addition, lung induced pluripotent stem cells exhibited no chromosomal aberrations, complete silencing of reprogramming transgenes, genomic hypermethylation, upregulation of genes encoding components of polycomb repressive complex 2, hypermethylation of stem cell polycomb targets, and modulation of more than 15,000 other genes relative to parental small airway epithelial cells. Additional sex combs like-3 (ASXL3), encoding a polycomb repressive complex 2-associated protein not previously described in reprogrammed cells, was markedly upregulated in lung induced pluripotent stem cell as well as human small cell lung cancer lines and specimens. Overexpression of the additional sex combs like-3 gene correlated with increased genomic copy number in small cell lung cancer lines. Knock-down of the additional sex combs like-3 gene inhibited proliferation, clonogenicity, and teratoma formation by lung induced pluripotent stem cells and significantly diminished in vitro clonogenicity and growth of small cell lung cancer cells in vivo. Collectively, these studies highlight the potential utility of this lung induced pluripotent stem cell model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis and suggest that additional sex combs like-3 is a novel target for small cell lung cancer therapy.

Mitigation of paracetamol-induced reproductive damage by chrysin in male rats via reducing oxidative stress.

PubMed

Aksu, E H; Özkaraca, M; Kandemir, F M; Ömür, A D; Eldutar, E; Küçükler, S; Çomaklı, S

2016-12-01

Paracetamol (PRC) is a nonsteroidal anti-inflammatory drug used widely as a painkiller for various diseases and as the symptomatic flu cure in several countries worldwide. PRC toxicity may occur under conditions of the overdose usage. Chrysin (CR) is a flavonoid that is naturally present in several plants, honey and propolis. The aim of this study was to investigate the effects of CR (at the doses of 25 mg kg -1 and 50 mg kg -1 ) pre-treatment over seven consecutive days against PRC-induced reproductive toxicity in male rats. Our results showed that PRC toxicity decreased the sperm motility, and increased dead sperm rate, abnormal sperm cell rate, apoptosis and MDA levels in testicular tissues. Pre-treatment with CR at the dose of 25 and 50 mg kg -1 for 7 days mitigated side effects of acute PRC toxicity in male reproductive system proportionally in a dose-dependent manner. This possible protection mechanism might be dependent on the antioxidant activity of CR. In conclusion, pre-treatment with CR at the dose of 25 and 50 mg kg -1 for 7 days can be the beneficial against PRC-induced reproductive toxicity proportionally in a dose-dependent manner. © 2016 Blackwell Verlag GmbH.

77 FR 19620 - Certain Preserved Mushrooms from the People's Republic of China: Initiation of Antidumping Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-02

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-851] Certain Preserved Mushrooms... certain preserved mushrooms from the People's Republic of China (PRC). In accordance with section 751(a)(2... mushrooms from the PRC.\\1\\ The antidumping duty order on certain preserved mushrooms from the PRC therefore...

2-D Structure of the A Region of Xist RNA and Its Implication for PRC2 Association

PubMed Central

Maenner, Sylvain; Blaud, Magali; Fouillen, Laetitia; Savoye, Anne; Marchand, Virginie; Dubois, Agnès; Sanglier-Cianférani, Sarah; Van Dorsselaer, Alain; Clerc, Philippe; Avner, Philip; Visvikis, Athanase; Branlant, Christiane

2010-01-01

In placental mammals, inactivation of one of the X chromosomes in female cells ensures sex chromosome dosage compensation. The 17 kb non-coding Xist RNA is crucial to this process and accumulates on the future inactive X chromosome. The most conserved Xist RNA region, the A region, contains eight or nine repeats separated by U-rich spacers. It is implicated in the recruitment of late inactivated X genes to the silencing compartment and likely in the recruitment of complex PRC2. Little is known about the structure of the A region and more generally about Xist RNA structure. Knowledge of its structure is restricted to an NMR study of a single A repeat element. Our study is the first experimental analysis of the structure of the entire A region in solution. By the use of chemical and enzymatic probes and FRET experiments, using oligonucleotides carrying fluorescent dyes, we resolved problems linked to sequence redundancies and established a 2-D structure for the A region that contains two long stem-loop structures each including four repeats. Interactions formed between repeats and between repeats and spacers stabilize these structures. Conservation of the spacer terminal sequences allows formation of such structures in all sequenced Xist RNAs. By combination of RNP affinity chromatography, immunoprecipitation assays, mass spectrometry, and Western blot analysis, we demonstrate that the A region can associate with components of the PRC2 complex in mouse ES cell nuclear extracts. Whilst a single four-repeat motif is able to associate with components of this complex, recruitment of Suz12 is clearly more efficient when the entire A region is present. Our data with their emphasis on the importance of inter-repeat pairing change fundamentally our conception of the 2-D structure of the A region of Xist RNA and support its possible implication in recruitment of the PRC2 complex. PMID:20052282

77 FR 31309 - Crystalline Silicon Photovoltaic Cells, Whether or Not Assembled Into Modules, From the People's...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-25

... into modules (``solar cells''), from the People's Republic of China (``PRC'') are being, or are likely... a petition concerning imports of solar cells from the PRC filed in proper form by SolarWorld...'') duty investigation of solar cells from the PRC on November 8, 2011.\\3\\ \\1\\ See Petition for the...

Polycomb group protein bodybuilding: working out the routines.

PubMed

Sievers, Cem; Paro, Renato

2013-09-30

Polycomb group (PcG) proteins regulate gene expression by modifying chemical and structural properties of chromatin. Isono et al. (2013) now report in Developmental Cell a polymerization-dependent mechanism used by PcG proteins to form higher-order chromatin structures, referred to as Polycomb bodies, and demonstrate its necessity for gene silencing. Copyright © 2013 Elsevier Inc. All rights reserved.

Carpal height and postoperative strength after proximal row carpectomy or four-corner arthrodesis: Clinical, anatomical and biomechanical study.

PubMed

Laronde, Pascale; Christiaens, Nicolas; Aumar, Aurélien; Chantelot, Christophe; Fontaine, Christian

2016-04-01

Proximal row carpectomy (PRC) and four-corner arthrodesis (4CA) are the two most commonly performed surgical procedures to treat wrist arthritis. Postoperative strength is one of the criteria for choosing between the two techniques. Some authors believe that strength is correlated with residual carpal height. The goal of this study was to determine if postoperative carpal height was predictive of postoperative strength. This study consisted of two parts: a clinical evaluation of grip strength after 4CA or PRC; anatomical and radiological measurements of carpal height before and after 4CA or PRC. Grip strength was better preserved after PRC (87.5%) than after 4CA (76.1%), when expressed relative to the opposite hand (P=0.053). There was a significant decrease in carpal height for the PRC group with a Youm's index of 0.37 versus 0.50 for the 4CA group (P<0.0001). Our clinical results and analysis of the literature indicate that 4CA is not superior to PRC when it comes to grip strength, whereas carpal height is significantly decreased after PRC. The decreased tendon excursion after PRC is balanced by an increase in joint stresses after 4CA. Copyright © 2016 SFCM. Published by Elsevier Masson SAS. All rights reserved.

Radioprotective Effect of Aminothiol PrC-210 on Irradiated Inner Ear of Guinea Pig

PubMed Central

Choo, Daniel I.; Riazuddin, Saima; Ahmed, Zubair M.

2015-01-01

Radiotherapy of individuals suffering with head & neck or brain tumors subserve the risk of sensorineural hearing loss. Here, we evaluated the protective effect of Aminothiol PrC-210 (3-(methyl-amino)-2-((methylamino)methyl)propane-1-thiol) on the irradiated inner ear of guinea pigs. An intra-peritoneal or intra-tympanic dose of PrC-210 was administered prior to receiving a dose of gamma radiation (3000 cGy) to each ear. Auditory Brainstem Responses (ABRs) were recorded one week and two weeks after the radiation and compared with the sham animal group. ABR thresholds of guinea pigs that received an intra-peritoneal dose of PrC-210 were significantly better compared to the non-treated, control animals at one week post-radiation. Morphologic analysis of the inner ear revealed significant inflammation and degeneration of the spiral ganglion in the irradiated animals not treated with PrC-210. In contrast, when treated with PrC-210 the radiation effect and injury to the spiral ganglion was significantly alleviated. PrC-210 had no apparent cytotoxic effect in vivo and did not affect the morphology or count of cochlear hair cells. These findings suggest that aminothiol PrC-210 attenuated radiation-induced cochlea damage for at least one week and protected hearing. PMID:26599238

Memory-guided drawing training increases Granger causal influences from the perirhinal cortex to V1 in the blind

PubMed Central

Cacciamani, Laura; Likova, Lora T.

2017-01-01

The perirhinal cortex (PRC) is a medial temporal lobe structure that has been implicated in not only visual memory in the sighted, but also tactile memory in the blind (Cacciamani & Likova, 2016). It has been proposed that, in the blind, the PRC may contribute to modulation of tactile memory responses that emerge in low-level “visual” area V1 as a result of training-induced cortical reorganization (Likova, 2012; 2015). While some studies in the sighted have indicated that the PRC is indeed structurally and functionally connected to the visual cortex (Clavagnier et al., 2004; Peterson et al., 2012), the PRC’s direct modulation of V1 is unknown—particularly in those who lack the visual input that typically stimulates this region. In the present study, we tested Likova’s PRC modulation hypothesis; specifically, we used fMRI to assess the PRC’s Granger causal influence on V1 activation in the blind during a tactile memory task. To do so, we trained congenital and acquired blind participants on a unique memory-guided drawing technique previously shown to result in V1 reorganization towards tactile memory representations (Likova, 2012). The tasks (20s each) included: tactile exploration of raised line drawings of faces and objects, tactile memory retrieval via drawing, and a scribble motor/memory control. FMRI before and after a week of the Cognitive-Kinesthetic training on these tasks revealed a significant increase in PRC-to-V1 Granger causality from pre- to post-training during the memory drawing task, but not during the motor/memory control. This increase in causal connectivity indicates that the training strengthened the top-down modulation of visual cortex from the PRC. This is the first study to demonstrate enhanced directed functional connectivity from the PRC to the visual cortex in the blind, implicating the PRC as a potential source of the reorganization towards tactile representations that occurs in V1 in the blind brain (Likova, 2012). PMID:28347878

[SINEs in mammalian genomes can serve as additional signals in formation of facultative heterochromatin].

PubMed

Usmanova, N M; Kazakov, V I; Tomilin, N V

2008-01-01

Using computer-based methods we determined the global distribution of short interspersed nuclear elements (SINEs) in the human and mouse X chromosomes. It has been shown that this distributions is similar to the distributions of CpG islands and genes but is different from the distribution of LINE1 elements. Since SINEs (human Alu and mouse B2) may have binding sites for Polycomb protein YY1, we suggest that these repeats can serve as additional signals ("boosters") in Polycomb-dependent silencing of gene rich segments during X inactivation.

Dopamine Signaling Leads to Loss of Polycomb Repression and Aberrant Gene Activation in Experimental Parkinsonism

PubMed Central

Lerdrup, Mads; Gomes, Ana-Luisa; Kryh, Hanna; Spigolon, Giada; Caboche, Jocelyne; Fisone, Gilberto; Hansen, Klaus

2014-01-01

Polycomb group (PcG) proteins bind to and repress genes in embryonic stem cells through lineage commitment to the terminal differentiated state. PcG repressed genes are commonly characterized by the presence of the epigenetic histone mark H3K27me3, catalyzed by the Polycomb repressive complex 2. Here, we present in vivo evidence for a previously unrecognized plasticity of PcG-repressed genes in terminally differentiated brain neurons of parkisonian mice. We show that acute administration of the dopamine precursor, L-DOPA, induces a remarkable increase in H3K27me3S28 phosphorylation. The induction of the H3K27me3S28p histone mark specifically occurs in medium spiny neurons expressing dopamine D1 receptors and is dependent on Msk1 kinase activity and DARPP-32-mediated inhibition of protein phosphatase-1. Chromatin immunoprecipitation (ChIP) experiments showed that increased H3K27me3S28p was accompanied by reduced PcG binding to regulatory regions of genes. An analysis of the genome wide distribution of L-DOPA-induced H3K27me3S28 phosphorylation by ChIP sequencing (ChIP-seq) in combination with expression analysis by RNA-sequencing (RNA-seq) showed that the induction of H3K27me3S28p correlated with increased expression of a subset of PcG repressed genes. We found that induction of H3K27me3S28p persisted during chronic L-DOPA administration to parkisonian mice and correlated with aberrant gene expression. We propose that dopaminergic transmission can activate PcG repressed genes in the adult brain and thereby contribute to long-term maladaptive responses including the motor complications, or dyskinesia, caused by prolonged administration of L-DOPA in Parkinson's disease. PMID:25254549

Decision-making and evidence use during the process of prenatal record review in Canada: a multiphase qualitative study.

PubMed

Semenic, Sonia; Edwards, Nancy; Premji, Shahirose; Olson, Joanne; Williams, Beverly; Montgomery, Phyllis

2015-03-31

Prenatal records are potentially powerful tools for the translation of best-practice evidence into routine prenatal care. Although all jurisdictions in Canada use standardized prenatal records to guide care and provide data for health surveillance, their content related to risk factors such as maternal smoking and alcohol use varies widely. Literature is lacking on how prenatal records are developed or updated to integrate research evidence. This multiphase project aimed to identify key contextual factors influencing decision-making and evidence use among Canadian prenatal record committees (PRCs), and formulate recommendations for the prenatal record review process in Canada. Phase 1 comprised key informant interviews with PRC leaders across 10 Canadian jurisdictions. Phase 2, was a qualitative comparative case study of PRC factors influencing evidence-use and decision-making in five selected jurisdictions. Interview data were analysed using qualitative content analysis. Phase 3 involved a dissemination workshop with key stakeholders to review and refine recommendations derived from Phases 1 and 2. Prenatal record review processes differed considerably across Canadian jurisdictions. PRC decision-making was complex, revealing the competing functions of the prenatal record as a clinical guide, documentation tool and data source. Internal contextual factors influencing evidence use included PRC resources to conduct evidence reviews; group composition and dynamics; perceived function of the prenatal record; and expert opinions. External contextual factors included concerns about user buy-in; health system capacities; and pressures from public health stakeholders. Our recommendations highlight the need for: broader stakeholder involvement and explicit use of decision-support strategies to support the revision process; a national template of evidence-informed changes that can be used across jurisdictions; consideration of both clinical and surveillance functions of the prenatal record; and dissemination plans to communicate prenatal record modifications. Decision-making related to prenatal record content involves a negotiated effort to balance research evidence with the needs and preferences of prenatal care providers, health system capacities as well as population health priorities. The development of a national template for prenatal records would reduce unnecessary duplication of PRC work and enhance the consistency of prenatal care delivery and perinatal surveillance data across Canada.

Development of KMnO(4)-releasing composites for in situ chemical oxidation of TCE-contaminated groundwater.

PubMed

Liang, S H; Chen, K F; Wu, C S; Lin, Y H; Kao, C M

2014-05-01

The objective of this study was to develop a controlled-oxidant-release technology combining in situ chemical oxidation (ISCO) and permeable reactive barrier (PRB) concepts to remediate trichloroethene (TCE)-contaminated groundwater. In this study, a potassium permanganate (KMnO4)-releasing composite (PRC) was designed for KMnO4 release. The components of this PRC included polycaprolactone (PCL), KMnO4, and starch with a weight ratio of 1.14:2:0.96. Approximately 64% (w/w) of the KMnO4 was released from the PRC after 76 days of operation in a batch system. The results indicate that the released KMnO4 could oxidize TCE effectively. The results from a column study show that the KMnO4 released from 200 g of PRC could effectively remediate 101 pore volumes (PV) of TCE-contaminated groundwater (initial TCE concentration = 0.5 mg/L) and achieve up to 95% TCE removal. The effectiveness of the PRC system was verified by the following characteristics of the effluents collected after the PRC columns (barrier): (1) decreased TCE concentrations, (2) increased ORP and pH values, and (3) increased MnO2 and KMnO4 concentrations. The results of environmental scanning electron microscope (ESEM) analysis show that the PCL and starch completely filled up the pore spaces of the PRC, creating a composite with low porosity. Secondary micro-scale capillary permeability causes the KMnO4 release, mainly through a reaction-diffusion mechanism. The PRC developed could be used as an ISCO-based passive barrier system for plume control, and it has the potential to become a cost-effective alternative for the remediation of chlorinated solvent-contaminated groundwater. Copyright © 2014 Elsevier Ltd. All rights reserved.

Fine-tuning of chromatin composition and Polycomb recruitment by two Mi2 homologues during C. elegans early embryonic development.

PubMed

Käser-Pébernard, Stéphanie; Pfefferli, Catherine; Aschinger, Caroline; Wicky, Chantal

2016-01-01

The nucleosome remodeling and deacetylase complex promotes cell fate decisions throughout embryonic development. Its core enzymatic subunit, the SNF2-like ATPase and Helicase Mi2, is well conserved throughout the eukaryotic kingdom and can be found in multiple and highly homologous copies in all vertebrates and some invertebrates. However, the reasons for such duplications and their implications for embryonic development are unknown. Here we studied the two C. elegans Mi2 homologues, LET-418 and CHD-3, which displayed redundant activities during early embryonic development. At the transcriptional level, these two Mi2 homologues redundantly repressed the expression of a large gene population. We found that LET-418 physically accumulated at TSS-proximal regions on transcriptionally active genomic targets involved in growth and development. Moreover, LET-418 acted redundantly with CHD-3 to block H3K4me3 deposition at these genes. Our study also revealed that LET-418 was partially responsible for recruiting Polycomb to chromatin and for promoting H3K27me3 deposition. Surprisingly, CHD-3 displayed opposite activities on Polycomb, as it was capable of moderating its LET-418-dependent recruitment and restricted the amount of H3K27me3 on the studied target genes. Although closely homologous, LET-418 and CHD-3 showed both redundant and opposite functions in modulating the chromatin environment at developmental target genes. We identified the interplay between LET-418 and CHD-3 to finely tune the levels of histone marks at developmental target genes. More than just repressors, Mi2-containing complexes appear as subtle modulators of gene expression throughout development. The study of such molecular variations in vertebrate Mi2 counterparts might provide crucial insights to our understanding of the epigenetic control of early development.

Identification of interacting proteins of the TaFVE protein involved in spike development in bread wheat.

PubMed

Zheng, Yong-Sheng; Lu, Yu-Qing; Meng, Ying-Ying; Zhang, Rong-Zhi; Zhang, Han; Sun, Jia-Mei; Wang, Mu-Mu; Li, Li-Hui; Li, Ru-Yu

2017-05-01

WD-40 repeat-containing protein MSI4 (FVE)/MSI4 plays important roles in determining flowering time in Arabidopsis. However, its function is unexplored in wheat. In the present study, coimmunoprecipitation and nanoscale liquid chromatography coupled to MS/MS were used to identify FVE in wheat (TaFVE)-interacting or associated proteins. Altogether 89 differentially expressed proteins showed the same downregulated expression trends as TaFVE in wheat line 5660M. Among them, 62 proteins were further predicted to be involved in the interaction network of TaFVE and 11 proteins have been shown to be potential TaFVE interactors based on curated databases and experimentally determined in other species by the STRING. Both yeast two-hybrid assay and bimolecular fluorescence complementation assay showed that histone deacetylase 6 and histone deacetylase 15 directly interacted with TaFVE. Multiple chromatin-remodelling proteins and polycomb group proteins were also identified and predicted to interact with TaFVE. These results showed that TaFVE directly interacted with multiple proteins to form multiple complexes to regulate spike developmental process, e.g. histone deacetylate, chromatin-remodelling and polycomb repressive complex 2 complexes. In addition, multiple flower development regulation factors (e.g. flowering locus K homology domain, flowering time control protein FPA, FY, flowering time control protein FCA, APETALA 1) involved in floral transition were also identified in the present study. Taken together, these results further elucidate the regulatory functions of TaFVE and help reveal the genetic mechanisms underlying wheat spike differentiation. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

78 FR 58449 - Generator Requirements at the Transmission Interface

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-24

... Connection Requirements), FAC-003-3 (Transmission Vegetation Management), PRC-004- 2.1a (Analysis and... and Generation Protection System Maintenance and Testing). The modifications improve reliability... Standards FAC-001-1 (Facility Connection Requirements), FAC-003-3 (Transmission Vegetation Management), PRC...

77 FR 59151 - Regional Reliability Standard PRC-006-NPCC-1-Automatic Underfrequency Load Shedding

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-26

... Commission also proposes to approve the associated violation risk factors (VRF) and violation severity levels... Requirement of the proposed regional Reliability Standard PRC-006-NPCC-1 includes one VRF and one VSL and that...

Prenatal Alcohol Exposure and Cellular Differentiation

PubMed Central

Veazey, Kylee J.; Muller, Daria; Golding, Michael C.

2013-01-01

Exposure to alcohol significantly alters the developmental trajectory of progenitor cells and fundamentally compromises tissue formation (i.e., histogenesis). Emerging research suggests that ethanol can impair mammalian development by interfering with the execution of molecular programs governing differentiation. For example, ethanol exposure disrupts cellular migration, changes cell–cell interactions, and alters growth factor signaling pathways. Additionally, ethanol can alter epigenetic mechanisms controlling gene expression. Normally, lineage-specific regulatory factors (i.e., transcription factors) establish the transcriptional networks of each new cell type; the cell’s identity then is maintained through epigenetic alterations in the way in which the DNA encoding each gene becomes packaged within the chromatin. Ethanol exposure can induce epigenetic changes that do not induce genetic mutations but nonetheless alter the course of fetal development and result in a large array of patterning defects. Two crucial enzyme complexes—the Polycomb and Trithorax proteins—are central to the epigenetic programs controlling the intricate balance between self-renewal and the execution of cellular differentiation, with diametrically opposed functions. Prenatal ethanol exposure may disrupt the functions of these two enzyme complexes, altering a crucial aspect of mammalian differentiation. Characterizing the involvement of Polycomb and Trithorax group complexes in the etiology of fetal alcohol spectrum disorders will undoubtedly enhance understanding of the role that epigenetic programming plays in this complex disorder. PMID:24313167

Improving PET Quantification of Small Animal [68Ga]DOTA-Labeled PET/CT Studies by Using a CT-Based Positron Range Correction.

PubMed

Cal-Gonzalez, Jacobo; Vaquero, Juan José; Herraiz, Joaquín L; Pérez-Liva, Mailyn; Soto-Montenegro, María Luisa; Peña-Zalbidea, Santiago; Desco, Manuel; Udías, José Manuel

2018-01-19

Image quality of positron emission tomography (PET) tracers that emits high-energy positrons, such as Ga-68, Rb-82, or I-124, is significantly affected by positron range (PR) effects. PR effects are especially important in small animal PET studies, since they can limit spatial resolution and quantitative accuracy of the images. Since generators accessibility has made Ga-68 tracers wide available, the aim of this study is to show how the quantitative results of [ 68 Ga]DOTA-labeled PET/X-ray computed tomography (CT) imaging of neuroendocrine tumors in mice can be improved using positron range correction (PRC). Eighteen scans in 12 mice were evaluated, with three different models of tumors: PC12, AR42J, and meningiomas. In addition, three different [ 68 Ga]DOTA-labeled radiotracers were used to evaluate the PRC with different tracer distributions: [ 68 Ga]DOTANOC, [ 68 Ga]DOTATOC, and [ 68 Ga]DOTATATE. Two PRC methods were evaluated: a tissue-dependent (TD-PRC) and a tissue-dependent spatially-variant correction (TDSV-PRC). Taking a region in the liver as reference, the tissue-to-liver ratio values for tumor tissue (TLR tumor ), lung (TLR lung ), and necrotic areas within the tumors (TLR necrotic ) and their respective relative variations (ΔTLR) were evaluated. All TLR values in the PRC images were significantly different (p < 0.05) than the ones from non-PRC images. The relative differences of the tumor TLR values, respect to the case with no PRC, were ΔTLR tumor 87 ± 41 % (TD-PRC) and 85 ± 46 % (TDSV-PRC). TLR lung decreased when applying PRC, being this effect more remarkable for the TDSV-PRC method, with relative differences respect to no PRC: ΔTLR lung  = - 45 ± 24 (TD-PRC), - 55 ± 18 (TDSV-PRC). TLR necrotic values also decreased when using PRC, with more noticeable differences for TD-PRC: ΔTLR necrotic  = - 52 ± 6 (TD-PRC), - 48 ± 8 (TDSV-PRC). The PRC methods proposed provide a significant quantitative improvement in [ 68 Ga]DOTA-labeled PET/CT imaging of mice with neuroendocrine tumors, hence demonstrating that these techniques could also ameliorate the deleterious effect of the positron range in clinical PET imaging.

Loss of MAX results in meiotic entry in mouse embryonic and germline stem cells

PubMed Central

Suzuki, Ayumu; Hirasaki, Masataka; Hishida, Tomoaki; Wu, Jun; Okamura, Daiji; Ueda, Atsushi; Nishimoto, Masazumi; Nakachi, Yutaka; Mizuno, Yosuke; Okazaki, Yasushi; Matsui, Yasuhisa; Belmonte, Juan Carlos Izpisua; Okuda, Akihiko

2016-01-01

Meiosis is a unique process that allows the generation of reproductive cells. It remains largely unknown how meiosis is initiated in germ cells and why non-germline cells do not undergo meiosis. We previously demonstrated that knockdown of Max expression, a gene encoding a partner of MYC family proteins, strongly activates expression of germ cell-related genes in ESCs. Here we find that complete ablation of Max expression in ESCs results in profound cytological changes reminiscent of cells undergoing meiotic cell division. Furthermore, our analyses uncovers that Max expression is transiently attenuated in germ cells undergoing meiosis in vivo and its forced reduction induces meiosis-like cytological changes in cultured germline stem cells. Mechanistically, Max depletion alterations are, in part, due to impairment of the function of an atypical PRC1 complex (PRC1.6), in which MAX is one of the components. Our data highlight MAX as a new regulator of meiotic onset. PMID:27025988

Passive PE Sampling in Support of In Situ Remediation of Contaminated Sediments - Passive Sampler PRC Calculation Software User’s Guide

DTIC Science & Technology

2014-07-01

different value and pressing Enter. The PRC- Calc session can be saved for future use with these new values using the Save Session button in the upper...describe (a) how the PRC Correction Calculator (PRC- Calc ) uses the model of Fernandez et al. (2009), (b) how well its performance compares against...experimental data, (c) how the user may prepare their computer with software to use the PRC calculator, and then (d) how to use PRC- Calc to process PRC

SSX and the synovial-sarcoma-specific chimaeric protein SYT-SSX co-localize with the human Polycomb group complex.

PubMed

Soulez, M; Saurin, A J; Freemont, P S; Knight, J C

1999-04-29

Chromosome translocation t(X;18)(p11.2;q11.2) is unique to synovial sarcomas and results in an 'in frame' fusion of the SYT gene with the SSX1 or closely-related SSX2 gene. Wild-type SYT and SSX proteins, and the SYT-SSX chimaeric proteins, can modulate transcription in gene reporter assays. To help elucidate the role of these proteins in cell function and neoplasia we have performed immunolabelling experiments to determine their subcellular localization in three cell types. Transient expression of epitope-tagged proteins produced distinctive nuclear staining patterns. The punctate staining of SYT and SYT-SSX proteins showed some similarities. We immunolabelled a series of endogenous nuclear antigens and excluded the SYT and SYT-SSX focal staining from association with these domains (e.g. sites of active transcription, snRNPs). In further experiments we immunolabelled the Polycomb group (PcG) proteins RING1 or BMI-1 and showed that SSX and SYT-SSX proteins, but not SYT, co-localized with these markers. Consistent with this we show that SSX and SYT-SSX associate with chromatin, and also associate with condensed chromatin at metaphase. Noteably, SSX produced a dense signal over the surface of metaphase chromosomes whereas SYT-SSX produced discrete focal staining. Our data indicate that SSX and SYT-SSX proteins are recruited to nuclear domains occupied by PcG complexes, and this provides us with a new insight into the possible function of wild-type SSX and the mechanism by which the aberrant SYT-SSX protein might disrupt fundamental mechanisms controlling cell division and cell fate.

Additional sex combs-like 1 belongs to the enhancer of trithorax and Polycomb Group and genetically interacts with Cbx2 in mice

PubMed Central

Fisher, C.L.; Lee, I.; Bloyer, S.; Bozza, S.; Chevalier, J.; Dahl, A; Bodner, C.; Helgason, C. D.; Hess, J.L.; Humphries, R.K.; Brock, H.W.

2009-01-01

The Additional sex combs (Asx) gene of Drosophila behaves genetically as an enhancer of trithorax and Polycomb (ETP) in displaying bidirectional homeotic phenotypes, suggesting that is required for maintenance of both activation and silencing of Hox genes. There are 3 murine homologs of Asx called Additional sex combs-like1, 2, and-3. Asxl1 is required for normal adult hematopoiesis; however its embryonic function is unknown. We used a targeted mouse mutant line Asxl1tm1Bc to determine if Asxl1 is required to silence and activate Hox genes in mice during axial patterning. The mutant embryos exhibit simultaneous anterior and posterior transformations of the axial skeleton, consistent with a role for Asxl1 in activation and silencing of Hox genes. Transformations of the axial skeleton are enhanced in compound mutant embryos for the Polycomb group gene M33/Cbx2. Hox a4, a7, and c8 are derepressed in Asxl1tm1Bc mutants in the antero-posterior axis, but Hox c8 expression is reduced in the brain of mutants, consistent with Asxl1 being required both for activation and repression of Hox genes. We discuss the genetic and molecular definition of ETPs, and suggest that the function of Asxl1 depends on its cellular context. PMID:19833123

78 FR 13213 - Regional Reliability Standard PRC-006-NPCC-1- Automatic Underfrequency Load Shedding

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-27

...; Order No. 775] Regional Reliability Standard PRC-006-NPCC-1--Automatic Underfrequency Load Shedding... transferred to the system upon loss of the facility.'' \\27\\ Compensatory load shedding is automatic shedding of load adequate to compensate for the loss of a generator due to the generator tripping early (i.e...

Nanos promotes epigenetic reprograming of the germline by down-regulation of the THAP transcription factor LIN-15B

PubMed Central

Lee, Chih-Yung Sean; Lu, Tu

2017-01-01

Nanos RNA-binding proteins are required for germline development in metazoans, but the underlying mechanisms remain poorly understood. We have profiled the transcriptome of primordial germ cells (PGCs) lacking the nanos homologs nos-1 and nos-2 in C. elegans. nos-1nos-2 PGCs fail to silence hundreds of transcripts normally expressed in oocytes. We find that this misregulation is due to both delayed turnover of maternal transcripts and inappropriate transcriptional activation. The latter appears to be an indirect consequence of delayed turnover of the maternally-inherited transcription factor LIN-15B, a synMuvB class transcription factor known to antagonize PRC2 activity. PRC2 is required for chromatin reprogramming in the germline, and the transcriptome of PGCs lacking PRC2 resembles that of nos-1nos-2 PGCs. Loss of maternal LIN-15B restores fertility to nos-1nos-2 mutants. These findings suggest that Nanos promotes germ cell fate by downregulating maternal RNAs and proteins that would otherwise interfere with PRC2-dependent reprogramming of PGC chromatin. PMID:29111977

Nanos promotes epigenetic reprograming of the germline by down-regulation of the THAP transcription factor LIN-15B.

PubMed

Lee, Chih-Yung Sean; Lu, Tu; Seydoux, Geraldine

2017-11-07

Nanos RNA-binding proteins are required for germline development in metazoans, but the underlying mechanisms remain poorly understood. We have profiled the transcriptome of primordial germ cells (PGCs) lacking the nanos homologs nos-1 and nos-2 in C. elegans. nos-1nos-2 PGCs fail to silence hundreds of transcripts normally expressed in oocytes. We find that this misregulation is due to both delayed turnover of maternal transcripts and inappropriate transcriptional activation. The latter appears to be an indirect consequence of delayed turnover of the maternally-inherited transcription factor LIN-15B, a synMuvB class transcription factor known to antagonize PRC2 activity. PRC2 is required for chromatin reprogramming in the germline, and the transcriptome of PGCs lacking PRC2 resembles that of nos-1nos-2 PGCs. Loss of maternal LIN-15B restores fertility to nos-1nos-2 mutants. These findings suggest that Nanos promotes germ cell fate by downregulating maternal RNAs and proteins that would otherwise interfere with PRC2-dependent reprogramming of PGC chromatin.

Conjunctive Coding of Complex Object Features

PubMed Central

Erez, Jonathan; Cusack, Rhodri; Kendall, William; Barense, Morgan D.

2016-01-01

Critical to perceiving an object is the ability to bind its constituent features into a cohesive representation, yet the manner by which the visual system integrates object features to yield a unified percept remains unknown. Here, we present a novel application of multivoxel pattern analysis of neuroimaging data that allows a direct investigation of whether neural representations integrate object features into a whole that is different from the sum of its parts. We found that patterns of activity throughout the ventral visual stream (VVS), extending anteriorly into the perirhinal cortex (PRC), discriminated between the same features combined into different objects. Despite this sensitivity to the unique conjunctions of features comprising objects, activity in regions of the VVS, again extending into the PRC, was invariant to the viewpoints from which the conjunctions were presented. These results suggest that the manner in which our visual system processes complex objects depends on the explicit coding of the conjunctions of features comprising them. PMID:25921583

EZH2 Impairs Human Dental Pulp Cell Mineralization via the Wnt/β-Catenin Pathway.

PubMed

Li, B; Yu, F; Wu, F; Hui, T; A, P; Liao, X; Yin, B; Wang, C; Ye, L

2018-05-01

The enhancer of zeste homolog 2 (EZH2) is a catalytic subunit of PRC2 (polycomb repressor complex 2). It mediates gene silencing via methyltransferase activity and is involved in the determination of cell lineage. However, the function of EZH2 and the underlying mechanisms by which it affects the differentiation of human dental pulp cell (hDPC) have remained underexplored. In this research, we found that EZH2 expression decreased during the mineralization of hDPCs, with attenuated H3K27me3 (trimethylation on lysine 27 in histone H3). Overexpression of EZH2 impaired the odontogenic differentiation of hDPCs, while EZH2 without methyltransferase activity mutation (mutation of suppressed variegation of 3 to 9, enhancer of zeste and trithorax domain, EZH2ΔSET) did not display this phenotype. In addition, siRNA knockdown studies showed that EZH2 negatively modulated hDPC differentiation in vitro and inhibited mineralized nodule formation in transplanted β-tricalcium phosphate / hDPC composites. To further investigate the underlying mechanisms, we explored the Wnt/β-catenin signaling pathway in view of the fact that previous research had documented the essential role that it plays during hDPC mineralization, as well as its links to EZH2 in other cells. We demonstrated for the first time that EZH2 depletion activated the Wnt/β-catenin signaling pathway and enhanced the accumulation of β-catenin in hDPCs. Chromatin immunoprecipitation analysis suggested that these effects are attributable to the level of the EZH2-regulated H3K27me3 on the β-catenin promoter. We conclude that EZH2 plays a negative role during the odontogenic differentiation of hDPCs. Suppression of EZH2 could promote hDPC mineralization by epigenetically regulating the expression of β-catenin and activating the Wnt canonical signaling pathway.

Enhancer of zeste acts as a major developmental regulator of Ciona intestinalis embryogenesis

PubMed Central

Le Goff, Emilie; Martinand-Mari, Camille; Martin, Marianne; Feuillard, Jérôme; Boublik, Yvan; Godefroy, Nelly; Mangeat, Paul; Baghdiguian, Stephen; Cavalli, Giacomo

2015-01-01

ABSTRACT The paradigm of developmental regulation by Polycomb group (PcG) proteins posits that they maintain silencing outside the spatial expression domains of their target genes, particularly of Hox genes, starting from mid embryogenesis. The Enhancer of zeste [E(z)] PcG protein is the catalytic subunit of the PRC2 complex, which silences its targets via deposition of the H3K27me3 mark. Here, we studied the ascidian Ciona intestinalis counterpart of E(z). Ci-E(z) is detected by immunohistochemistry as soon as the 2- and 4-cell stages as a cytoplasmic form and becomes exclusively nuclear thereafter, whereas the H3K27me3 mark is detected starting from the gastrula stage and later. Morpholino invalidation of Ci-E(z) leads to the total disappearance of both Ci-E(z) protein and its H3K27me3 mark. Ci-E(z) morphants display a severe phenotype. Strikingly, the earliest defects occur at the 4-cell stage with the dysregulation of cell positioning and mitotic impairment. At later stages, Ci-E(z)-deficient embryos are affected by terminal differentiation defects of neural, epidermal and muscle tissues, by the failure to form a notochord and by the absence of caudal nerve. These major phenotypic defects are specifically rescued by injection of a morpholino-resistant Ci-E(z) mRNA, which restores expression of Ci-E(z) protein and re-deposition of the H3K27me3 mark. As observed by qPCR analyses, Ci-E(z) invalidation leads to the early derepression of tissue-specific developmental genes, whereas late-acting developmental genes are generally down-regulated. Altogether, our results suggest that Ci-E(z) plays a major role during embryonic development in Ciona intestinalis by silencing early-acting developmental genes in a Hox-independent manner. PMID:26276097

Human Mammary Epithelial Cell Transformation by Rho GTPase Through a Novel Mechanism

DTIC Science & Technology

2009-08-01

cells were transfected with myc-tagged Prks -ROCK1 or Prks -ROCK2, flag-tagged Prc-PKN-AL, or mDia1 using calcium phosphate method. The transfectants...plasmids, Prks -ROCK1, Prks -ROCK2, Prc-PKN-AL, and pFL-mDia1, were transfected into 293T cells, and cell lysates were incubated with GTP-g-S–loaded GST

Passive sampling of DDT, DDE and DDD in sediments: accounting for degradation processes with reaction-diffusion modeling.

PubMed

Tcaciuc, A Patricia; Borrelli, Raffaella; Zaninetta, Luciano M; Gschwend, Philip M

2018-01-24

Passive sampling is becoming a widely used tool for assessing freely dissolved concentrations of hydrophobic organic contaminants in environmental media. For certain media and target analytes, the time to reach equilibrium exceeds the deployment time, and in such cases, the loss of performance reference compounds (PRCs), loaded in the sampler before deployment, is one of the common ways used to assess the fractional equilibration of target analytes. The key assumption behind the use of PRCs is that their release is solely diffusion driven. But in this work, we show that PRC transformations in the sediment can have a measurable impact on the PRC releases and even allow estimation of that compound's transformation rate in the environment of interest. We found that in both field and lab incubations, the loss of the 13 C 2,4'-DDT PRC from a polyethylene (PE) passive sampler deployed at the sediment-water interface was accelerated compared to the loss of other PRCs ( 13 C-labeled PCBs, 13 C-labeled DDE and DDD). The DDT PRC loss was also accompanied by accumulation in the PE of its degradation product, 13 C 2,4'-DDD. Using a 1D reaction-diffusion model, we deduced the in situ degradation rates of DDT from the measured PRC loss. The in situ degradation rates increased with depth into the sediment bed (0.14 d -1 at 0-10 cm and 1.4 d -1 at 30-40 cm) and although they could not be independently validated, these rates compared favorably with literature values. This work shows that passive sampling users should be cautious when choosing PRCs, as degradation processes can affect some PRC's releases from the passive sampler. More importantly, this work opens up the opportunity for novel applications of passive samplers, particularly with regard to investigating in situ degradation rates, pathways, and products for both legacy and emerging contaminants. However, further work is needed to confirm that the rates deduced from model fitting of PRC loss are a true reflection of DDT transformation rates in sediments.

Comparison of stored umbilical cord blood and adult donor blood: transfusion feasibility.

PubMed

Tokan, Rola Sahyoun; Arsan, Saadet; Erdeve, Omer; Solaz, Nuri; Avcı, Aslıhan; Ulkar, Serenay Elgün; Gülyapar, Elif; Ustünyurt, Zeynep; Bıyıklı, Zeynep; Kemahlı, Sabri

2012-09-01

This study aimed to compare the storage properties of red blood cell (RBC) concentrates of umbilical cordblood (UCB) and adult donor blood (ADB), and to evaluate the feasibility of UCB-RBC concentrate as an autologoussource for blood transfusion in very low birth weight (VLBW) preterm neonates. In all, 30 newborn (10 preterm, 20 full term) UCB and 31 ADB units were collected.RBC concentrates were stored and compared with regard to pH, potassium (K(+)), 2,3-biphosphoglycerate (2-3-BPG),adenosine tri-phosphate (ATP), plasma Hb, and bacterial contamination on d 1, 21, and 35 of storage. The K(+) level increased with time and differed significantly between storage d 1 and 21, and between storaged 1 and 35 in both the UCB and ADB units. Initial and d 21 K(+) levels were higher in the UCB units than in the ADBunits. The 2,3-BPG level did not differ significantly between the UCB-PRC and ADB-PRC samples. After 35 d of storageboth UCB-PRC and ADB-PRC samples exhibited significant differences from the initial free Hb, intracellular ATP, andpH values. Significant differences in intracellular ATP and pH were also observed between the UCB-PRC and ADB-PRCsamples. The volume of harvested and prepared UCB-PRC can be used for some of the blood transfusions requiredduring the neonatal period and thus may decrease the number of allogeneic transfusions, especially in preterm newborns.The hematological and biochemical changes that occurred in UCB during storage were comparable with those observedin ADB, and do not pose a risk to the immature metabolism of neonates. UCB-RPC prepared and stored under standardconditions can be a safe alternative RBC source for transfusions in VLBW newborns.

Shaping epigenetic memory via genomic bookmarking.

PubMed

Michieletto, Davide; Chiang, Michael; Colì, Davide; Papantonis, Argyris; Orlandini, Enzo; Cook, Peter R; Marenduzzo, Davide

2018-01-09

Reconciling the stability of epigenetic patterns with the rapid turnover of histone modifications and their adaptability to external stimuli is an outstanding challenge. Here, we propose a new biophysical mechanism that can establish and maintain robust yet plastic epigenetic domains via genomic bookmarking (GBM). We model chromatin as a recolourable polymer whose segments bear non-permanent histone marks (or colours) which can be modified by 'writer' proteins. The three-dimensional chromatin organisation is mediated by protein bridges, or 'readers', such as Polycomb Repressive Complexes and Transcription Factors. The coupling between readers and writers drives spreading of biochemical marks and sustains the memory of local chromatin states across replication and mitosis. In contrast, GBM-targeted perturbations destabilise the epigenetic patterns. Strikingly, we demonstrate that GBM alone can explain the full distribution of Polycomb marks in a whole Drosophila chromosome. We finally suggest that our model provides a starting point for an understanding of the biophysics of cellular differentiation and reprogramming. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Shaping epigenetic memory via genomic bookmarking

PubMed Central

Chiang, Michael; Colì, Davide; Papantonis, Argyris; Orlandini, Enzo; Cook, Peter R

2018-01-01

Abstract Reconciling the stability of epigenetic patterns with the rapid turnover of histone modifications and their adaptability to external stimuli is an outstanding challenge. Here, we propose a new biophysical mechanism that can establish and maintain robust yet plastic epigenetic domains via genomic bookmarking (GBM). We model chromatin as a recolourable polymer whose segments bear non-permanent histone marks (or colours) which can be modified by ‘writer’ proteins. The three-dimensional chromatin organisation is mediated by protein bridges, or ‘readers’, such as Polycomb Repressive Complexes and Transcription Factors. The coupling between readers and writers drives spreading of biochemical marks and sustains the memory of local chromatin states across replication and mitosis. In contrast, GBM-targeted perturbations destabilise the epigenetic patterns. Strikingly, we demonstrate that GBM alone can explain the full distribution of Polycomb marks in a whole Drosophila chromosome. We finally suggest that our model provides a starting point for an understanding of the biophysics of cellular differentiation and reprogramming. PMID:29190361

Polycomb Group (PcG) Proteins and Human Cancers: Multifaceted Functions and Therapeutic Implications

PubMed Central

Wang, Wei; Qin, Jiang-Jiang; Voruganti, Sukesh; Nag, Subhasree; Zhou, Jianwei; Zhang, Ruiwen

2016-01-01

Polycomb group (PcG) proteins are transcriptional repressors that regulate several crucial developmental and physiological processes in the cell. More recently, they have been found to play important roles in human carcinogenesis and cancer development and progression. The deregulation and dysfunction of PcG proteins often lead to blocking or inappropriate activation of developmental pathways, enhancing cellular proliferation, inhibiting apoptosis, and increasing the cancer stem cell population. Genetic and molecular investigations of PcG proteins have long been focused on their PcG functions. However, PcG proteins have recently been shown to exert non-polycomb functions, contributing to the regulation of diverse cellular functions. We and others have demonstrated that PcG proteins regulate the expression and function of several oncogenes and tumor suppressor genes in a PcG-independent manner, and PcG proteins are associated with the survival of patients with cancer. In this review, we summarize the recent advances in the research on PcG proteins, including both the polycomb-repressive and non-polycomb functions. We specifically focus on the mechanisms by which PcG proteins play roles in cancer initiation, development, and progression. Finally, we discuss the potential value of PcG proteins as molecular biomarkers for the diagnosis and prognosis of cancer, and as molecular targets for cancer therapy. PMID:26227500

75 FR 66352 - Glycine From the People's Republic of China: Initiation of Antidumping Anti-circumvention Inquiry

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-28

... agent, re-absorbable amino acid, chemical intermediate, and a metal complexing agent. Glycine is... and Chiyuen International Trading Ltd., a manufacturer in the PRC of amino acetic acid (i.e., glycine...

78 FR 55679 - High Pressure Steel Cylinders From the People's Republic of China; Rescission of the 2011-2013...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-11

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-977] High Pressure Steel... antidumping duty order on high pressure steel cylinders from the People's Republic of China (``PRC'') for the... order on high pressure steel cylinders from the PRC.\\1\\ In response, on July 1, 2013, Beijing Tianhai...

The histone demethylase Jarid1b ensures faithful mouse development by protecting developmental genes from aberrant H3K4me3.

PubMed

Albert, Mareike; Schmitz, Sandra U; Kooistra, Susanne M; Malatesta, Martina; Morales Torres, Cristina; Rekling, Jens C; Johansen, Jens V; Abarrategui, Iratxe; Helin, Kristian

2013-04-01

Embryonic development is tightly regulated by transcription factors and chromatin-associated proteins. H3K4me3 is associated with active transcription and H3K27me3 with gene repression, while the combination of both keeps genes required for development in a plastic state. Here we show that deletion of the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) results in major neonatal lethality due to respiratory failure. Jarid1b knockout embryos have several neural defects including disorganized cranial nerves, defects in eye development, and increased incidences of exencephaly. Moreover, in line with an overlap of Jarid1b and Polycomb target genes, Jarid1b knockout embryos display homeotic skeletal transformations typical for Polycomb mutants, supporting a functional interplay between Polycomb proteins and Jarid1b. To understand how Jarid1b regulates mouse development, we performed a genome-wide analysis of histone modifications, which demonstrated that normally inactive genes encoding developmental regulators acquire aberrant H3K4me3 during early embryogenesis in Jarid1b knockout embryos. H3K4me3 accumulates as embryonic development proceeds, leading to increased expression of neural master regulators like Pax6 and Otx2 in Jarid1b knockout brains. Taken together, these results suggest that Jarid1b regulates mouse development by protecting developmental genes from inappropriate acquisition of active histone modifications.

The Histone Demethylase Jarid1b Ensures Faithful Mouse Development by Protecting Developmental Genes from Aberrant H3K4me3

PubMed Central

Kooistra, Susanne M.; Malatesta, Martina; Morales Torres, Cristina; Rekling, Jens C.; Johansen, Jens V.; Abarrategui, Iratxe; Helin, Kristian

2013-01-01

Embryonic development is tightly regulated by transcription factors and chromatin-associated proteins. H3K4me3 is associated with active transcription and H3K27me3 with gene repression, while the combination of both keeps genes required for development in a plastic state. Here we show that deletion of the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) results in major neonatal lethality due to respiratory failure. Jarid1b knockout embryos have several neural defects including disorganized cranial nerves, defects in eye development, and increased incidences of exencephaly. Moreover, in line with an overlap of Jarid1b and Polycomb target genes, Jarid1b knockout embryos display homeotic skeletal transformations typical for Polycomb mutants, supporting a functional interplay between Polycomb proteins and Jarid1b. To understand how Jarid1b regulates mouse development, we performed a genome-wide analysis of histone modifications, which demonstrated that normally inactive genes encoding developmental regulators acquire aberrant H3K4me3 during early embryogenesis in Jarid1b knockout embryos. H3K4me3 accumulates as embryonic development proceeds, leading to increased expression of neural master regulators like Pax6 and Otx2 in Jarid1b knockout brains. Taken together, these results suggest that Jarid1b regulates mouse development by protecting developmental genes from inappropriate acquisition of active histone modifications. PMID:23637629

Epigenetic Therapy of Hematopoietic Malignancies: Novel Approaches for Tissue-Specific and Global Inhibition of EZH2 Enzymatic Activities

DTIC Science & Technology

2015-08-01

such as myelodysplastic syndromes (MDSs), primary myelofibrosis (PMF), myeloproliferative neoplasms (MPNs), and chronic myelomonocytic leukemia (CMML...Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelo- dysplastic/ myeloproliferative neoplasms . Blood. 2012;119:1208...and emerges as regulator of myeloid neoplasms .19,20 Inhibitors selective to EZH2 have recently been developed and shown to be effective in killing

78 FR 22228 - Freshwater Crawfish Tail Meat From the People's Republic of China: Final Results of Antidumping...

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2013-04-15

... Meat From the People's Republic of China: Final Results of Antidumping Duty Administrative Review and... crawfish tail meat from the People's Republic of China (the PRC). The period of review (POR) is September 1... meat from the PRC.\\1\\ On January 14, 2013, we issued a memorandum extending the time limit for the...

78 FR 43142 - Lightweight Thermal Paper From the People's Republic of China: Rescission of Antidumping Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-19

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-920] Lightweight Thermal Paper... lightweight thermal paper from the People's Republic of China (``PRC'') because Appleton Papers Inc... antidumping duty order on lightweight thermal paper from the PRC.\\1\\ The period of review (``POR'') is...

BRCA1-deficient mammary tumor cells are dependent on EZH2 expression and sensitive to Polycomb Repressive Complex 2-inhibitor 3-deazaneplanocin A.

PubMed

Puppe, Julian; Drost, Rinske; Liu, Xiaoling; Joosse, Simon A; Evers, Bastiaan; Cornelissen-Steijger, Paulien; Nederlof, Petra; Yu, Qiang; Jonkers, Jos; van Lohuizen, Maarten; Pietersen, Alexandra M

2009-01-01

Treatment of breast cancer is becoming more individualized with the recognition of tumor subgroups that respond differently to available therapies. Breast cancer 1 gene (BRCA1)-deficient tumors are usually of the basal subtype and associated with poor survival rates, highlighting the need for more effective therapy. We investigated a mouse model that closely mimics breast cancer arising in BRCA1-mutation carriers to better understand the molecular mechanism of tumor progression and tested whether targeting of the Polycomb-group protein EZH2 would be a putative therapy for BRCA1-deficient tumors. Gene expression analysis demonstrated that EZH2 is overexpressed in BRCA1-deficient mouse mammary tumors. By immunohistochemistry we show that an increase in EZH2 protein levels is also evident in tumors from BRCA1-mutation carriers. EZH2 is responsible for repression of genes driving differentiation and could thus be involved in the undifferentiated phenotype of these tumors. Importantly, we show that BRCA1-deficient cancer cells are selectively dependent on their elevated EZH2 levels. In addition, a chemical inhibitor of EZH2, 3-deazaneplanocin A (DZNep), is about 20-fold more effective in killing BRCA1-deficient cells compared to BRCA1-proficient mammary tumor cells. We demonstrate by specific knock-down experiments that EZH2 overexpression is functionally relevant in BRCA1-deficient breast cancer cells. The effectiveness of a small molecule inhibitor indicates that EZH2 is a druggable target. The overexpression of EZH2 in all basal-like breast cancers warrants further investigation of the potential for targeting the genetic make-up of this particular breast cancer type.

A New Orally Active, Aminothiol Radioprotector-Free of Nausea and Hypotension Side Effects at Its Highest Radioprotective Doses

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

Soref, Cheryl M.; Hacker, Timothy A.; Fahl, William E., E-mail: fahl@oncology.wisc.edu

Purpose: A new aminothiol, PrC-210, was tested for orally conferred radioprotection (rats, mice; 9.0 Gy whole-body, which was otherwise lethal to 100% of the animals) and presence of the debilitating side effects (nausea/vomiting, hypotension/fainting) that restrict use of the current aminothiol, amifostine (Ethyol, WR-2721). Methods and Materials: PrC-210 in water was administered to rats and mice at times before irradiation, and percent-survival was recorded for 60 days. Subcutaneous (SC) amifostine (positive control) or SC PrC-210 was administered to ferrets (Mustela putorius furo) and retching/emesis responses were recorded. Intraperitoneal amifostine (positive control) or PrC-210 was administered to arterial cannulated rats tomore » score drug-induced hypotension. Results: Oral PrC-210 conferred 100% survival in rat and mouse models against an otherwise 100% lethal whole-body radiation dose (9.0 Gy). Oral PrC-210, administered by gavage 30-90 min before irradiation, conferred a broad window of radioprotection. The comparison of PrC-210 and amifostine side effects was striking because there was no retching or emesis in 10 ferrets treated with PrC-210 and no induced hypotension in arterial cannulated rats treated with PrC-210. The tested PrC-210 doses were the ferret and rat equivalent doses of the 0.5 maximum tolerated dose (MTD) PrC-210 dose in mice. The human equivalent of this mouse 0.5 MTD PrC-210 dose would likely be the highest PrC-210 dose used in humans. By comparison, the mouse 0.5 MTD amifostine dose, 400 {mu}g/g body weight (equivalent to the human amifostine dose of 910 mg/m{sup 2}), when tested at equivalent ferret and rat doses in the above models produced 100% retching/vomiting in ferrets and 100% incidence of significant, progressive hypotension in rats. Conclusions: The PrC-210 aminothiol, with no detectable nausea/vomiting or hypotension side effects in these preclinical models, is a logical candidate for human drug development to use in healthy humans in a wide variety of radioprotection settings, including medical radiation, space travel, and nuclear accidents.« less

The Polycomb proteins RING1B and EZH2 repress the tumoral pro-inflammatory function in metastasizing primary cutaneous squamous cell carcinoma.

PubMed

Hernández-Ruiz, Eugenia; Toll, Agustí; García-Diez, Irene; Andrades, Evelyn; Ferrandiz-Pulido, Carla; Masferrer, Emili; Yébenes, Mireia; Jaka, Ane; Gimeno, Javier; Gimeno, Ramón; García-Patos, Vicenç; Pujol, Ramón M; Hernández-Muñoz, Inmaculada

2018-03-08

Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy in humans and approximately 5% metastasize, usually to regional lymph nodes. Epigenetic regulation of gene expression may allow tumoral cells to acquire new functions in order to escape from the primary tumor. The aim of this study was to investigate the expression and function of proteins of the Polycomb family of epigenetic regulators in the metastatic process of cSCC. A higher expression of RING1B and EZH2 was detected by immunohistochemistry in a series of primary cSCC tumors that metastasized (MSCCs) when compared with non-metastasizing cSCCs (non-MSCCs). Stable downregulation of RING1B and EZH2 in cSCC cells results in enhanced expression of inflammatory cytokines and activation of the NF-κB signaling pathway. Accordingly, non-MSCCs display higher levels of membranous pS176-inhibitor of NF-kB kinase, and their stroma is enriched in neutrophils and eosinophils when compared with MSCCs. In vitro, hematopoietic cells exhibit a substantial migratory response to supernatants from Polycomb-depleted cSCC cells. Altogether, these data indicate that RING1B and EZH2 repress the innate inflammatory cSCC function and impair tumor immunosurveillance and suggest that patients with high-risk cSCCs could benefit from clinical therapies addressed to harness the immune response.

China Report, Political, Sociological and Military Affairs PRC State Council Bulletin, No. 20, 10 Sep 1984

DTIC Science & Technology

1985-03-11

the following regulations did not exist to give tax exemptions, reductions, or reimbursments; A. " Income Tax Law for Chinese-Foreign Joint Ventures...in the PRC", Arts V and VI and "Detailed Rules for the Implementation of the Income Tax Law for Chinese-Foreign Joint Ventures in the PRC" Art III...B. Arts IV and V of the "PRC Income Tax Law for Foreign Companies": C. Any other special incentive measures adopted by the PRC in its laws after the

Human phase response curve to a single 6.5 h pulse of short-wavelength light

PubMed Central

Rüger, Melanie; St Hilaire, Melissa A; Brainard, George C; Khalsa, Sat-Bir S; Kronauer, Richard E; Czeisler, Charles A; Lockley, Steven W

2013-01-01

The photic resetting response of the human circadian pacemaker depends on the timing of exposure, and the direction and magnitude of the resulting shift is described by a phase response curve (PRC). Previous PRCs in humans have utilized high-intensity polychromatic white light. Given that the circadian photoreception system is maximally sensitive to short-wavelength visible light, the aim of the current study was to construct a PRC to blue (480 nm) light and compare it to a 10,000 lux white light PRC constructed previously using a similar protocol. Eighteen young healthy participants (18–30 years) were studied for 9–10 days in a time-free environment. The protocol included three baseline days followed by a constant routine (CR) to assess initial circadian phase. Following this CR, participants were exposed to a 6.5 h 480 nm light exposure (11.8 μW cm−2, 11.2 lux) following mydriasis via a modified Ganzfeld dome. A second CR was conducted following the light exposure to re-assess circadian phase. Phase shifts were calculated from the difference in dim light melatonin onset (DLMO) between CRs. Exposure to 6.5 h of 480 nm light resets the circadian pacemaker according to a conventional type 1 PRC with fitted maximum delays and advances of −2.6 h and 1.3 h, respectively. The 480 nm PRC induced ∼75% of the response of the 10,000 lux white light PRC. These results may contribute to a re-evaluation of dosing guidelines for clinical light therapy and the use of light as a fatigue countermeasure. PMID:23090946

Natriuretic peptides buffer renin-dependent hypertension.

PubMed

Demerath, Theo; Staffel, Janina; Schreiber, Andrea; Valletta, Daniela; Schweda, Frank

2014-06-15

The renin-angiotensin-aldosterone system and cardiac natriuretic peptides [atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)] are opposing control mechanisms for arterial blood pressure. Accordingly, an inverse relationship between plasma renin concentration (PRC) and ANP exists in most circumstances. However, PRC and ANP levels are both elevated in renovascular hypertension. Because ANP can directly suppress renin release, we used ANP knockout (ANP(-/-)) mice to investigate whether high ANP levels attenuate the increase in PRC in response to renal hypoperfusion, thus buffering renovascular hypertension. ANP(-/-) mice were hypertensive and had reduced PRC compared with that in wild-type ANP(+/+) mice under control conditions. Unilateral renal artery stenosis (2-kidney, 1-clip) for 1 wk induced similar increases in blood pressure and PRC in both genotypes. Unexpectedly, plasma BNP concentrations in ANP(-/-) mice significantly increased in response to two-kidney, one-clip treatment, potentially compensating for the lack of ANP. In fact, in mice lacking guanylyl cyclase A (GC-A(-/-) mice), which is the common receptor for both ANP and BNP, renovascular hypertension was markedly augmented compared with that in wild-type GC-A(+/+) mice. However, the higher blood pressure in GC-A(-/-) mice was not caused by disinhibition of the renin system because PRC and renal renin synthesis were significantly lower in GC-A(-/-) mice than in GC-A(+/+) mice. Thus, natriuretic peptides buffer renal vascular hypertension via renin-independent effects, such as vasorelaxation. The latter possibility is supported by experiments in isolated perfused mouse kidneys, in which physiological concentrations of ANP and BNP elicited renal vasodilatation and attenuated renal vasoconstriction in response to angiotensin II. Copyright © 2014 the American Physiological Society.

78 FR 34036 - Certain Magnesia Carbon Bricks From the People's Republic of China: Rescission of Antidumping...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-06

... Bricks From the People's Republic of China: Rescission of Antidumping Duty Administrative Review; 2011... bricks from the People's Republic of China (``PRC'') covering the period September 1, 2011, through... magnesia carbon bricks from the PRC.\\2\\ Fengchi Imp. & Exp. Co., Ltd. of Haicheng City (``Fengchi'') and...

76 FR 55031 - Galvanized Steel Wire From the People's Republic of China: Preliminary Affirmative Countervailing...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-06

... DEPARTMENT OF COMMERCE International Trade Administration [C-570-976] Galvanized Steel Wire From... galvanized steel wire (galvanized wire) from the People's Republic of China (PRC). For information on the..., filed in proper form, concerning imports of galvanized wire from the PRC.\\1\\ The Department initiated a...

77 FR 6060 - Second Administrative Review of Sodium Hexametaphosphate From the People's Republic of China...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-07

... of Sodium Hexametaphosphate From the People's Republic of China: Extension of Preliminary Results... administrative review of sodium hexametaphosphate (``sodium hex'') from the People's Republic of China (``PRC... duty order on sodium hex from the PRC.\\1\\ On November 29, 2011 the Department extended the deadline for...

76 FR 73599 - Second Administrative Review of Sodium Hexametaphosphate From the People's Republic of China...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-29

... of Sodium Hexametaphosphate From the People's Republic of China: Extension of Preliminary Results... administrative review of sodium hexametaphosphate (``sodium hex'') from the People's Republic of China (``PRC... duty order on sodium hex from the PRC.\\1\\ The preliminary results of the review for sodium hex from the...

Neural Correlates of Object-Associated Choice Behavior in the Perirhinal Cortex of Rats

PubMed Central

Ahn, Jae-Rong

2015-01-01

The perirhinal cortex (PRC) is reportedly important for object recognition memory, with supporting physiological evidence obtained largely from primate studies. Whether neurons in the rodent PRC also exhibit similar physiological correlates of object recognition, however, remains to be determined. We recorded single units from the PRC in a PRC-dependent, object-cued spatial choice task in which, when cued by an object image, the rat chose the associated spatial target from two identical discs appearing on a touchscreen monitor. The firing rates of PRC neurons were significantly modulated by critical events in the task, such as object sampling and choice response. Neuronal firing in the PRC was correlated primarily with the conjunctive relationships between an object and its associated choice response, although some neurons also responded to the choice response alone. However, we rarely observed a PRC neuron that represented a specific object exclusively regardless of spatial response in rats, although the neurons were influenced by the perceptual ambiguity of the object at the population level. Some PRC neurons fired maximally after a choice response, and this post-choice feedback signal significantly enhanced the neuronal specificity for the choice response in the subsequent trial. Our findings suggest that neurons in the rat PRC may not participate exclusively in object recognition memory but that their activity may be more dynamically modulated in conjunction with other variables, such as choice response and its outcomes. PMID:25632144

U.S.-China Relations: Policy Issues

DTIC Science & Technology

2010-03-12

China (PRC) include promoting U.S. trade and investment, protecting national security interests, addressing global environmental and climate change...influence and natural resources. Other U.S. concerns include the bilateral trade deficit with China and allegations of PRC unfair trade practices, PRC...with the PRC include promoting U.S. trade and investment, protecting national security interests, addressing global environmental and climate change

Estimation of the phase response curve from Parkinsonian tremor.

PubMed

Saifee, Tabish A; Edwards, Mark J; Kassavetis, Panagiotis; Gilbertson, Tom

2016-01-01

Phase response curves (PRCs), characterizing the response of an oscillator to weak external perturbation, have been estimated from a broad range of biological oscillators, including single neurons in vivo. PRC estimates, in turn, provide an intuitive insight into how oscillatory systems become entrained and how they can be desynchronized. Here, we explore the application of PRC theory to the case of Parkinsonian tremor. Initial attempts to establish a causal effect of subthreshold transcranial magnetic stimulation applied to primary motor cortex on the filtered tremor phase were unsuccessful. We explored the possible explanations of this and demonstrate that assumptions made when estimating the PRC in a traditional setting, such as a single neuron, are not arbitrary when applied to the case of tremor PRC estimation. We go on to extract the PRC of Parkinsonian tremor using an iterative method that requires varying the definition of the tremor cycle and estimating the PRC at multiple peristimulus time samples. Justification for this method is supported by estimates of PRC from simulated single neuron data. We provide an approach to estimating confidence limits for tremor PRC and discuss the interpretational caveats introduced by tremor harmonics and the intrinsic variability of the tremor's period. Copyright © 2016 the American Physiological Society.

Estimation of the phase response curve from Parkinsonian tremor

PubMed Central

Saifee, Tabish A.; Edwards, Mark J.; Kassavetis, Panagiotis

2015-01-01

Phase response curves (PRCs), characterizing the response of an oscillator to weak external perturbation, have been estimated from a broad range of biological oscillators, including single neurons in vivo. PRC estimates, in turn, provide an intuitive insight into how oscillatory systems become entrained and how they can be desynchronized. Here, we explore the application of PRC theory to the case of Parkinsonian tremor. Initial attempts to establish a causal effect of subthreshold transcranial magnetic stimulation applied to primary motor cortex on the filtered tremor phase were unsuccessful. We explored the possible explanations of this and demonstrate that assumptions made when estimating the PRC in a traditional setting, such as a single neuron, are not arbitrary when applied to the case of tremor PRC estimation. We go on to extract the PRC of Parkinsonian tremor using an iterative method that requires varying the definition of the tremor cycle and estimating the PRC at multiple peristimulus time samples. Justification for this method is supported by estimates of PRC from simulated single neuron data. We provide an approach to estimating confidence limits for tremor PRC and discuss the interpretational caveats introduced by tremor harmonics and the intrinsic variability of the tremor's period. PMID:26561596

USAWC (US Army War College) Military Studies Program Paper. An Investigation of the Value of Taiwan To Future United States Relations with the People’s Republic of China.

DTIC Science & Technology

1986-02-18

instrum-ent of power in future U.S.- PRC relations. During the 1949-1978 timeframe, U.S.-PRC relations ran the gamut from armed conflict in the Korean...PRC relations ran the gamut from armed conflict in the Korean War to diplomatic relations declared in 1978. The first thawing in relations occurred...PRC relations. US-PRC relations during the 1949-1978 timeframe ran the gamut frou armed conflict during the Korean War to diplomatic recognition. With

Functional characterization of EZH2β reveals the increased complexity of EZH2 isoforms involved in the regulation of mammalian gene expression

PubMed Central

2013-01-01

Background Histone methyltransferase enhancer of zeste homologue 2 (EZH2) forms an obligate repressive complex with suppressor of zeste 12 and embryonic ectoderm development, which is thought, along with EZH1, to be primarily responsible for mediating Polycomb-dependent gene silencing. Polycomb-mediated repression influences gene expression across the entire gamut of biological processes, including development, differentiation and cellular proliferation. Deregulation of EZH2 expression is implicated in numerous complex human diseases. To date, most EZH2-mediated function has been primarily ascribed to a single protein product of the EZH2 locus. Results We report that the EZH2 locus undergoes alternative splicing to yield at least two structurally and functionally distinct EZH2 methyltransferases. The longest protein encoded by this locus is the conventional enzyme, which we refer to as EZH2α, whereas EZH2β, characterized here, represents a novel isoform. We find that EZH2β localizes to the cell nucleus, complexes with embryonic ectoderm development and suppressor of zeste 12, trimethylates histone 3 at lysine 27, and mediates silencing of target promoters. At the cell biological level, we find that increased EZH2β induces cell proliferation, demonstrating that this protein is functional in the regulation of processes previously attributed to EZH2α. Biochemically, through the use of genome-wide expression profiling, we demonstrate that EZH2β governs a pattern of gene repression that is often ontologically redundant from that of EZH2α, but also divergent for a wide variety of specific target genes. Conclusions Combined, these results demonstrate that an expanded repertoire of EZH2 writers can modulate histone code instruction during histone 3 lysine 27-mediated gene silencing. These data support the notion that the regulation of EZH2-mediated gene silencing is more complex than previously anticipated and should guide the design and interpretation of future studies aimed at understanding the biochemical and biological roles of this important family of epigenomic regulators. PMID:23448518

78 FR 12035 - Tapered Roller Bearings and Parts Thereof, Finished and Unfinished From the People's Republic of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-21

... investigated or reviewed PRC and non-PRC exporters not listed above that have separate rates, the cash deposit... cash deposit rate will be the PRC- wide rate of 92.84 percent; and (4) for all non-PRC exporters of... expenses twice for certain sales. We unintentionally failed to offset CPZ/SKF's freight expenses with its...

A polycomb-mediated epigenetic field defect precedes invasive cervical carcinoma

PubMed Central

Wijetunga, Neil Ari; Ben-Dayan, Miriam; Tozour, Jessica; Burk, Robert D.; Schlecht, Nicolas F.; Einstein, Mark H.; Greally, John M.

2016-01-01

Human papillomavirus (HPV)-associated cervical carcinoma is preceded by stages of cervical intra-epithelial neoplasia (CIN) that can variably progress to malignancy. Understanding the different molecular processes involved in the progression of pre-malignant CIN is critical to the development of improved predictive and interventional capabilities. We tested the role of regulators of transcription in both the development and the progression of HPV-associated CIN, performing the most comprehensive genomic survey to date of DNA methylation in HPV-associated cervical neoplasia, testing ~2 million loci throughout the human genome in biopsies from 78 HPV+ women, identifying changes starting in early CIN and maintained through carcinogenesis. We identified loci at which DNA methylation is consistently altered, beginning early in the course of neoplastic disease and progressing with disease advancement. While the loss of DNA methylation occurs mostly at intergenic regions, acquisition of DNA methylation is at sites involved in transcriptional regulation, with strong enrichment for targets of polycomb repression. Using an independent cohort from The Cancer Genome Atlas, we validated the loci with increased DNA methylation and found that these regulatory changes were associated with locally decreased gene expression. Secondary validation using immunohistochemistry showed that the progression of neoplasia was associated with increasing polycomb protein expression specifically in the cervical epithelium. We find that perturbations of genomic regulatory processes occur early and persist in cervical carcinoma. The results indicate a polycomb-mediated epigenetic field defect in cervical neoplasia that may represent a target for early, topical interventions using polycomb inhibitors. PMID:27557505

A polycomb-mediated epigenetic field defect precedes invasive cervical carcinoma.

PubMed

Wijetunga, Neil Ari; Ben-Dayan, Miriam; Tozour, Jessica; Burk, Robert D; Schlecht, Nicolas F; Einstein, Mark H; Greally, John M

2016-09-20

Human papillomavirus (HPV)-associated cervical carcinoma is preceded by stages of cervical intra-epithelial neoplasia (CIN) that can variably progress to malignancy. Understanding the different molecular processes involved in the progression of pre-malignant CIN is critical to the development of improved predictive and interventional capabilities. We tested the role of regulators of transcription in both the development and the progression of HPV-associated CIN, performing the most comprehensive genomic survey to date of DNA methylation in HPV-associated cervical neoplasia, testing ~2 million loci throughout the human genome in biopsies from 78 HPV+ women, identifying changes starting in early CIN and maintained through carcinogenesis. We identified loci at which DNA methylation is consistently altered, beginning early in the course of neoplastic disease and progressing with disease advancement. While the loss of DNA methylation occurs mostly at intergenic regions, acquisition of DNA methylation is at sites involved in transcriptional regulation, with strong enrichment for targets of polycomb repression. Using an independent cohort from The Cancer Genome Atlas, we validated the loci with increased DNA methylation and found that these regulatory changes were associated with locally decreased gene expression. Secondary validation using immunohistochemistry showed that the progression of neoplasia was associated with increasing polycomb protein expression specifically in the cervical epithelium. We find that perturbations of genomic regulatory processes occur early and persist in cervical carcinoma. The results indicate a polycomb-mediated epigenetic field defect in cervical neoplasia that may represent a target for early, topical interventions using polycomb inhibitors.

Identification of polycomb and trithorax group responsive elements in the regulatory region of the Drosophila homeotic gene Sex combs reduced

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

Gindhart, J.G. Jr.; Kaufman, T.C.

1995-02-01

The Drosophilia homeotic gene Sex combs reduced (Scr) is necessary for the establishment and maintenance of the morphological identity of the labial and prothoracic segments. In the early embryo, its expression pattern is established through the activity of several gap and segmentation gene products, as well as other transcription factors. Once established, the Polycomb group (Pc-G) and trithorax group (trx-G) gene products maintain the spatial pattern of Scr expression for the remainder of development. We report the identification of DNA fragments in the Scr regulatory region that may be important for its regulation by Polycomb and trithorax group gene products.more » When DNA fragments containing these regulatory sequences are subcloned into P-element vectors containing a white minigene, transformants containing these constructs exhibit mosaic patterns of pigmentation in the adult eye, indicating that white minigene expression is repressed in a clonally heritable manner. The size of pigmented and nonpigmented clones in the adult eye suggests that the event determining whether a cell in the eye anlagen will express white occurs at least as early as the first larval instar. The amount of white minigene repression is reduced in some Polycomb group mutants, whereas repression is enhanced in flies mutant for a subset of trithorax group loci. The repressor activity of one fragment, normally located in Scr Intron 2, is increased when it is able to homologously pair, a property consistent with genetic data suggesting that Scr exhibits transvection. Another Scr regulatory fragment, normally located 40 kb upstream of the Scr promoter, silences ectopic expression of an Scr-lacZ fusion gene in the embryo and does so in a Polycomb-dependent manner. We propose that the regulatory sequences located within these DNA fragments may normally mediate the regulation of Scr by proteins encoded by members of Polycomb and trithorax group loci. 98 refs., 6 figs., 4 tabs.« less

The Prevention Research Centers Healthy Aging Research Network.

PubMed

Lang, Jason E; Anderson, Lynda; LoGerfo, James; Sharkey, Joseph; Belansky, Elaine; Bryant, Lucinda; Prohaska, Tom; Altpeter, Mary; Marshall, Victor; Satariano, William; Ivey, Susan; Bayles, Constance; Pluto, Delores; Wilcox, Sara; Goins, R Turner; Byrd, Robert C

2006-01-01

The Prevention Research Centers Healthy Aging Research Network (PRC-HAN), funded by the Centers for Disease Control and Prevention's (CDC's) Healthy Aging program, was created in 2001 to help develop partnerships and create a research agenda that promotes healthy aging. The nine universities that participate in the network use their expertise in aging research to collaborate with their communities and other partners to develop and implement health promotion interventions for older adults at the individual, organizational, environmental, and policy levels. The population of older adults in the United States is growing rapidly; approximately 20% of Americans will be aged 65 years or older by 2030. The health and economic impact of an aging society compel the CDC and the public health community to place increased emphasis on preventing unnecessary disease, disability, and injury among older Americans. The PRC-HAN has a broad research agenda that addresses health-promoting skills and behaviors, disease and syndrome topics, and knowledge domains. The network chose physical activity for older adults as its initial focus for research and has initiated two networkwide projects: a comprehensive, multisite survey that collected information on the capacity, content, and accessibility of physical activity programs for older adults and a peer-reviewed publication that describes the role of public health in promoting physical activity among older adults. In addition to participating in the core research area, each network member works independently with its community committee on PRC-HAN activities. As a result, the network is 1) expanding prevention research for older adults and their communities; 2) promoting the translation and dissemination of findings to key stakeholders; 3) strengthening PRC-HAN capacity through partnerships and expanded funding; and 4) stimulating the adoption of policies and programs by engaging policymakers, planners, and practitioners. In 2003, the PRC-HAN initiated an internal evaluation to better define the network's contributions to healthy aging, formalize internal processes, and better equip itself to serve as a model for other PRC thematic networks. The PRC-HAN is conducting a pilot evaluation for eventual inclusion in the PRC national evaluation. The PRC-HAN has established itself as an effective research network to promote healthy aging. It has developed trust and mutual respect among participants, forged strong ties to local communities, and shown the ability to combine its expertise in healthy aging with that of partners in national, state, and local organizations.

76 FR 70960 - Crystalline Silicon Photovoltaic Cells, Whether or Not Assembled Into Modules, From the People's...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-16

... silicon photovoltaic cells, whether or not assembled into modules (``solar cells'') from the People's Republic of China (``PRC'') filed in proper form by SolarWorld Industries America Inc. (``Petitioner'').\\1... Tariff Act of 1930, as amended (``the Act''), Petitioner alleges that imports of solar cells from the PRC...

78 FR 65277 - Certain Frozen Warmwater Shrimp From the People's Republic of China: Partial Rescission of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-31

... Shrimp From the People's Republic of China: Partial Rescission of Administrative Review; 2012-2013 AGENCY... shrimp (``shrimp'') from the People's Republic of China (``PRC'') covering the period February 1, 2012... published the final results of the seventh administrative review of shrimp (``AR7'') from the PRC, in which...

75 FR 54595 - Certain Iron Construction Castings From Brazil, Canada, and the People's Republic of China: Final...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-08

...] Certain Iron Construction Castings From Brazil, Canada, and the People's Republic of China: Final Results... construction castings from Brazil, Canada, and the People's Republic of China (PRC), pursuant to section 751(c... antidumping duty orders\\1\\ on certain iron construction castings from Brazil, Canada, and the PRC pursuant to...

76 FR 30656 - Multilayered Wood Flooring From the People's Republic of China: Preliminary Determination of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-26

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-970] Multilayered Wood Flooring... multilayered wood flooring from the People's Republic of China (``PRC'') is being, or is likely to be, sold in... multilayered wood flooring from the PRC filed in proper form by the Coalition for American Hardwood Parity \\1...

Loss of the tumor suppressor BAP1 causes myeloid transformation

PubMed Central

Dey, Anwesha; Seshasayee, Dhaya; Noubade, Rajkumar; French, Dorothy M.; Liu, Jinfeng; Chaurushiya, Mira S.; Kirkpatrick, Donald S.; Pham, Victoria C.; Lill, Jennie R.; Bakalarski, Corey E.; Wu, Jiansheng; Phu, Lilian; Katavolos, Paula; Saunders, Lindsay M.; Abdel-Wahab, Omar; Modrusan, Zora; Seshagiri, Somasekar; Dong, Ken; Lin, Zhonghua; Balazs, Mercedesz; Suriben, Rowena; Newton, Kim; Hymowitz, Sarah; Garcia-Manero, Guillermo; Martin, Flavius; Levine, Ross L.; Dixit, Vishva M.

2016-01-01

Deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with increased risk of mesothelioma and uveal melanoma. Somatic BAP1 mutations occur in various malignancies. We show that mouse Bap1 gene deletion is lethal during embryogenesis, but systemic or hematopoietic-restricted deletion in adults recapitulates features of human myelodysplastic syndrome (MDS). Knock-in mice expressing BAP1 with a 3xFlag tag revealed that BAP1 interacts with HCF-1, OGT, and the polycomb group proteins ASXL1 and ASXL2 in vivo. OGT and HCF-1 levels were decreased by Bap1 deletion, indicating a critical role for BAP1 in stabilizing these epigenetic regulators. Human ASXL1 is mutated frequently in chronic myelomonocytic leukemia (CMML) so an ASXL/BAP1 complex may suppress CMML. A novel BAP1 catalytic mutation found in a MDS patient implies that BAP1 loss of function has similar consequences in mouse and man. PMID:22878500

77 FR 50464 - Honey From the People's Republic of China: Affirmative Final Determination of Circumvention of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-21

... Determination \\1\\ of this anticircumvention inquiry, and determined that blends of honey and rice syrup are... are blends of honey and rice syrup, regardless of the percentage of honey they contain, from the PRC... of blends of honey and rice syrup in the antidumping duty order on honey from the PRC.\\3\\ The ITC...

77 FR 17430 - Galvanized Steel Wire From the People's Republic of China: Final Determination of Sales at Less...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-26

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-975] Galvanized Steel Wire From... wire from the People's Republic of China (``PRC'').\\1\\ On November 29, 2011, the Department published... galvanized steel wire from the PRC is being, or is likely to be, sold in the United States at LTFV, as...

4-corner arthrodesis and proximal row carpectomy: a biomechanical comparison of wrist motion and tendon forces.

PubMed

Debottis, Daniel P; Werner, Frederick W; Sutton, Levi G; Harley, Brian J

2013-05-01

Controversy exists as to whether a proximal row carpectomy (PRC) is a better procedure than scaphoid excision with 4-corner arthrodesis for preserving motion in the painful posttraumatic arthritic wrist. The purpose of this study was to determine how the kinematics and tendon forces of the wrist are altered after PRC and 4-corner arthrodesis. We tested 6 fresh cadaver forearms for the extremes of wrist motion and then used a wrist simulator to move them through 4 cyclic dynamic wrist motions, during which time we continuously recorded the tendon forces. We repeated the extremes of wrist motion measurements and the dynamic motions after scaphoid excision with 4-corner arthrodesis, and then again after PRC. We analyzed extremes of wrist motion and the peak tendon forces required for each dynamic motion using a repeated measures analysis of variance. Wrist extremes of motion significantly decreased after both the PRC and 4-corner arthrodesis compared with the intact wrist. Wrist flexion decreased on average 13° after 4-corner arthrodesis and 12° after PRC. Extension decreased 20° after 4-corner arthrodesis and 12° after PRC. Four-corner arthrodesis significantly decreased wrist ulnar deviation from the intact wrist. Four-corner arthrodesis allowed more radial deviation but less ulnar deviation than the PRC. The average peak tendon force was significantly greater after 4-corner arthrodesis than after PRC for the extensor carpi ulnaris during wrist flexion-extension, circumduction, and dart throw motions. The peak forces were significantly greater after 4-corner arthrodesis than in the intact wrist for the extensor carpi ulnaris during the dart throw motion and for the flexor carpi ulnaris during the circumduction motion. The peak extensor carpi radialis brevis force after PRC was significantly less than in the intact wrist. The measured wrist extremes of motion decreased after both 4-corner arthrodesis and PRC. Larger peak tendon forces were required to achieve identical wrist motions with the 4-corner arthrodesis compared with the intact wrist. We observed smaller forces for the PRC. These results may help explain why PRC shows early clinical improvement, yet may lead to degenerative arthritis. Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Integrated health management and control of complex dynamical systems

NASA Astrophysics Data System (ADS)

Tolani, Devendra K.

2005-11-01

A comprehensive control and health management strategy for human-engineered complex dynamical systems is formulated for achieving high performance and reliability over a wide range of operation. Results from diverse research areas such as Probabilistic Robust Control (PRC), Damage Mitigating/Life Extending Control (DMC), Discrete Event Supervisory (DES) Control, Symbolic Time Series Analysis (STSA) and Health and Usage Monitoring System (HUMS) have been employed to achieve this goal. Continuous-domain control modules at the lower level are synthesized by PRC and DMC theories, whereas the upper-level supervision is based on DES control theory. In the PRC approach, by allowing different levels of risk under different flight conditions, the control system can achieve the desired trade off between stability robustness and nominal performance. In the DMC approach, component damage is incorporated in the control law to reduce the damage rate for enhanced structural durability. The DES controller monitors the system performance and, based on the mission requirements (e.g., performance metrics and level of damage mitigation), switches among various lower-level controllers. The core idea is to design a framework where the DES controller at the upper-level, mimics human intelligence and makes appropriate decisions to satisfy mission requirements, enhance system performance and structural durability. Recently developed tools in STSA have been used for anomaly detection and failure prognosis. The DMC deals with the usage monitoring or operational control part of health management, where as the issue of health monitoring is addressed by the anomaly detection tools. The proposed decision and control architecture has been validated on two test-beds, simulating the operations of rotorcraft dynamics and aircraft propulsion.

Individual efforts to reduce salt intake in China, Japan, UK, USA: what did people achieve? The INTERMAP Population Study.

PubMed

Okuda, Nagako; Stamler, Jeremiah; Brown, Ian J; Ueshima, Hirotsugu; Miura, Katsuyuki; Okayama, Akira; Saitoh, Shigeyuki; Nakagawa, Hideaki; Sakata, Kiyomi; Yoshita, Katsushi; Zhao, Liancheng; Elliott, Paul

2014-12-01

Habitual high-salt intake raises blood pressure and risk of cardiovascular diseases. To prevent/control these risks, reduced salt diet (RSD) is recommended in many countries and some people report practicing it; however, little is known about actual achievement. This population-based study assessed level of 24-h dietary sodium intake of participants reporting RSD and others. Participants were 4680 men and women ages 40-59 years randomly selected from 17 populations in People's Republic of China (PRC), Japan, UK and USA, for an observational study on diet and blood pressure (INTERMAP). Daily sodium intake was determined by two timed 24-h urine collections. Antihypertensive treatment status and RSD were ascertained by questionnaire. Participants reporting RSD were few; 3.1% (Japan), 1.3% (PRC), 2.5% (UK), 7.2% (USA); 15.1, 7.9, 16.7 and 16.8% of people with treated hypertension. For those reporting RSD, 24-h urinary sodium excretion was significantly, but only modestly lower than for others, by 17.9 mmol/day (Japan), 56.7 (PRC) and 14.7 (USA), but higher by 10.5 in UK. Sodium intakes for participants reporting RSD remained higher than recommended; 181.0 mmol/day (Japan), 171.5 (PRC), 155.2 (UK) and 148.9 (USA). For these people, as for others, main sources of salt were processed foods in Japan, UK and USA; in PRC, salt added in preparation at home. Enhanced sustained efforts are needed to raise general awareness of the harmful effects of salt on health and the benefits of salt reduction. Population approaches are needed to reduce salt content of processed foods and restaurant meals.

EZH2 Protects Glioma Stem Cells from Radiation-Induced Cell Death in a MELK/FOXM1-Dependent Manner

PubMed Central

Kim, Sung-Hak; Joshi, Kaushal; Ezhilarasan, Ravesanker; Myers, Toshia R.; Siu, Jason; Gu, Chunyu; Nakano-Okuno, Mariko; Taylor, David; Minata, Mutsuko; Sulman, Erik P.; Lee, Jeongwu; Bhat, Krishna P.L.; Salcini, Anna Elisabetta; Nakano, Ichiro

2015-01-01

Summary Glioblastoma (GBM)-derived tumorigenic stem-like cells (GSCs) may play a key role in therapy resistance. Previously, we reported that the mitotic kinase MELK binds and phosphorylates the oncogenic transcription factor FOXM1 in GSCs. Here, we demonstrate that the catalytic subunit of Polycomb repressive complex 2, EZH2, is targeted by the MELK-FOXM1 complex, which in turn promotes resistance to radiation in GSCs. Clinically, EZH2 and MELK are coexpressed in GBM and significantly induced in postirradiation recurrent tumors whose expression is inversely correlated with patient prognosis. Through a gain-and loss-of-function study, we show that MELK or FOXM1 contributes to GSC radioresistance by regulation of EZH2. We further demonstrate that the MELK-EZH2 axis is evolutionarily conserved in Caenorhabditis elegans. Collectively, these data suggest that the MELK-FOXM1-EZH2 signaling axis is essential for GSC radioresistance and therefore raise the possibility that MELK-FOXM1-driven EZH2 signaling can serve as a therapeutic target in irradiation-resistant GBM tumors. PMID:25601206

Single center experience with percutaneous and laparoscopic cryoablation of small renal masses.

PubMed

Malcolm, John B; Berry, Tristan T; Williams, Michael B; Logan, Joshua E; Given, Robert W; Lance, Raymond S; Barone, Bethany; Shaves, Sarah; Vingan, Harlan; Fabrizio, Michael D

2009-06-01

While partial nephrectomy remains the gold standard for the management of most small renal masses, increasing experience with renal cryoablation has suggested a viable alternative with a favorable morbidity profile and good efficacy. We report intermediate-term oncologic outcomes from a single-center experience with laparoscopic and percutaneous renal cryoablation. We performed a retrospective review of our laparoscopic renal cryoablation (LRC) and percutaneous renal cryoablation (PRC) experience between January 2003 and April 2007. Patients with at least 12 months of follow-up were included in the analysis. Follow-up consisted of imaging and laboratory studies at regular intervals. Persistent mass enhancement or interval tumor growth was considered a treatment failure. Sixty-six patients (44% women/56% men; 42% African-American/58% Caucasian/other; mean body mass index, 29.7) with 72 tumors underwent either LRC (n = 52) or PRC (n = 20) with a mean follow-up of 30 months (median 25.1 mos; range 13-63 mos). Average patient age was 66.5 years (range 34-82 yrs). Mean tumor size was 2.33 cm (range 1-4.6 cm). Comorbid conditions were prevalent: 76% hypertension, 36% hyperlipidemia, 24% chronic kidney disease, 29% diabetes mellitus, 36% tobacco use, and 32% heart disease. RESULTS of pretreatment biopsy were 62% renal-cell carcinoma and 38% benign or nondiagnostic. Overall cancer-specific and cancer-free survival were 100% and 97%, respectively. There were two treatment failures (3.8%) in the LRC group and five primary failures in the PRC group (25%) (P = 0.015), four of which were salvaged with repeated PRC with no evidence of recurrence at 6 to 36 months of follow-up. There has been no significant local or metastatic progression. LRC and PRC achieved good oncologic control with minimal morbidity at a mean follow-up of 30 months in a patient cohort characterized by numerous comorbid conditions. PRC had a significantly higher primary treatment failure rate than LRC, but re-treatment offered salvage oncologic control with no significant complications.

Chromatin-Bound IκBα Regulates a Subset of Polycomb Target Genes in Differentiation and Cancer

PubMed Central

Mulero, María Carmen; Ferres-Marco, Dolors; Islam, Abul; Margalef, Pol; Pecoraro, Matteo; Toll, Agustí; Drechsel, Nils; Charneco, Cristina; Davis, Shelly; Bellora, Nicolás; Gallardo, Fernando; López-Arribillaga, Erika; Asensio-Juan, Elena; Rodilla, Verónica; González, Jessica; Iglesias, Mar; Shih, Vincent; Albà, M. Mar; Di Croce, Luciano; Hoffmann, Alexander; Miyamoto, Shigeki; Villà-Freixa, Jordi; López-Bigas, Nuria; Keyes, William M.; Domínguez, María; Bigas, Anna; Espinosa, Lluís

2014-01-01

Summary IκB proteins are the primary inhibitors of NF-κB. Here, we demonstrate that sumoylated and phosphorylated IκBα accumulates in the nucleus of keratinocytes and interacts with histones H2A and H4 at the regulatory region of HOX and IRX genes. Chromatin-bound IκBα modulates Polycomb recruitment and imparts their competence to be activated by TNFα. Mutations in the Drosophila IκBα gene cactus enhance the homeotic phenotype of Polycomb mutants, which is not counteracted by mutations in dorsal/NF-κB. Oncogenic transformation of keratinocytes results in cytoplasmic IκBα translocation associated with a massive activation of Hox. Accumulation of cytoplasmic IκBα was found in squamous cell carcinoma (SCC) associated with IKK activation and HOX upregulation. PMID:23850221

A multioutput LLC-type parallel resonant converter

NASA Astrophysics Data System (ADS)

Liu, Rui; Lee, C. Q.; Upadhyay, Anand K.

1992-07-01

When an LLC-type parallel resonant converter (LLC-PRC) operates above resonant frequency, the switching transistors can be turned off at zero voltage. Further study reveals that the LLC-PRC possesses the advantage of lower converter voltage gain as compared with the conventional PRC. Based on analytic results, a complete set of design curves is obtained, from which a systematic design procedure is developed. Experimental results from a 150 W 150 kHz multioutput LLC-type PRC power supply are presented.

A network of epigenetic regulators guides developmental haematopoiesis in vivo.

PubMed

Huang, Hsuan-Ting; Kathrein, Katie L; Barton, Abby; Gitlin, Zachary; Huang, Yue-Hua; Ward, Thomas P; Hofmann, Oliver; Dibiase, Anthony; Song, Anhua; Tyekucheva, Svitlana; Hide, Winston; Zhou, Yi; Zon, Leonard I

2013-12-01

The initiation of cellular programs is orchestrated by key transcription factors and chromatin regulators that activate or inhibit target gene expression. To generate a compendium of chromatin factors that establish the epigenetic code during developmental haematopoiesis, a large-scale reverse genetic screen was conducted targeting orthologues of 425 human chromatin factors in zebrafish. A set of chromatin regulators was identified that target different stages of primitive and definitive blood formation, including factors not previously implicated in haematopoiesis. We identified 15 factors that regulate development of primitive erythroid progenitors and 29 factors that regulate development of definitive haematopoietic stem and progenitor cells. These chromatin factors are associated with SWI/SNF and ISWI chromatin remodelling, SET1 methyltransferase, CBP-p300-HBO1-NuA4 acetyltransferase, HDAC-NuRD deacetylase, and Polycomb repressive complexes. Our work provides a comprehensive view of how specific chromatin factors and their associated complexes play a major role in the establishment of haematopoietic cells in vivo.

Values, Music and Education in China

ERIC Educational Resources Information Center

Ho, Wai-Chung; Law, Wing-Wah

2004-01-01

This article examines the complexity of the education of values in the People's Republic of China (PRC) since the beginning of the Cultural Revolution (1966-1976). It attempts to provide an insight into how the central state has managed the values of music education with respect to the dynamic changes to its political ideology across these four…

Synaptic activation patterns of the perirhinal-entorhinal inter-connections.

PubMed

de Villers-Sidani, E; Tahvildari, B; Alonso, A

2004-01-01

Ample neuropsychological evidence supports the role of rhinal cortices in memory. The perirhinal cortex (PRC) represents one of the main conduits for the bi-directional flow of information between the entorhinal-hippocampal network and the cortical mantle, a process essential in memory formation. However, despite anatomical evidence for a robust reciprocal connectivity between the perirhinal and entorhinal cortices, neurophysiological understanding of this circuitry is lacking. We now present the results of a series of electrophysiological experiments in rats that demonstrate robust synaptic activation patterns of the perirhinal-entorhinal inter-connections. First, using silicon multi-electrode arrays placed under visual guidance in vivo we performed current source density (CSD) analysis of lateral entorhinal cortex (LEC) responses to PRC stimulation, which demonstrated a current sink in layers II-III of the LEC with a latency consistent with monosynaptic activation. To further substantiate and extend this conclusion, we developed a PRC-LEC slice preparation where CSD analysis also revealed a current sink in superficial LEC layers in response to PRC stimulation. Importantly, intracellular recording of superficial LEC layer neurons confirmed that they receive a major monosynaptic excitatory input from the PRC. Finally, CSD analysis of the LEC to PRC projection in vivo also allowed us to document robust feedback synaptic activation of PRC neurons to deep LEC layer activation. We conclude that a clear bidirectional pattern of synaptic interactions exists between the PRC and LEC that would support a dynamic flow of information subserving memory function in the temporal lobe.

The effect of retrograde autologous priming on intraoperative blood product transfusion in coronary artery bypass grafting.

PubMed

Nanjappa, A; Gill, J; Sadat, U; Colah, S; Abu-Omar, Y; Nair, S

2013-11-01

Retrograde autologous priming (RAP) of the cardiopulmonary bypass (CPB) circuit could reduce the degree of haemodilution associated with priming with acellular solutions. However, there is no strong evidence to prove that the practice of RAP reduced intraoperative packed red cell (PRC) or blood product transfusion. To evaluate the effect of RAP on intraoperative PRC usage in coronary artery bypass grafting (CABG). This study is a prospective, observational study on patients who underwent first-time, isolated CABG using CPB between April 2012 and July 2012. Two groups of patients were identified: 1. Non-RAP group (n=128) and 2. RAP group (n=73). The primary outcome for the study was the amount of PRC and blood product usage between the induction of anaesthesia and the cessation of CPB. Use of PRC and blood products in the operating room was comparable in both groups. Univariate logistic regression showed that RAP was not an independent predictor of PRC or blood product transfusion (p=0.43). Multivariate logistic regression showed that CPB time, preoperative haemoglobin (Hb) levels and creatinine clearance were independent predictors of blood product transfusion. Practising RAP with mean volumes of 300 ml does not necessarily reduce PRC and other blood product transfusion requirements during CABG. In our practice, RAP was performed, aiming at displacing CPB circuit prime volume with which the perfusionist felt comfortable and dictated by haemodynamic parameters prior to commencing CPB. We presume this is the case in many units around the world. This practice, in our opinion, is not enough to achieve the benefits of RAP, if any, in the form of a reduction of packed red cell transfusion requirements. The true advantages of RAP in cardiac surgery need to be studied in a prospective, randomized, controlled trial.

Polycomb (PcG) Proteins, BMI1 and SUZ12, Regulate Arsenic-induced Cell Transformation*

PubMed Central

Kim, Hong-Gyum; Kim, Dong Joon; Li, Shengqing; Lee, Kun Yeong; Li, Xiang; Bode, Ann M.; Dong, Zigang

2012-01-01

Inorganic arsenic is a well-documented human carcinogen associated with cancers of the skin, lung, liver, and bladder. However, the underlying mechanisms explaining the tumorigenic role of arsenic are not well understood. The present study explored a potential mechanism of cell transformation induced by arsenic exposure. Exposure to a low dose (0.5 μm) of arsenic trioxide (As2O3) caused transformation of BALB/c 3T3 cells. In addition, in a xenograft mouse model, tumor growth of the arsenic-induced transformed cells was dramatically increased. In arsenic-induced transformed cells, polycomb group (PcG) proteins, including BMI1 and SUZ12, were activated resulting in enhanced histone H3K27 tri-methylation levels. On the other hand, tumor suppressor p16INK4a and p19ARF mRNA and protein expression were dramatically suppressed. Introduction of small hairpin (sh) RNA-BMI1 or -SUZ12 into BALB/c 3T3 cells resulted in suppression of arsenic-induced transformation. Histone H3K27 tri-methylation returned to normal in BMI1- or SUZ12-knockdown BALB/c 3T3 cells compared with BMI1- or SUZ12-wildtype cells after arsenic exposure. As a consequence, the expression of p16INK4a and p19ARF was recovered in arsenic-treated BMI1- or SUZ12-knockdown cells. Thus, arsenic-induced cell transformation was blocked by inhibition of PcG function. Taken together, these results strongly suggest that the polycomb proteins, BMI1 and SUZ12 are required for cell transformation induced by organic arsenic exposure. PMID:22843710

28 CFR 16.85 - Exemption of U.S. Parole Commission-limited access.

Code of Federal Regulations, 2010 CFR

2010-07-01

...) Statistical, Educational and Developmental System (JUSTICE/PRC-006). (5) Workload Record, Decision Result, and...-limited access. 16.85 Section 16.85 Judicial Administration DEPARTMENT OF JUSTICE PRODUCTION OR DISCLOSURE... Scheduling and Control System (JUSTICE/PRC-001). (2) Inmate and Supervision Files System (JUSTICE/PRC-003...

A Balanced Scorecard Approach to Public Relations Management Assessment.

ERIC Educational Resources Information Center

Fleisher, Craig S.; Mahaffy, Darren

1997-01-01

Describes a new managerial approach to assessing public relations/communications (PR/C) performance using a "balanced scorecard." Reviews the current state of PR/C management assessment; illustrates the balanced scorecard framework; highlights its strengths and weaknesses; describes the process of applying the scorecard to PR/C units;…

Psychological Distress in Jordanian Parents of Children with Autism Spectrum Disorder: The Role of Positive Reappraisal Coping.

PubMed

Rayan, Ahmad; Ahmad, Muayyad

2017-02-01

Parents of children with autism spectrum disorder (ASD) frequently report poor psychological well-being. Positive reappraisal coping (PRC) is a coping strategy which offers a protective effect from anxiety and depression. However, the association between PRC and the psychological distress in parents of children with ASD has yet to be established. This study examines the association between PRC and the psychological distress in parents of children with ASD. In this descriptive correlational study, 104 parents of children with ASD completed measures of psychological distress and PRC. Hierarchical multiple regression analysis was used to examine the association between PRC and the psychological distress in parents after controlling the influence of parental age and gender. The PRC was associated with the psychological distress in parents above and beyond the variance accounted for by parental age and gender. After controlling for parental age and gender, PRC had significant negative correlation with the levels of anxiety, stress, and depression in parents (Anxiety: β=-0.36, p<0.001; Stress: β=-0.21, p=0.03; Depression: β=- 0.37, p<0.001). Using positive reappraisal coping strategy may help to reduce psychological distress in parents of children with ASD. Copyright © 2016 Elsevier Inc. All rights reserved.

Macroscopic phase-resetting curves for spiking neural networks

NASA Astrophysics Data System (ADS)

Dumont, Grégory; Ermentrout, G. Bard; Gutkin, Boris

2017-10-01

The study of brain rhythms is an open-ended, and challenging, subject of interest in neuroscience. One of the best tools for the understanding of oscillations at the single neuron level is the phase-resetting curve (PRC). Synchronization in networks of neurons, effects of noise on the rhythms, effects of transient stimuli on the ongoing rhythmic activity, and many other features can be understood by the PRC. However, most macroscopic brain rhythms are generated by large populations of neurons, and so far it has been unclear how the PRC formulation can be extended to these more common rhythms. In this paper, we describe a framework to determine a macroscopic PRC (mPRC) for a network of spiking excitatory and inhibitory neurons that generate a macroscopic rhythm. We take advantage of a thermodynamic approach combined with a reduction method to simplify the network description to a small number of ordinary differential equations. From this simplified but exact reduction, we can compute the mPRC via the standard adjoint method. Our theoretical findings are illustrated with and supported by numerical simulations of the full spiking network. Notably our mPRC framework allows us to predict the difference between effects of transient inputs to the excitatory versus the inhibitory neurons in the network.

The psychophysiological assessment method for pilot's professional reliability.

PubMed

Zhang, L M; Yu, L S; Wang, K N; Jing, B S; Fang, C

1997-05-01

Previous research has shown that a pilot's professional reliability depends on two relative factors: the pilot's functional state and the demands of task workload. The Psychophysiological Reserve Capacity (PRC) is defined as a pilot's ability to accomplish additive tasks without reducing the performance of the primary task (flight task). We hypothesized that the PRC was a mirror of the pilot's functional state. The purpose of this study was to probe the psychophysiological method for evaluating a pilot's professional reliability on a simulator. The PRC Comprehensive Evaluating System (PRCCES) which was used in the experiment included four subsystems: a) quantitative evaluation system for pilot's performance on simulator; b) secondary task display and quantitative estimating system; c) multiphysiological data monitoring and statistical system; and d) comprehensive evaluation system for pilot PRC. Two studies were performed. In study one, 63 healthy and 13 hospitalized pilots participated. Each pilot performed a double 180 degrees circuit flight program with and without secondary task (three digit operation). The operator performance, score of secondary task and cost of physiological effort were measured and compared by PRCCES in the two conditions. Then, each pilot's flight skill in training was subjectively scored by instructor pilot ratings. In study two, 7 healthy pilots volunteered to take part in the experiment on the effects of sleep deprivation on pilot's PRC. Each participant had PRC tested pre- and post-8 h sleep deprivation. The results show that the PRC values of a healthy pilot was positively correlated with abilities of flexibility, operating and correcting deviation, attention distribution, and accuracy of instrument flight in the air (r = 0.27-0.40, p < 0.05), and negatively correlated with emotional anxiety in flight (r = -0.40, p < 0.05). The values of PRC in healthy pilots (0.61 +/- 0.17) were significantly higher than that of hospitalized pilots (0.43 +/- 0.15) (p < 0.05). The PRC value after 8 h sleep loss (0.50 +/- 0.17) was significantly lower than those before sleep loss (0.70 +/- 0.15) (p < 0.05). We conclude that a pilot's PRC, which was closely related to flight ability and functional state, could partly represent the pilot's professional reliability. It is worthwhile to further research using a pilot's PRC as a predictor of mental workload in aircraft design.

China’s Muslims: Separatism and Prospects for Ethnic Peace

DTIC Science & Technology

2006-09-01

Management and Budget, Paperwork Reduction Project (0704-0188) Washington DC 20503. 1. AGENCY USE ONLY (Leave blank) 2. REPORT DATE September...unlike Uighur ethnic identity, Hui identity stems from and is compatible with the PRC and Chinese society. This study uses primary sources including...and is compatible with the PRC and Chinese society. This study uses primary sources including interviews with Uighurs, Hui and Han Chinese conducted

Worldwide Report, Telecommunications Policy, Research and Development

DTIC Science & Technology

1985-12-31

3 Hong Kong Database Signs Contract With PRC (K. Gopinath; Hong Kong HONGKONG STANDARD, 18 Oct 85) .... 5 Briefs Hong Kong-London Data Link...KONG HONG KONG DATABASE SIGNS CONTRACT WITH PRC Hong Kong HONGKONG STANDARD in English Supplement 18 Oct 85 p 1 [Article by K. Gopinath] [Text...information group. The agreement between state-owned China Hua Yang Technology and Trade Corporation and DataBase Asia of Hong- kong, authorises

Heavy metal removal capacity of individual components of permeable reactive concrete

NASA Astrophysics Data System (ADS)

Holmes, Ryan R.; Hart, Megan L.; Kevern, John T.

2017-01-01

Permeable reactive barriers (PRBs) are a well-known technique for groundwater remediation using industrialized reactive media such as zero-valent iron and activated carbon. Permeable reactive concrete (PRC) is an alternative reactive medium composed of relatively inexpensive materials such as cement and aggregate. A variety of multimodal, simultaneous processes drive remediation of metals from contaminated groundwater within PRC systems due to the complex heterogeneous matrix formed during cement hydration. This research investigated the influence coarse aggregate, portland cement, fly ash, and various combinations had on the removal of lead, cadmium, and zinc in solution. Absorption, adsorption, precipitation, co-precipitation, and internal diffusion of the metals are common mechanisms of removal in the hydrated cement matrix and independent of the aggregate. Local aggregates can be used as the permeable structure also possessing high metal removal capabilities, however calcareous sources of aggregate are preferred due to improved removal with low leachability. Individual adsorption isotherms were linear or curvilinear up, indicating a preferred removal process. For PRC samples, metal saturation was not reached over the range of concentrations tested. Results were then used to compare removal against activated carbon and aggregate-based PRBs by estimating material costs for the remediation of an example heavy metal contaminated Superfund site located in the Midwestern United States, Joplin, Missouri.

Chromatin-bound IκBα regulates a subset of polycomb target genes in differentiation and cancer.

PubMed

Mulero, María Carmen; Ferres-Marco, Dolors; Islam, Abul; Margalef, Pol; Pecoraro, Matteo; Toll, Agustí; Drechsel, Nils; Charneco, Cristina; Davis, Shelly; Bellora, Nicolás; Gallardo, Fernando; López-Arribillaga, Erika; Asensio-Juan, Elena; Rodilla, Verónica; González, Jessica; Iglesias, Mar; Shih, Vincent; Mar Albà, M; Di Croce, Luciano; Hoffmann, Alexander; Miyamoto, Shigeki; Villà-Freixa, Jordi; López-Bigas, Nuria; Keyes, William M; Domínguez, María; Bigas, Anna; Espinosa, Lluís

2013-08-12

IκB proteins are the primary inhibitors of NF-κB. Here, we demonstrate that sumoylated and phosphorylated IκBα accumulates in the nucleus of keratinocytes and interacts with histones H2A and H4 at the regulatory region of HOX and IRX genes. Chromatin-bound IκBα modulates Polycomb recruitment and imparts their competence to be activated by TNFα. Mutations in the Drosophila IκBα gene cactus enhance the homeotic phenotype of Polycomb mutants, which is not counteracted by mutations in dorsal/NF-κB. Oncogenic transformation of keratinocytes results in cytoplasmic IκBα translocation associated with a massive activation of Hox. Accumulation of cytoplasmic IκBα was found in squamous cell carcinoma (SCC) associated with IKK activation and HOX upregulation. Copyright © 2013 Elsevier Inc. All rights reserved.

Significant Suppression of CT Radiation-Induced DNA Damage in Normal Human Cells by the PrC-210 Radioprotector.

PubMed

Jermusek, Frank; Benedict, Chelsea; Dreischmeier, Emma; Brand, Michael; Uder, Michael; Jeffery, Justin J; Ranallo, Frank N; Fahl, William E

2018-05-21

While computed tomography (CT) is now commonly used and considered to be clinically valuable, significant DNA double-strand breaks (γ-H2AX foci) in white blood cells from adult and pediatric CT patients have been frequently reported. In this study to determine whether γ-H2AX foci and X-ray-induced naked DNA damage are suppressed by administration of the PrC-210 radioprotector, human blood samples were irradiated in a CT scanner at 50-150 mGy with or without PrC-210, and γ-H2AX foci were scored. X-ray-induced naked DNA damage was also studied, and the DNA protective efficacy of PrC-210 was compared against 12 other common "antioxidants." PrC-210 reduced CT radiation-induced γ-H2AX foci in white blood cells to near background ( P < 0.0001) at radiation doses of 50-150 mGy. PrC-210 was most effective among the 13 "antioxidants" in reducing naked DNA X-ray damage, and its addition at 30 s before an • OH pulse reduced to background the • OH insult that otherwise induced >95% DNA damage. A systemic PrC-210 dose known to confer 100% survival in irradiated mice had no discernible effect on micro-CT image signal-to-noise ratio and CT image integrity. PrC-210 suppressed DNA damage to background or near background in each of these assay systems, thus supporting its development as a radioprotector for humans in multiple radiation exposure settings.

75 FR 70956 - Post Office Closing

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-19

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2011-07-01

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The Effects of Attention Problems on Psychosocial Functioning in Childhood Brain Tumor Survivors: A 2-Year Postcraniospinal Irradiation Follow-up.

PubMed

Oh, Yunhye; Seo, Hyunjung; Sung, Ki Woong; Joung, Yoo Sook

2017-03-01

To examine the psychosocial outcomes and impact of attention problems in survivors of pediatric brain tumor. The survivors' cognitive functioning was measured using the Wechsler Intelligence Scale for Children. The Child Behavior Checklist-Attention Problems scale was used to screen for attention problems, and participants were classified as having attention problems (n=15) or normal attention (n=36). Psychosocial functioning was examined with the Korean Personality Rating scale for Children (K-PRC) at precraniospinal radiation and at 2-year follow-up. The attention problem group showed significantly higher depression and externalizing symptoms (delinquency, hyperactivity) and more significant impairment in family relationships than did the normal attention group at baseline. At follow-up, the attention problem group demonstrated significantly more delinquency and impaired family and social relationships. With the K-PRC scores, except for the somatization, social relationship subscale, there were significant differences between groups, but not in terms of treatment by time interaction or within time. At follow-up, multiple linear regressions showed that age at diagnosis significantly predicted K-PRC somatization (B=-1.7, P=0.004) and social relationships (B=-1.7, P=0.004), baseline full-scale intelligence quotient predicted K-PRC depression (B=-0.4, P=0.032) and somatization (B=-0.3, P=0.015), and attention problems at baseline predicted K-PRC depression (B=-15.2, P=0.036) and social relationships (B=-11.6, P=0.016). Pediatric brain tumor survivors, in particular, patients with attention problems, had worse psychosocial functioning at baseline and follow-up. Attention problems at baseline need to be carefully evaluated in assessing psychosocial functioning of pediatric brain tumor survivors.

Provider perspectives on rehabilitation of patients with polytrauma.

PubMed

Friedemann-Sánchez, Greta; Sayer, Nina A; Pickett, Treven

2008-01-01

To describe, from the perspective of U.S. Department of Veterans Affairs (VA) polytrauma rehabilitation providers, (1) patients with combat-related polytrauma and their rehabilitation, (2) polytrauma patient family member involvement in rehabilitation, and (3) the impact on providers of providing polytrauma rehabilitation. Qualitative study based on rapid assessment process methodology, which included semistructured interviews, observation, and use of a field liaison. The 4 VA polytrauma rehabilitation centers (PRCs). Fifty-six purposefully selected PRC providers and providers from consulting services. Not applicable. Provider self-report of polytrauma patient characteristics, polytrauma patient family member involvement in rehabilitation, and the impact of polytrauma rehabilitation on providers themselves. According to PRC providers, polytrauma patients are younger than VA rehabilitation patients. Strong military identities affect rehabilitation needs and reactions to severe injury. The public and the media have particular interest in war-injured patients. Patients with blast-related polytrauma have unique constellations of visible (including amputations, craniectomies, and burns) and invisible (including traumatic brain injury, pain, and posttraumatic stress disorder) injuries. Providers have adjusted treatment strategies and involved services outside of rehabilitation because of this clinical complexity. Family members are intensely involved in rehabilitation and have service needs that may surpass those of families of rehabilitation patients without polytrauma. Sources of provider stress include new responsibilities, media attention, increased oversight, and emotional costs associated with treating severely injured young patients and their families. Providers also described the work as deeply rewarding. The VA should prioritize the identification or development and implementation of strategies to address family member needs and to monitor and ensure that PRC providers have access to appropriate resources. Future research should determine whether findings generalize to patients injured in other wars and to people who sustain polytraumatic injuries outside of a war zone, including victims of terrorist attacks.

76 FR 70966 - Crystalline Silicon Photovoltaic Cells, Whether or Not Assembled Into Modules, From the People's...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-16

... modules (solar cells), from the People's Republic of China (PRC) filed in proper form by SolarWorld...), Petitioner alleges that producers/exporters of solar cells from the PRC received countervailable subsidies... the scope of this investigation are solar cells from the PRC. For a full description of the scope of...

76 FR 4634 - Diamond Sawblades and Parts Thereof From the People's Republic of China (PRC): Rescission of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-26

... Thereof From the People's Republic of China (PRC): Rescission of Antidumping Duty New-Shipper Review... (the Department) initiated a new-shipper review of the antidumping duty order on diamond sawblades and parts thereof from the People's Republic of China (PRC) covering the period January 23, 2009, through...

Research Results

NASA Astrophysics Data System (ADS)

2010-10-01

Relations found between human memories and similar neural patterns Double Star Program Received the IAA Laurels for Team Achievement Award Prof. Piao's Review Paper Published in Nature Arsenic Trioxide Controls the Fate of the PML-RARα Oncoprotein by Directly Binding PML Setdb2 restricts dorsal organizer territory and regulates left-right asymmetry through suppressing fgf8 activity Short-range scattering in quantum dots Single-molecule magnets may find their use in microelectronics β-Arrestin1 Regulates Zebrafish Hematopoiesis through Binding to YY1 and Relieving Polycomb Group Repression Studies shown gene present and absent complementation may contribute to the heterosis of maize Low frequency genetic variation may determine complex diseases Cation-π interaction playing vital roles in the regulation of integrin affinity, signaling, and biological functions Soybean diversity map may provide important basis for breeding Mutations related to Alzheimer's and rare skin disease

Actively Shaken In-Situ Passive Sampler Platform for Methylmercury and Organics

DTIC Science & Technology

2016-02-01

Figure 3.2- PRC dissipation and compound uptake kinetics generally assumed for the Performance Reference Compound (PRC) approach...dissipation and compound uptake kinetics generally assumed for the performance reference compound (PRC) approach. C(t) and C(ss) refer to target...under-equilibrated passive sampler measurements that need to be corrected for equilibrium, typically by extrapolation of the loss kinetics of

75 FR 38983 - Magnesium Metal From the People's Republic of China and the Russian Federation: Final Results of...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-07

... (``PRC'') and the Russian Federation (``Russia''), pursuant to section 751(c) of the Tariff Act of 1930... investigation, notified the Department that it intended to participate in the PRC and Russia sunset reviews. The... the 2000-2001 investigations of magnesium from the PRC, Israel, and Russia. See Notice of Final...

Damage assessment in PRC and RC beams by dynamic tests

NASA Astrophysics Data System (ADS)

Capozucca, R.

2011-07-01

The present paper reports on damaged prestressed reinforced concrete (PRC) beams and reinforced concrete (RC) beams experimentally investigated through dynamic testing in order to verify damage degree due to reinforcement corrosion or cracking correlated to loading. The experimental program foresaw that PRC beams were subjected to artificial reinforcement corrosion and static loading while RC beams were damaged by increasing applied loads to produce bending cracking. Dynamic investigation was developed both on undamaged and damaged PRC and RC beams measuring natural frequencies and evaluating vibration mode shapes. Dynamic testing allowed the recording of frequency response variations at different vibration modes. The experimental results are compared with theoretical results and discussed.

Taiwan-U.S. Relations: Recent Developments and Their Policy Implications

DTIC Science & Technology

2008-10-27

August) and the Paralympic Games (September). For instance, while appearing more conciliatory in a reported letter to U.N. Secretary-General Ban Ki...official PRC sources had been using “Zhongguo Taipei” — or “Taipei, China,” leading up to the Olympic Games . A 1989 agreement stipulated that Taiwan be...MOFA unsurprised by PRC reaction to U.N. participation,” Taipei Times, August 28, 2008, p. 1. Taiwan during the 2008 Olympic Games .24 Taiwan’s

China and Proliferation of Weapons of Mass Destruction and Missiles: Policy Issues

DTIC Science & Technology

2006-12-11

Ghauri (Hatf-5) medium-range ballistic missile (MRBM), which is based on the North Korean No Dong missile. U.S. intelligence was said to suspect that...confirming these stories, the DCI reported in August 2000 that, besides North Korean help, PRC entities provided “increased assistance” to Pakistan’s...ranges, respectively, of about 800 mi. and 1,250 mi.). Over 100 PRC and North Korean experts worked there, reported the Washington Times (November 23

Chitosan-coated doxorubicin nano-particles drug delivery system inhibits cell growth of liver cancer via p53/PRC1 pathway.

PubMed

Ye, Bai-Liang; Zheng, Ru; Ruan, Xiao-Jiao; Zheng, Zhi-Hai; Cai, Hua-Jie

2018-01-01

Nano-particles have been widely used in target-specific drug delivery system and showed advantages in cancers treatment. This study aims to evaluate the effect of chitosan coated doxorubicin nano-particles drug delivery system in liver cancer. The chitosan nano-particles were prepared by using the ionic gelation method. The characterizations of the nano-particles were determined by transmission electron microscopy. The cytotoxicity was detected by MTT assay, and the endocytosis, cell apoptosis and cell cycle were examined by flow cytometry. The protein level was analyzed with western blot. The dual luciferase reporter assay was performed to assess the interaction between p53 and the promoter of PRC1, and chromatin immune-precipitation was used to verify the binding between them. The FA-CS-DOX nano-particles were irregular and spherical particles around 30-40 nm, with uniform size and no adhesion. No significant difference was noted in doxorubicin release rate between CS-DOX and FA-CS-DOX. FA-CS-DOX nano-particles showed stronger cytotoxicity than CS-DOX. FA-CS-DOX nano-particles promoted the apoptosis and arrested cell cycle at G2/M phase, and they up-regulated p53. FA-CS-DOX nano-particles inhibited cell survival through p53/PRC1 pathway. Chitosan-coated doxorubicin nano-particles drug delivery system inhibits cell growth of liver cancer by promoting apoptosis and arresting cell cycle at G2/M phase through p53/PRC1 pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

75 FR 22114 - Aluminum Extrusions from the People's Republic of China: Initiation of Countervailing Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-27

... sampling method. Section 771(4)(A) of the Act defines the ``industry'' as the producers as a whole of a... the PRC. At this time, given the unique nature of the alleged subsidy and the complex methodological... process, such as aluminum products produced by a method of casting. Cast aluminum products are properly...

Role Split Phenomenon of Academic Staff in Chinese Higher Education: A Case Study of Fudan University

ERIC Educational Resources Information Center

Xiaoxin, Du

2018-01-01

This study explains the dual task on both political and academic issues in Chinese higher education, using Fudan University in Hong Kong SAR, People's Republic of China (PRC), as a case study. The research problem focuses on the dynamics and complexity of the interplay among the state, university, staff, and students in the process of…

Multi-template analysis of human perirhinal cortex in brain MRI: Explicitly accounting for anatomical variability

PubMed Central

Xie, Long; Pluta, John B.; Das, Sandhitsu R.; Wisse, Laura E.M.; Wang, Hongzhi; Mancuso, Lauren; Kliot, Dasha; Avants, Brian B.; Ding, Song-Lin; Manjón, José V.; Wolk, David A.; Yushkevich, Paul A.

2016-01-01

Rational The human perirhinal cortex (PRC) plays critical roles in episodic and semantic memory and visual perception. The PRC consists of Brodmann areas 35 and 36 (BA35, BA36). In Alzheimer's disease (AD), BA35 is the first cortical site affected by neurofibrillary tangle pathology, which is closely linked to neural injury in AD. Large anatomical variability, manifested in the form of different cortical folding and branching patterns, makes it difficult to segment the PRC in MRI scans. Pathology studies have found that in ~97% of specimens, the PRC falls into one of three discrete anatomical variants. However, current methods for PRC segmentation and morphometry in MRI are based on single-template approaches, which may not be able to accurately model these discrete variants Methods A multi-template analysis pipeline that explicitly accounts for anatomical variability is used to automatically label the PRC and measure its thickness in T2-weighted MRI scans. The pipeline uses multi-atlas segmentation to automatically label medial temporal lobe cortices including entorhinal cortex, PRC and the parahippocampal cortex. Pairwise registration between label maps and clustering based on residual dissimilarity after registration are used to construct separate templates for the anatomical variants of the PRC. An optimal path of deformations linking these templates is used to establish correspondences between all the subjects. Experimental evaluation focuses on the ability of single-template and multi-template analyses to detect differences in the thickness of medial temporal lobe cortices between patients with amnestic mild cognitive impairment (aMCI, n=41) and age-matched controls (n=44). Results The proposed technique is able to generate templates that recover the three dominant discrete variants of PRC and establish more meaningful correspondences between subjects than a single-template approach. The largest reduction in thickness associated with aMCI, in absolute terms, was found in left BA35 using both regional and summary thickness measures. Further, statistical maps of regional thickness difference between aMCI and controls revealed different patterns for the three anatomical variants. PMID:27702610

China and Proliferation of Weapons of Mass Destruction and Missiles: Policy Issues

DTIC Science & Technology

2007-05-09

medium-range ballistic missile (MRBM), which is based on the North Korean No Dong missile. U.S. intelligence was said to suspect that China Poly Ventures...stories, the DCI reported in August 2000 that, besides North Korean help, PRC entities provided “increased assistance” to Pakistan’s ballistic missile...development of the Shahab-3 and Shahab-4 MRBMs (with ranges, respectively, of about 800 mi. and 1,250 mi.). Over 100 PRC and North Korean experts worked there

China and Proliferation of Weapons of Mass Destruction and Missiles: Policy Issues

DTIC Science & Technology

2007-01-31

based on the North Korean No Dong missile. U.S. intelligence was said to suspect that China Poly Ventures Company delivered, perhaps in 1999, U.S.-made...besides North Korean help, PRC entities provided “increased assistance” to Pakistan’s ballistic missile program in the second half of 1999. Also...the Shahab-3 and Shahab-4 MRBMs (with ranges, respectively, of about 800 mi. and 1,250 mi.). Over 100 PRC and North Korean experts worked there

Teaching psychiatric mental health nursing in the People's Republic of China.

PubMed

Harmon, Rebecca Bouterie

2008-12-01

According to the World Health Organization's Health Policy Resource Book, mental disorders account for a high proportion of disability worldwide and are predicted to grow significantly in the coming years. This is especially true in developing countries such as the People's Republic of China (PRC) where, for historical social, political, and economic reasons, psychiatric mental health (PMH) nursing has not been an integral part of nursing curricula. As the number of persons in the PRC increases, so is the demand for mental health nurses, yet the PRC lacks experienced PMH nursing instructors. This article describes the challenges and opportunities that await Western PMH nursing specialists and faculty in the PRC.

MUC1-C ACTIVATES BMI1 IN HUMAN CANCER CELLS

PubMed Central

Hiraki, Masayuki; Maeda, Takahiro; Bouillez, Audrey; Alam, Maroof; Tagde, Ashujit; Hinohara, Kunihiko; Suzuki, Yozo; Markert, Tahireh; Miyo, Masaaki; Komura, Kazumasa; Ahmad, Rehan; Rajabi, Hasan; Kufe, Donald

2016-01-01

BMI1 is a component of the PRC1 complex that is overexpressed in breast and other cancers, and promotes self-renewal of cancer stem-like cells. The oncogenic mucin 1 (MUC1) C-terminal (MUC1-C) subunit is similarly overexpressed in human carcinoma cells and has been linked to their self-renewal. There is no known relationship between MUC1-C and BMI1 in cancer. The present studies demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism in breast and other cancer cells. In addition, we show that MUC1-C blocks miR-200c-mediated downregulation of BMI1 expression. The functional significance of this MUC1-C→BMI1 pathway is supported by the demonstration that targeting MUC1-C suppresses BMI1-induced ubiquitylation of H2A and thereby derepresses homeobox HOXC5 and HOXC13 gene expression. Notably, our results further show that MUC1-C binds directly to BMI1 and promotes occupancy of BMI1 on the CDKN2A promoter. In concert with BMI1-induced repression of the p16INK4a tumor suppressor, we found that targeting MUC1-C is associated with induction of p16INK4a expression. In support of these results, analysis of three gene expresssion datasets demonstrated highly significant correlations between MUC1-C and BMI1 in breast cancers. These findings uncover a previously unrecognized role for MUC1-C in driving BMI1 expression and in directly interacting with this stem cell factor, linking MUC1-C with function of the PRC1 in epigenetic gene silencing. PMID:27893710

Distinguishing between biochemical and cellular function: Are there peptide signatures for cellular function of proteins?

PubMed

Jain, Shruti; Bhattacharyya, Kausik; Bakshi, Rachit; Narang, Ankita; Brahmachari, Vani

2017-04-01

The genome annotation and identification of gene function depends on conserved biochemical activity. However, in the cell, proteins with the same biochemical function can participate in different cellular pathways and cannot complement one another. Similarly, two proteins of very different biochemical functions are put in the same class of cellular function; for example, the classification of a gene as an oncogene or a tumour suppressor gene is not related to its biochemical function, but is related to its cellular function. We have taken an approach to identify peptide signatures for cellular function in proteins with known biochemical function. ATPases as a test case, we classified ATPases (2360 proteins) and kinases (517 proteins) from the human genome into different cellular function categories such as transcriptional, replicative, and chromatin remodelling proteins. Using publicly available tool, MEME, we identify peptide signatures shared among the members of a given category but not between cellular functional categories; for example, no motif sharing is seen between chromatin remodelling and transporter ATPases, similarly between receptor Serine/Threonine Kinase and Receptor Tyrosine Kinase. There are motifs shared within each category with significant E value and high occurrence. This concept of signature for cellular function was applied to developmental regulators, the polycomb and trithorax proteins which led to the prediction of the role of INO80, a chromatin remodelling protein, in development. This has been experimentally validated earlier for its role in homeotic gene regulation and its interaction with regulatory complexes like the Polycomb and Trithorax complex. Proteins 2017; 85:682-693. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Enhancers of Polycomb EPC1 and EPC2 sustain the oncogenic potential of MLL leukemia stem cells

PubMed Central

Huang, Xu; Spencer, Gary J; Lynch, James T; Ciceri, Filippo; Somerville, Tim D D; Somervaille, Tim C P

2013-01-01

Through a targeted knockdown (KD) screen of chromatin regulatory genes we identified the EP400 complex components EPC1 and EPC2 as critical oncogenic co-factors in acute myeloid leukemia (AML). EPC1 and EPC2 were required for the clonogenic potential of human AML cells of multiple molecular subtypes. Focusing on MLL-mutated AML as an exemplar, Epc1 or Epc2 KD induced apoptosis of murine MLL-AF9 AML cells and abolished leukemia stem cell potential. By contrast, normal hematopoietic stem and progenitor cells (HSPC) were spared. Similar selectivity was observed for human primary AML cells versus normal CD34+ HSPC. In keeping with these distinct functional consequences, Epc1 or Epc2 KD induced divergent transcriptional consequences in murine MLL-AF9 granulocyte-macrophage progenitor-like (GMP) cells versus normal GMP, with a signature of increased MYC activity in leukemic but not normal cells. This was caused by accumulation of MYC protein and was also observed following KD of other EP400 complex genes. Pharmacological inhibition of MYC:MAX dimerization, or concomitant MYC KD, reduced apoptosis following EPC1 KD, linking the accumulation of MYC to cell death. Therefore EPC1 and EPC2 are components of a complex which directly or indirectly serves to prevent MYC accumulation and AML cell apoptosis, thus sustaining oncogenic potential. PMID:24166297

Diagnosing pediatric functional abdominal pain in children (4-15 years old) according to the Rome III Criteria: results from a Norwegian prospective study.

PubMed

Helgeland, Helene; Flagstad, Gro; Grøtta, Jon; Vandvik, Per Olav; Kristensen, Hanne; Markestad, Trond

2009-09-01

To determine the proportion of referred children with nonorganic abdominal pain who meet the criteria for 1 or more diagnoses of functional gastrointestinal disorders (FGID), explore the distribution of diagnoses according to the revised pediatric Rome III criteria (PRC-III), and to investigate reasons for failure to meet these criteria. We recruited children (4-15 years) consecutively referred by general practitioners to 4 general pediatric outpatient clinics for the evaluation of recurrent abdominal pain. FGID diagnoses were based on the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III version, completed by parents. To exclude organic disease, all patients underwent medical investigations and were reevaluated at follow-up after 6 to 9 months. Of the 152 patients included, 142 (93%) had functional abdominal pain. Of these, 124 (87%) met the criteria for 1 or more diagnoses according to the PRC-III: 66% met the criteria for 1, 29% for 2, and 5% for 3 diagnoses. Irritable bowel syndrome was the most common diagnosis (43%) and overlapped with aerophagia in 16 children (38% of the children with overlapping diagnoses) and with abdominal migraine in 14 (33%). In the 18 patients (13%) not fulfilling the PRC-III for any FGID diagnosis, the main reason was insufficient pain frequency (83%). Of the referred children with functional abdominal pain, 87% met the PRC-III for specific diagnoses. This supports the use of these criteria as a diagnostic tool. The significant overlap between different FGIDs, however, makes it unclear whether some of the diagnoses represent distinct disorders or artificial categories.

YY1 and HDAC9c transcriptionally regulate p38-mediated mesenchymal stem cell differentiation into osteoblasts

PubMed Central

Chen, Ya-Huey; Chung, Chiao-Chen; Liu, Yu-Chia; Lai, Wei-Chen; Lin, Zong-Shin; Chen, Tsung-Ming; Li, Long-Yuan; Hung, Mien-Chie

2018-01-01

Mesenchymal stem cells (MSCs) have a high self-renewal potential and can differentiate into various types of cells, including adipocytes, osteoblasts, and chondrocytes. Previously, we reported that the enhancer of zeste homolog 2 (EZH2), the catalytic component of the Polycomb-repressive complex 2, and HDAC9c mediate the osteogenesis and adipogenesis of MSCs. In the current study, we identify the role of p38 in osteogenic differentiation from a MAPK antibody array screen and investigate the mechanisms underlying its transcriptional regulation. Our data show that YY1, a ubiquitously expressed transcription factor, and HDAC9c coordinate p38 transcriptional activity to promote its expression to facilitate the osteogenic potential of MSCs. Our results show that p38 mediates osteogenic differentiation, and this has significant implications in bone-related diseases, bone tissue engineering, and regenerative medicine. PMID:29637005

Objects and categories: feature statistics and object processing in the ventral stream.

PubMed

Tyler, Lorraine K; Chiu, Shannon; Zhuang, Jie; Randall, Billi; Devereux, Barry J; Wright, Paul; Clarke, Alex; Taylor, Kirsten I

2013-10-01

Recognizing an object involves more than just visual analyses; its meaning must also be decoded. Extensive research has shown that processing the visual properties of objects relies on a hierarchically organized stream in ventral occipitotemporal cortex, with increasingly more complex visual features being coded from posterior to anterior sites culminating in the perirhinal cortex (PRC) in the anteromedial temporal lobe (aMTL). The neurobiological principles of the conceptual analysis of objects remain more controversial. Much research has focused on two neural regions-the fusiform gyrus and aMTL, both of which show semantic category differences, but of different types. fMRI studies show category differentiation in the fusiform gyrus, based on clusters of semantically similar objects, whereas category-specific deficits, specifically for living things, are associated with damage to the aMTL. These category-specific deficits for living things have been attributed to problems in differentiating between highly similar objects, a process that involves the PRC. To determine whether the PRC and the fusiform gyri contribute to different aspects of an object's meaning, with differentiation between confusable objects in the PRC and categorization based on object similarity in the fusiform, we carried out an fMRI study of object processing based on a feature-based model that characterizes the degree of semantic similarity and difference between objects and object categories. Participants saw 388 objects for which feature statistic information was available and named the objects at the basic level while undergoing fMRI scanning. After controlling for the effects of visual information, we found that feature statistics that capture similarity between objects formed category clusters in fusiform gyri, such that objects with many shared features (typical of living things) were associated with activity in the lateral fusiform gyri whereas objects with fewer shared features (typical of nonliving things) were associated with activity in the medial fusiform gyri. Significantly, a feature statistic reflecting differentiation between highly similar objects, enabling object-specific representations, was associated with bilateral PRC activity. These results confirm that the statistical characteristics of conceptual object features are coded in the ventral stream, supporting a conceptual feature-based hierarchy, and integrating disparate findings of category responses in fusiform gyri and category deficits in aMTL into a unifying neurocognitive framework.

A Mathematical Model of the Circadian Phase-Shifting Effects of Exogenous Melatonin

PubMed Central

Breslow, Emily R.; Phillips, Andrew J.K.; Huang, Jean M.; St. Hilaire, Melissa A.; Klerman, Elizabeth B.

2013-01-01

Melatonin is endogenously produced and released in humans during nighttime darkness and is suppressed by ocular light exposure. Exogenous melatonin is used to induce circadian phase shifts and sleep. The circadian phase-shifting ability of a stimulus (e.g., melatonin or light) relative to its timing may be displayed as a phase response curve (PRC). Published PRCs to exogenous melatonin show a transition from phase advances to delays approximately 1 h after dim light melatonin onset. A previously developed mathematical model simulates endogenous production and clearance of melatonin as a function of circadian phase, light-induced suppression, and resetting of circadian phase by light. We extend this model to include the pharmacokinetics of oral exogenous melatonin and phase-shifting effects via melatonin receptors in the suprachiasmatic nucleus of the mammalian hypothalamus. Model parameters are fit using 2 data sets: (1) blood melatonin concentration following a 0.3- or 5.0-mg dose, and (2) a PRC to a 3.0-mg dose of melatonin. After fitting to the 3.0-mg PRC, the model correctly predicts that, by comparison, the 0.5-mg PRC is slightly decreased in amplitude and shifted to a later circadian phase. This model also reproduces blood concentration profiles of various melatonin preparations that differ only in absorption rate and percentage degradation by first-pass hepatic metabolism. This model can simulate experimental protocols using oral melatonin, with potential application to guide dose size and timing to optimally shift and entrain circadian rhythms. PMID:23382594

Spectral reconstruction of phase response curves reveals the synchronization properties of mouse globus pallidus neurons

PubMed Central

Atherton, Jeremy F.; Surmeier, D. James

2013-01-01

The propensity of a neuron to synchronize is captured by its infinitesimal phase response curve (iPRC). Determining whether an iPRC is biphasic, meaning that small depolarizing perturbations can actually delay the next spike, if delivered at appropriate phases, is a daunting experimental task because negative lobes in the iPRC (unlike positive ones) tend to be small and may be occluded by the normal discharge variability of a neuron. To circumvent this problem, iPRCs are commonly derived from numerical models of neurons. Here, we propose a novel and natural method to estimate the iPRC by direct estimation of its spectral modes. First, we show analytically that the spectral modes of the iPRC of an arbitrary oscillator are readily measured by applying weak harmonic perturbations. Next, applying this methodology to biophysical neuronal models, we show that a low-dimensional spectral reconstruction is sufficient to capture the structure of the iPRC. This structure was preserved reasonably well even with added physiological scale jitter in the neuronal models. To validate the methodology empirically, we applied it first to a low-noise electronic oscillator with a known design and then to cortical pyramidal neurons, recorded in whole cell configuration, that are known to possess a monophasic iPRC. Finally, using the methodology in conjunction with perforated-patch recordings from pallidal neurons, we show, in contrast to recent modeling studies, that these neurons have biphasic somatic iPRCs. Biphasic iPRCs would cause lateral somatically targeted pallidal inhibition to desynchronize pallidal neurons, providing a plausible explanation for their lack of synchrony in vivo. PMID:23966679

Commercial Vessel Safety Economic Benefits.

DTIC Science & Technology

1980-02-01

AD-A09b 319 PRC SYSTEMS SERVICES CO MELEAN VA F/S 5/4 CMOMERCIAL VESSEL SAFET Y ECONOM IC BENEFITS (U) FEB Al C A CROOK , W R WHITTEMORE , M MARR5 DOT...N ., . . i* . .... ........ ’q m m l w ’ .. ... .... . .J F Y* •LEVEV teprt N. CB-ID-2-81 Commercial Vessel Safety Economic Benefits PRELIMINARY PRC...constitute endorsement or approval of such products. COMMERCIAL VESSEL SAFETY ECONOMIC BENEFITS PRC Systems Services Company 7600 Old Springhouse

A parametric method for assessing diversification-rate variation in phylogenetic trees.

PubMed

Shah, Premal; Fitzpatrick, Benjamin M; Fordyce, James A

2013-02-01

Phylogenetic hypotheses are frequently used to examine variation in rates of diversification across the history of a group. Patterns of diversification-rate variation can be used to infer underlying ecological and evolutionary processes responsible for patterns of cladogenesis. Most existing methods examine rate variation through time. Methods for examining differences in diversification among groups are more limited. Here, we present a new method, parametric rate comparison (PRC), that explicitly compares diversification rates among lineages in a tree using a variety of standard statistical distributions. PRC can identify subclades of the tree where diversification rates are at variance with the remainder of the tree. A randomization test can be used to evaluate how often such variance would appear by chance alone. The method also allows for comparison of diversification rate among a priori defined groups. Further, the application of the PRC method is not restricted to monophyletic groups. We examined the performance of PRC using simulated data, which showed that PRC has acceptable false-positive rates and statistical power to detect rate variation. We apply the PRC method to the well-studied radiation of North American Plethodon salamanders, and support the inference that the large-bodied Plethodon glutinosus clade has a higher historical rate of diversification compared to other Plethodon salamanders. © 2012 The Author(s). Evolution© 2012 The Society for the Study of Evolution.

Prospective multi-institutional study evaluating the performance of prostate cancer risk calculators.

PubMed

Nam, Robert K; Kattan, Michael W; Chin, Joseph L; Trachtenberg, John; Singal, Rajiv; Rendon, Ricardo; Klotz, Laurence H; Sugar, Linda; Sherman, Christopher; Izawa, Jonathan; Bell, David; Stanimirovic, Aleksandra; Venkateswaran, Vasundara; Diamandis, Eleftherios P; Yu, Changhong; Loblaw, D Andrew; Narod, Steven A

2011-08-01

Prostate cancer risk calculators incorporate many factors to evaluate an individual's risk for prostate cancer. We validated two common North American-based, prostate cancer risk calculators. We conducted a prospective, multi-institutional study of 2,130 patients who underwent a prostate biopsy for prostate cancer detection from five centers. We evaluated the performance of the Sunnybrook nomogram-based prostate cancer risk calculator (SRC) and the Prostate Cancer Prevention Trial (PCPT) -based risk calculator (PRC) to predict the presence of any cancer and high-grade cancer. We examined discrimination, calibration, and decision curve analysis techniques to evaluate the prediction models. Of the 2,130 patients, 867 men (40.7%) were found to have cancer, and 1,263 (59.3%) did not have cancer. Of the patients with cancer, 403 (46.5%) had a Gleason score of 7 or more. The area under the [concentration-time] curve (AUC) for the SRC was 0.67 (95% CI, 0.65 to 0.69); the AUC for the PRC was 0.61 (95% CI, 0.59 to 0.64). The AUC was higher for predicting aggressive disease from the SRC (0.72; 95% CI, 0.70 to 0.75) compared with that from the PRC (0.67; 95% CI, 0.64 to 0.70). Decision curve analyses showed that the SRC performed better than the PRC for risk thresholds of more than 30% for any cancer and more than 15% for aggressive cancer. The SRC performed better than the PRC, but neither one added clinical benefit for risk thresholds of less than 30%. Further research is needed to improve the AUCs of the risk calculators, particularly for higher-grade cancer.

Molecular crowding at microtubule plus-ends acts as a physical barrier to microtubule sliding for the organization of stable anti-parallel overlaps by PRC1 and Kif4A

NASA Astrophysics Data System (ADS)

Wijeratne, Sitara; Subramanian, Radhika

The relative sliding of microtubules by motor proteins is important for the organization of specialized cellular microtubule networks. In cells, sliding filaments are likely to encounter crowded regions of microtubules, such as the plus-ends, which are densely occupied by motor and non-motor proteins. How molecular crowding impacts microtubule sliding is not well understood. Here, we reconstitute the collective activities of the non-motor protein PRC1 and the motor protein Kif4A on anti-parallel microtubules to address this question. We find that the accumulation of PRC1 and Kif4A at microtubule-plus ends (`end-tags') can act as a physical barrier to Kif4A-mediated microtubule sliding. This enables the formation of stable microtubule overlaps that persist even after the deactivation of the motor protein. Our data suggest that while end-tags stabilize anti-parallel overlaps by inhibiting relative sliding, they permit the remodeling of the microtubule bundles by external forces, as may be required for the reorganization of microtubule networks during dynamic cellular processes.

Representation of 3-Dimenstional Objects by the Rat Perirhinal Cortex

PubMed Central

Burke, S.N.; Maurer, A.P.; Hartzell, A.L.; Nematollahi, S.; Uprety, A.; Wallace, J.L.; Barnes, C.A.

2012-01-01

The perirhinal cortex (PRC) is known to play an important role in object recognition. Little is known, however, regarding the activity of PRC neurons during the presentation of stimuli that are commonly used for recognition memory tasks in rodents, that is, 3-dimensional objects. Rats in the present study were exposed to 3-dimensional objects while they traversed a circular track for food reward. Under some behavioral conditions the track contained novel objects, familiar objects, or no objects. Approximately 38% of PRC neurons demonstrated ‘object fields’ (a selective increase in firing at the location of one or more objects). Although the rats spent more time exploring the objects when they were novel compared to familiar, indicating successful recognition memory, the proportion of object fields and the firing rates of PRC neurons were not affected by the rats’ previous experience with the objects. Together these data indicate that the activity of PRC cells is powerfully affected by the presence of objects while animals navigate through an environment, but under these conditions, the firing patterns are not altered by the relative novelty of objects during successful object recognition. PMID:22987680

Structural insight into the role of VAL1 B3 domain for targeting to FLC locus in Arabidopsis thaliana.

PubMed

Wu, Baixing; Zhang, Mengmeng; Su, Shichen; Liu, Hehua; Gan, Jianhua; Ma, Jinbiao

2018-06-22

Vernalization is a pivotal stage for some plants involving many epigenetic changes during cold exposure. In Arabidopsis, an essential step in vernalization for further flowering is successful silence the potent floral repressor Flowering Locus C (FLC) by repressing histone mark. AtVal1 is a multi-function protein containing five domains that participate into many recognition processes and is validated to recruit the repress histone modifier PHD-PRC2 complex and interact with components of the ASAP complex target to the FLC nucleation region through recognizing a cis element known as CME (cold memory element) by its plant-specific B3 domain. Here, we determine the crystal structure of the B3 domain in complex with Sph/RY motif in CME. Our structural analysis reveals the specific DNA recognition by B3 domain, combined with our in vitro experiments, we provide the structural insight into the important implication of AtVAL1-B3 domain in flowering process. Copyright © 2018 Elsevier Inc. All rights reserved.

Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool

PubMed Central

2013-01-01

Background System-wide profiling of genes and proteins in mammalian cells produce lists of differentially expressed genes/proteins that need to be further analyzed for their collective functions in order to extract new knowledge. Once unbiased lists of genes or proteins are generated from such experiments, these lists are used as input for computing enrichment with existing lists created from prior knowledge organized into gene-set libraries. While many enrichment analysis tools and gene-set libraries databases have been developed, there is still room for improvement. Results Here, we present Enrichr, an integrative web-based and mobile software application that includes new gene-set libraries, an alternative approach to rank enriched terms, and various interactive visualization approaches to display enrichment results using the JavaScript library, Data Driven Documents (D3). The software can also be embedded into any tool that performs gene list analysis. We applied Enrichr to analyze nine cancer cell lines by comparing their enrichment signatures to the enrichment signatures of matched normal tissues. We observed a common pattern of up regulation of the polycomb group PRC2 and enrichment for the histone mark H3K27me3 in many cancer cell lines, as well as alterations in Toll-like receptor and interlukin signaling in K562 cells when compared with normal myeloid CD33+ cells. Such analyses provide global visualization of critical differences between normal tissues and cancer cell lines but can be applied to many other scenarios. Conclusions Enrichr is an easy to use intuitive enrichment analysis web-based tool providing various types of visualization summaries of collective functions of gene lists. Enrichr is open source and freely available online at: http://amp.pharm.mssm.edu/Enrichr. PMID:23586463

Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool.

PubMed

Chen, Edward Y; Tan, Christopher M; Kou, Yan; Duan, Qiaonan; Wang, Zichen; Meirelles, Gabriela Vaz; Clark, Neil R; Ma'ayan, Avi

2013-04-15

System-wide profiling of genes and proteins in mammalian cells produce lists of differentially expressed genes/proteins that need to be further analyzed for their collective functions in order to extract new knowledge. Once unbiased lists of genes or proteins are generated from such experiments, these lists are used as input for computing enrichment with existing lists created from prior knowledge organized into gene-set libraries. While many enrichment analysis tools and gene-set libraries databases have been developed, there is still room for improvement. Here, we present Enrichr, an integrative web-based and mobile software application that includes new gene-set libraries, an alternative approach to rank enriched terms, and various interactive visualization approaches to display enrichment results using the JavaScript library, Data Driven Documents (D3). The software can also be embedded into any tool that performs gene list analysis. We applied Enrichr to analyze nine cancer cell lines by comparing their enrichment signatures to the enrichment signatures of matched normal tissues. We observed a common pattern of up regulation of the polycomb group PRC2 and enrichment for the histone mark H3K27me3 in many cancer cell lines, as well as alterations in Toll-like receptor and interlukin signaling in K562 cells when compared with normal myeloid CD33+ cells. Such analyses provide global visualization of critical differences between normal tissues and cancer cell lines but can be applied to many other scenarios. Enrichr is an easy to use intuitive enrichment analysis web-based tool providing various types of visualization summaries of collective functions of gene lists. Enrichr is open source and freely available online at: http://amp.pharm.mssm.edu/Enrichr.

Safeguards Challenges for Pebble-Bed Reactors (PBRs):Peoples Republic of China (PRC)

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

Forsberg, Charles W.; Moses, David Lewis

2009-11-01

The Peoples Republic of China (PRC) is operating the HTR-10 pebble-bed reactor (PBR) and is in the process of building a prototype PBR plant with two modular reactors (250-MW(t) per reactor) feeding steam to a single turbine-generator. It is likely to be the first modular hightemperature reactor to be ready for commercial deployment in the world because it is a highpriority project for the PRC. The plant design features multiple modular reactors feeding steam to a single turbine generator where the number of modules determines the plant output. The design and commercialization strategy are based on PRC strengths: (1) amore » rapidly growing electric market that will support low-cost mass production of modular reactor units and (2) a balance of plant system based on economics of scale that uses the same mass-produced turbine-generator systems used in PRC coal plants. If successful, in addition to supplying the PRC market, this strategy could enable China to be the leading exporter of nuclear reactors to developing countries. The modular characteristics of the reactor match much of the need elsewhere in the world. PBRs have major safety advantages and a radically different fuel. The fuel, not the plant systems, is the primary safety system to prevent and mitigate the release of radionuclides under accident conditions. The fuel consists of small (6-cm) pebbles (spheres) containing coatedparticle fuel in a graphitized carbon matrix. The fuel loading per pebble is small (~9 grams of low-enriched uranium) and hundreds of thousands of pebbles are required to fuel a nuclear plant. The uranium concentration in the fuel is an order of magnitude less than in traditional nuclear fuels. These characteristics make the fuel significantly less attractive for illicit use (weapons production or dirty bomb); but, its unusual physical form may require changes in the tools used for safeguards. This report describes PBRs, what is different, and the safeguards challenges. A series of safeguards recommendations are made based on the assumption that the reactor is successfully commercialized and is widely deployed.« less

Program 6 Technical Interchange Meeting Proceedings

DTIC Science & Technology

1992-10-01

Buteau PRC (703)556-1355 Gary R. Dolson PRC (703) 5561859 David J. Gray Sterling (315)336-0500 Noreen S. Heyda Harris (407)984-6384 Jay Jesse GTE (719)570...Reed Sterling John Sautter Sterling (315)336-0500 Kevin Sculley PRC (402)291-5533 Stefan Shrier MRJ (703)934-9249 Peter Soliz Orion (505)262-2260...4730 Howard A. Melching GTE (719)570-8898 Noreen S. Heyda Harris (407)984-6384 Jonathan H. Reed Harris (407)984-6008 Stefan Shrier MRJ (703) 934-9249

The PRC Medium and Long-Term National Science and Technology Development Plan: A Manifesto to Steal

DTIC Science & Technology

2015-02-17

rise in Chinese espionage cases, lax export laws in Hong Kong and recent changes to U.S. visa laws U.S. lawmakers must increase the focus on the...and embedded overseas Chinese scholars, importation of foreign technology through Hong Kong , joint ventures and export relationships with foreign...particularly hardware - to the PRC is through Hong Kong front companies. As example, just last year on 10 November 2014 a PRC national from Hong Kong

China Report, Political, Sociological and Military Affairs, PRC State Council Bulletin, No. 13, 20 May 1985

DTIC Science & Technology

1986-05-16

municipal people’s governments concerned. Please approve and issue this report for implementation by various areas andr departments if the report is found...State Council Pierre Mauroy , Premier Protocol At the signing of the agreement between the Government of the PRC and the Government of the Republic of...Government of the PRC: For the Government of the Republic of France: Zhao Ziyang Pierre Mauroy Premier of the State Council Premier /8309 CSO: 4005/171 37

Rapid and reversible epigenome editing by endogenous chromatin regulators.

PubMed

Braun, Simon M G; Kirkland, Jacob G; Chory, Emma J; Husmann, Dylan; Calarco, Joseph P; Crabtree, Gerald R

2017-09-15

Understanding the causal link between epigenetic marks and gene regulation remains a central question in chromatin biology. To edit the epigenome we developed the FIRE-Cas9 system for rapid and reversible recruitment of endogenous chromatin regulators to specific genomic loci. We enhanced the dCas9-MS2 anchor for genome targeting with Fkbp/Frb dimerizing fusion proteins to allow chemical-induced proximity of a desired chromatin regulator. We find that mSWI/SNF (BAF) complex recruitment is sufficient to oppose Polycomb within minutes, leading to activation of bivalent gene transcription in mouse embryonic stem cells. Furthermore, Hp1/Suv39h1 heterochromatin complex recruitment to active promoters deposits H3K9me3 domains, resulting in gene silencing that can be reversed upon washout of the chemical dimerizer. This inducible recruitment strategy provides precise kinetic information to model epigenetic memory and plasticity. It is broadly applicable to mechanistic studies of chromatin in mammalian cells and is particularly suited to the analysis of endogenous multi-subunit chromatin regulator complexes.Understanding the link between epigenetic marks and gene regulation requires the development of new tools to directly manipulate chromatin. Here the authors demonstrate a Cas9-based system to recruit chromatin remodelers to loci of interest, allowing rapid, reversible manipulation of epigenetic states.

Gene duplication, silencing and expression alteration govern the molecular evolution of PRC2 genes in plants.

PubMed

Furihata, Hazuka Y; Suenaga, Kazuya; Kawanabe, Takahiro; Yoshida, Takanori; Kawabe, Akira

2016-10-13

PRC2 genes were analyzed for their number of gene duplications, d N /d S ratios and expression patterns among Brassicaceae and Gramineae species. Although both amino acid sequences and copy number of the PRC2 genes were generally well conserved in both Brassicaceae and Gramineae species, we observed that some rapidly evolving genes experienced duplications and expression pattern changes. After multiple duplication events, all but one or two of the duplicated copies tend to be silenced. Silenced copies were reactivated in the endosperm and showed ectopic expression in developing seeds. The results indicated that rapid evolution of some PRC2 genes is initially caused by a relaxation of selective constraint following the gene duplication events. Several loci could become maternally expressed imprinted genes and acquired functional roles in the endosperm.

Regulation of stem cell maintenance by the Polycomb protein FIE has been conserved during land plant evolution.

PubMed

Mosquna, Assaf; Katz, Aviva; Decker, Eva L; Rensing, Stefan A; Reski, Ralf; Ohad, Nir

2009-07-01

The Polycomb group (PcG) complex is involved in the epigenetic control of gene expression profiles. In flowering plants, PcG proteins regulate vegetative and reproductive programs. Epigenetically inherited states established in the gametophyte generation are maintained after fertilization in the sporophyte generation, having a profound influence on seed development. The gametophyte size and phase dominance were dramatically reduced during angiosperm evolution, and have specialized in flowering plants to support the reproductive process. The moss Physcomitrella patens is an ideal organism in which to study epigenetic processes during the gametophyte stage, as it possesses a dominant photosynthetic gametophytic haploid phase and efficient homologous recombination, allowing targeted gene replacement. We show that P. patens PcG protein FIE (PpFIE) accumulates in haploid meristematic cells and in cells that undergo fate transition during dedifferentiation programs in the gametophyte. In the absence of PpFIE, meristems overproliferate and are unable to develop leafy gametophytes or reach the reproductive phase. This aberrant phenotype might result from failure of the PcG complex to repress proliferation and differentiation of three-faced apical stem cells, which are designated to become lateral shoots. The PpFIE phenotype can be partially rescued by FIE of Arabidopsis thaliana, a flowering plant that diverged >450 million years ago from bryophytes. PpFIE can partially complement the A. thaliana fie mutant, illustrating functional conservation of the protein during evolution in regulating the differentiation of meristematic cells in gametophyte development, both in bryophytes and angiosperms. This mechanism was harnessed at the onset of the evolution of alternating generations, facilitating the establishment of sporophytic developmental programs.

Unusual Properties of Regulatory DNA from the Drosophila Engrailed Gene: Three ``pairing-Sensitive'' Sites within a 1.6-Kb Region

PubMed Central

Kassis, J. A.

1994-01-01

We have previously shown that a 2-kb fragment of engrailed DNA can suppress expression of a linked marker gene, white, in the P element vector CaSpeR. This suppression is dependent on the presence of two copies of engrailed DNA-containing P elements (P[en]) in proximity in the Drosophila genome (either in cis or in trans). In this study, the 2-kb fragment was dissected and found to contain three fragments of DNA which could mediate white suppression [called ``pairing-sensitive sites'' (PS)]. A PS site was also identified in regulatory DNA from the Drosophila escargot gene. The eye colors of six different P[en] insertions in the escargot gene suggest an interaction between P[en]-encoded and genome-encoded PS sites. I hypothesize that white gene expression from P[en] is repressed by the formation of a protein complex which is initiated at the engrailed PS sites and also requires interactions with flanking genomic DNA. Genes were sought which influence the function of PS sites. Mutations in some Polycomb and trithorax group genes were found to affect the eye color from some P[en] insertion sites. However, different mutations affected expression from different P[en] insertion sites and no one mutation was found to affect expression from all P[en] insertion sites examined. These results suggest that white expression from P[en] is not directly regulated by members of the Polycomb and trithorax group genes, but in some cases can be influenced by them. I propose that engrailed PS sites normally act to promote interactions between distantly located engrailed regulatory sites and the engrailed promoter. PMID:8005412

Bmi-1: At the crossroads of physiological and pathological biology

PubMed Central

Bhattacharya, Resham; Mustafi, Soumyajit Banerjee; Street, Mark; Dey, Anindya; Dwivedi, Shailendra Kumar Dhar

2015-01-01

Bmi-1 is a member of the Polycomb Repressor Complex1 that mediates gene silencing by regulating chromatin structure and is indispensable for self-renewal of both normal and cancer stem cells. Despite three decades of research that have elucidated the transcriptional regulation, post-translational modifications and functions of Bmi-1 in regulating the DNA damage response, cellular bioenergetics, and pathologies, the entire potential of a protein with such varied function remains to be realized. This review attempts to synthesize the current knowledge on Bmi-1 with an emphasis on its role in both normal physiology and cancer. Additionally, since cancer stem cells are emerging as a new paradigm for therapy resistance, the role of Bmi-1 in this perspective is also highlighted. The wide spectrum of malignancies that implicate Bmi-1 as a signature for stemness and oncogenesis also make it a suitable candidate for therapy. Nonetheless new approaches are vitally needed to further characterize physiological roles of Bmi-1 with the long-term goal of using Bmi-1 as a prognostic marker and a therapeutic target. PMID:26448339

Functional characterization of an apple apomixis-related MhFIE gene in reproduction development.

PubMed

Liu, Dan-Dan; Dong, Qing-Long; Sun, Chao; Wang, Qing-Lian; You, Chun-Xiang; Yao, Yu-Xin; Hao, Yu-Jin

2012-04-01

The products of the FIS genes play important regulatory roles in diverse developmental processes, especially in seed formation after fertilization. In this study, a FIS-class gene MhFIE was isolated from apple. It encoded a predicted protein highly similar to polycomb group (PcG) protein FERTILIZATION-INDEPENDENT ENDOSPERM (FIE). MhFIE functioned as an Arabidopsis FIE homologue, as indicated by functional complementation experiment using Arabidopsis fie mutant. In addition, BiFC assay showed that MhFIE protein interacted with AtCLF. Furthermore, transgenic Arabidopsis ectopically expressing MhFIE produced less APETALA3 (AtAP3) and AGAMOUS (AtAG) transcripts than WT control, and therefore exhibited abnormal flower, seed development. These results suggested that polycomb complex including FIE and CLF proteins played an important role in reproductive development by regulating the expression of its downstream genes. In addition, it was found that MhFIE constitutively expressed in various tissues tested. Its expression levels were lower in apomictic apple species than the sexual reproductive species, suggested it was possibly involved into apomixis in apple. Furthermore, the hybrids of tea crabapple generated MhFIE transcripts at different levels. The parthenogenesis capacity was negatively correlated with MhFIE expression level in these hybrids. These results suggested that MhFIE was involved into the regulation of flower development and apomixis in apple. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Interpreting the human phase response curve to multiple bright-light exposures.

PubMed

Strogatz, S H

1990-01-01

Czeisler and his colleagues have recently reported that bright light can induce strong (Type O) resetting of the human circadian pacemaker. This surprising result shows that the human clock is more responsive to light than has been previously thought. The interpretation of their results is subtle, however, because of an unconventional aspect of their experimental protocol: They measured the phase shift after three cycles of the bright-light stimulus, rather than after the usual single pulse. A natural question is whether the apparent Type O response could reflect the summation of three weaker Type 1 responses to each of the daily light pulses. In this paper I show mathematically that repeated Type 1 resetting cannot account for the observed Type O response. This finding corroborates the strong resetting reported by Czeisler et al., and supports their claim that bright light induces strong resetting by crushing the amplitude of the circadian pacemaker. Furthermore, the results indicate that back-to-back light pulses can have a cooperative effect different from that obtained by simple iteration of a phase response curve (PRC). In this sense the resetting response of humans is similar to that of Drosophila, Kalanchoe, and Culex, and is more complex than that predicted by conventional PRC theory. To describe the way in which light resets the human circadian pacemaker, one needs a theory that includes amplitude resetting, as pioneered by Winfree and developed for humans by Kronauer.

Advanced Age Dissociates Dual Functions of the Perirhinal Cortex

PubMed Central

Burke, Sara N.; Maurer, Andrew P.; Nematollahi, Saman; Uprety, Ajay; Wallace, Jenelle L.

2014-01-01

The perirhinal cortex (PRC) is proposed to both represent high-order sensory information and maintain those representations across delays. These cognitive processes are required for recognition memory, which declines during normal aging. Whether or not advanced age affects the ability of PRC principal cells to support these dual roles, however, is not known. The current experiment recorded PRC neurons as young and aged rats traversed a track. When objects were placed on the track, a subset of the neurons became active at discrete locations adjacent to objects. Importantly, the aged rats had a lower proportion of neurons that were activated by objects. Once PRC activity patterns in the presence of objects were established, however, both age groups maintained these representations across delays up to 2 h. These data support the hypothesis that age-associated deficits in stimulus recognition arise from impairments in high-order stimulus representation rather than difficulty in sustaining stable activity patterns over time. PMID:24403147

Advanced age dissociates dual functions of the perirhinal cortex.

PubMed

Burke, Sara N; Maurer, Andrew P; Nematollahi, Saman; Uprety, Ajay; Wallace, Jenelle L; Barnes, Carol A

2014-01-08

The perirhinal cortex (PRC) is proposed to both represent high-order sensory information and maintain those representations across delays. These cognitive processes are required for recognition memory, which declines during normal aging. Whether or not advanced age affects the ability of PRC principal cells to support these dual roles, however, is not known. The current experiment recorded PRC neurons as young and aged rats traversed a track. When objects were placed on the track, a subset of the neurons became active at discrete locations adjacent to objects. Importantly, the aged rats had a lower proportion of neurons that were activated by objects. Once PRC activity patterns in the presence of objects were established, however, both age groups maintained these representations across delays up to 2 h. These data support the hypothesis that age-associated deficits in stimulus recognition arise from impairments in high-order stimulus representation rather than difficulty in sustaining stable activity patterns over time.

A Consistent Definition of Phase Resetting Using Hilbert Transform.

PubMed

Oprisan, Sorinel A

2017-01-01

A phase resetting curve (PRC) measures the transient change in the phase of a neural oscillator subject to an external perturbation. The PRC encapsulates the dynamical response of a neural oscillator and, as a result, it is often used for predicting phase-locked modes in neural networks. While phase is a fundamental concept, it has multiple definitions that may lead to contradictory results. We used the Hilbert Transform (HT) to define the phase of the membrane potential oscillations and HT amplitude to estimate the PRC of a single neural oscillator. We found that HT's amplitude and its corresponding instantaneous frequency are very sensitive to membrane potential perturbations. We also found that the phase shift of HT amplitude between the pre- and poststimulus cycles gives an accurate estimate of the PRC. Moreover, HT phase does not suffer from the shortcomings of voltage threshold or isochrone methods and, as a result, gives accurate and reliable estimations of phase resetting.

Altered Expression of Polycomb Group Genes in Glioblastoma Multiforme

PubMed Central

Li, Gang; Warden, Charles; Zou, Zhaoxia; Neman, Josh; Krueger, Joseph S.; Jain, Alisha; Jandial, Rahul; Chen, Mike

2013-01-01

The Polycomb group (PcG) proteins play a critical role in histone mediated epigenetics which has been implicated in the malignant evolution of glioblastoma multiforme (GBM). By systematically interrogating The Cancer Genome Atlas (TCGA), we discovered widespread aberrant expression of the PcG members in GBM samples compared to normal brain. The most striking differences were upregulation of EZH2, PHF19, CBX8 and PHC2 and downregulation of CBX7, CBX6, EZH1 and RYBP. Interestingly, changes in EZH2, PHF19, CBX7, CBX6 and EZH1 occurred progressively as astrocytoma grade increased. We validated the aberrant expression of CBX6, CBX7, CBX8 and EZH2 in GBM cell lines by Western blotting and qRT-PCR, and further the aberrant expression of CBX6 in GBM tissue samples by immunohistochemical staining. To determine if there was functional significance to the diminished CBX6 levels in GBM, CBX6 was overexpressed in GBM cells resulting in decreased proliferative capacity. In conclusion, aberrant expression of PcG proteins in GBMs may play a role in the development or maintenance of the malignancy. PMID:24260522

Altered expression of polycomb group genes in glioblastoma multiforme.

PubMed

Li, Gang; Warden, Charles; Zou, Zhaoxia; Neman, Josh; Krueger, Joseph S; Jain, Alisha; Jandial, Rahul; Chen, Mike

2013-01-01

The Polycomb group (PcG) proteins play a critical role in histone mediated epigenetics which has been implicated in the malignant evolution of glioblastoma multiforme (GBM). By systematically interrogating The Cancer Genome Atlas (TCGA), we discovered widespread aberrant expression of the PcG members in GBM samples compared to normal brain. The most striking differences were upregulation of EZH2, PHF19, CBX8 and PHC2 and downregulation of CBX7, CBX6, EZH1 and RYBP. Interestingly, changes in EZH2, PHF19, CBX7, CBX6 and EZH1 occurred progressively as astrocytoma grade increased. We validated the aberrant expression of CBX6, CBX7, CBX8 and EZH2 in GBM cell lines by Western blotting and qRT-PCR, and further the aberrant expression of CBX6 in GBM tissue samples by immunohistochemical staining. To determine if there was functional significance to the diminished CBX6 levels in GBM, CBX6 was overexpressed in GBM cells resulting in decreased proliferative capacity. In conclusion, aberrant expression of PcG proteins in GBMs may play a role in the development or maintenance of the malignancy.

Poly[[diaqua­hemi-μ4-oxalato-μ2-oxalato-praseodymium(III)] monohydrate

PubMed Central

Yang, Ting-Hai; Chen, Qiang; Zhuang, Wei; Wang, Zhe; Yue, Bang-Yi

2009-01-01

In the title complex, {[Pr(C2O4)1.5(H2O)2]·H2O}n, the PrIII ion, which lies on a crystallographic inversion centre, is coordinated by seven O atoms from four oxalate ligands and two O atoms from two water ligands; further Pr—O coordination from tetra­dentate oxalate ligands forms a three-dimensional structure. The compound crystallized as a monohydrate, the water mol­ecule occupying space in small voids and being secured by O—H⋯O hydrogen bonding as an acceptor from ligand water H atoms and as a donor to oxalate O-acceptor sites. PMID:21577485

Photic Resetting and Entrainment in CLOCK-Deficient Mice

PubMed Central

Dallmann, Robert; DeBruyne, Jason P.; Weaver, David R.

2012-01-01

Mice lacking CLOCK protein have a relatively subtle circadian phenotype, including a slightly shorter period in constant darkness, differences in phase resetting after 4-hr light pulses in the early and late night, and a variably advanced phase angle of entrainment in a light-dark (LD) cycle (DeBruyne et al., Neuron 50:465–477, 2006). The present series of experiments was conducted to more fully characterize the circadian phenotype of Clock−/− mice under various lighting conditions. A phase-response curve (PRC) to 4-hour light pulses in free-running mice was conducted; the results confirm that Clock−/− mice exhibit very large phase advances after 4 hrs light pulses in the late subjective night, but have relatively normal responses to light at other phases. The abnormal shape of the PRC to light may explain the tendency of CLOCK-deficient mice to begin activity before lights-out when housed in a 12 hrs light: 12 hrs dark lighting schedule. To assess this relationship further, Clock−/− and wild-type control mice were entrained to skeleton lighting cycles (1L:23D, and 1L:10D:1L:12D). Comparing entrainment under the two types of skeleton photoperiods revealed that exposure to 1 hr light in the morning leads to a phase advance of activity onset (expressed the following afternoon) in Clock−/− mice, but not in the controls. Constant light typically causes an intensity-dependent increase in circadian period in mice, but this did not occur in CLOCK-deficient mice. The failure of Clock−/− mice to respond to the period-lengthening effect of constant light likely results from the increased functional impact of light falling in the phase advance zone of the PRC. Collectively, these experiments reveal that alterations in the response of CLOCK-deficient mice to light in several paradigms are likely due to an imbalance in the shape of the PRC to light. PMID:21921293

Crumbs regulates rhodopsin transport by interacting with and stabilizing myosin V

PubMed Central

Shevchenko, Anna

2011-01-01

The evolutionarily conserved Crumbs (Crb) complex is crucial for photoreceptor morphogenesis and homeostasis. Loss of Crb results in light-dependent retinal degeneration, which is prevented by feeding mutant flies carotenoid-deficient medium. This suggests a defect in rhodopsin 1 (Rh1) processing, transport, and/or signaling, causing degeneration; however, the molecular mechanism of this remained elusive. In this paper, we show that myosin V (MyoV) coimmunoprecipitated with the Crb complex and that loss of crb led to severe reduction in MyoV levels, which could be rescued by proteasomal inhibition. Loss of MyoV in crb mutant photoreceptors was accompanied by defective transport of the MyoV cargo Rh1 to the light-sensing organelle, the rhabdomere. This resulted in an age-dependent accumulation of Rh1 in the photoreceptor cell (PRC) body, a well-documented trigger of degeneration. We conclude that Crb protects against degeneration by interacting with and stabilizing MyoV, thereby ensuring correct Rh1 trafficking. Our data provide, for the first time, a molecular mechanism for the light-dependent degeneration of PRCs observed in crb mutant retinas. PMID:22105348

MicroRNA-26a is a key regulon that inhibits progression and metastasis of c-Myc/EZH2 double high advanced hepatocellular carcinoma.

PubMed

Zhang, Xiang; Zhang, Xiao; Wang, Ting; Wang, Lei; Tan, Zhijun; Wei, Wei; Yan, Bo; Zhao, Jing; Wu, Kaichun; Yang, Angang; Zhang, Rui; Jia, Lintao

2018-07-10

The transcription factor c-Myc is a key driver for hepatocellular carcinomas (HCCs), while the polycombrepressive complex 2 (PRC2) subunit EZH2 is an essential biomarker of HCC. c-Myc epigenetically silences tumor suppressors by recruiting PRC2 and inducing methylation of histone H3 lysine 27. However, it remains elusive how they are regulated in HCC. We found here that microRNA-26a (miR-26a) suppresses c-Myc, a classical Wnt pathway target gene, by targeting the Wnt pathway coactivator, cyclin-dependent kinase 8 (CDK8); miR-26a also directly targets and inhibits EZH2. The expression of MIR26A2, a predominant origin of miR-26a transcripts in hepatic cells, is repressed by c-Myc/PRC2, thereby forming a c-Myc/miR-26a/CDK8 regulatory circuit in HCC. Meanwhile, miR-26a suppresses migration of HCC by targeting p21-activated kinase 2 (PAK2), a critical kinase linking Rho GTPases to cytoskeleton reorganization. Consequently, in vivo delivery of miR-26a remarkably suppressed the development of xenograft HCC and metastasis of orthotopic HCC by downregulating c-Myc, CDK8 and PAK2. These findings unraveled a novel mechanism of c-Myc and Wnt/β-catenin interplay that dictates HCC pathogenesis, and have implications for the potential applicability of miRNA delivery in targeting the newly identified signaling axis and treating metastatic HCCs. Copyright © 2018 Elsevier B.V. All rights reserved.

Human phase response curve to intermittent blue light using a commercially available device

PubMed Central

Revell, Victoria L; Molina, Thomas A; Eastman, Charmane I

2012-01-01

Light shifts the timing of the circadian clock according to a phase response curve (PRC). To date, all human light PRCs have been to long durations of bright white light. However, melanopsin, the primary photopigment for the circadian system, is most sensitive to short wavelength blue light. Therefore, to optimise light treatment it is important to generate a blue light PRC. We used a small, commercially available blue LED light box, screen size 11.2 × 6.6 cm at ∼50 cm, ∼200 μW cm−2, ∼185 lux. Subjects participated in two 5 day laboratory sessions 1 week apart. Each session consisted of circadian phase assessments to obtain melatonin profiles before and after 3 days of free-running through an ultradian light–dark cycle (2.5 h wake in dim light, 1.5 h sleep in the dark), forced desynchrony protocol. During one session subjects received intermittent blue light (three 30 min pulses over 2 h) once a day for the 3 days of free-running, and in the other session (control) they remained in dim room light, counterbalanced. The time of blue light was varied among subjects to cover the entire 24 h day. For each individual, the phase shift to blue light was corrected for the free-run determined during the control session. The blue light PRC had a broad advance region starting in the morning and extending through the afternoon. The delay region started a few hours before bedtime and extended through the night. This is the first PRC to be constructed to blue light and to a stimulus that could be used in the real world. PMID:22753544

Human phase response curve to intermittent blue light using a commercially available device.

PubMed

Revell, Victoria L; Molina, Thomas A; Eastman, Charmane I

2012-10-01

Light shifts the timing of the circadian clock according to a phase response curve (PRC). To date, all human light PRCs have been to long durations of bright white light. However, melanopsin, the primary photopigment for the circadian system, is most sensitive to short wavelength blue light. Therefore, to optimise light treatment it is important to generate a blue light PRC.We used a small, commercially available blue LED light box, screen size 11.2 × 6.6 cm at ∼50 cm, ∼200 μW cm(−2), ∼185 lux. Subjects participated in two 5 day laboratory sessions 1 week apart. Each session consisted of circadian phase assessments to obtain melatonin profiles before and after 3 days of free-running through an ultradian light–dark cycle (2.5 h wake in dim light, 1.5 h sleep in the dark), forced desynchrony protocol. During one session subjects received intermittent blue light (three 30 min pulses over 2 h) once a day for the 3 days of free-running, and in the other session (control) they remained in dim room light, counterbalanced. The time of blue light was varied among subjects to cover the entire 24 h day. For each individual, the phase shift to blue light was corrected for the free-run determined during the control session. The blue light PRC had a broad advance region starting in the morning and extending through the afternoon. The delay region started a few hours before bedtime and extended through the night. This is the first PRC to be constructed to blue light and to a stimulus that could be used in the real world.

The MAP kinase ERK and its scaffold protein MP1 interact with the chromatin regulator Corto during Drosophila wing tissue development

PubMed Central

2011-01-01

Background Mitogen-activated protein kinase (MAPK) cascades (p38, JNK, ERK pathways) are involved in cell fate acquisition during development. These kinase modules are associated with scaffold proteins that control their activity. In Drosophila, dMP1, that encodes an ERK scaffold protein, regulates ERK signaling during wing development and contributes to intervein and vein cell differentiation. Functional relationships during wing development between a chromatin regulator, the Enhancer of Trithorax and Polycomb Corto, ERK and its scaffold protein dMP1, are examined here. Results Genetic interactions show that corto and dMP1 act together to antagonize rolled (which encodes ERK) in the future intervein cells, thus promoting intervein fate. Although Corto, ERK and dMP1 are present in both cytoplasmic and nucleus compartments, they interact exclusively in nucleus extracts. Furthermore, Corto, ERK and dMP1 co-localize on several sites on polytene chromosomes, suggesting that they regulate gene expression directly on chromatin. Finally, Corto is phosphorylated. Interestingly, its phosphorylation pattern differs between cytoplasm and nucleus and changes upon ERK activation. Conclusions Our data therefore suggest that the Enhancer of Trithorax and Polycomb Corto could participate in regulating vein and intervein genes during wing tissue development in response to ERK signaling. PMID:21401930

Synchronization properties of heterogeneous neuronal networks with mixed excitability type

NASA Astrophysics Data System (ADS)

Leone, Michael J.; Schurter, Brandon N.; Letson, Benjamin; Booth, Victoria; Zochowski, Michal; Fink, Christian G.

2015-03-01

We study the synchronization of neuronal networks with dynamical heterogeneity, showing that network structures with the same propensity for synchronization (as quantified by master stability function analysis) may develop dramatically different synchronization properties when heterogeneity is introduced with respect to neuronal excitability type. Specifically, we investigate networks composed of neurons with different types of phase response curves (PRCs), which characterize how oscillating neurons respond to excitatory perturbations. Neurons exhibiting type 1 PRC respond exclusively with phase advances, while neurons exhibiting type 2 PRC respond with either phase delays or phase advances, depending on when the perturbation occurs. We find that Watts-Strogatz small world networks transition to synchronization gradually as the proportion of type 2 neurons increases, whereas scale-free networks may transition gradually or rapidly, depending upon local correlations between node degree and excitability type. Random placement of type 2 neurons results in gradual transition to synchronization, whereas placement of type 2 neurons as hubs leads to a much more rapid transition, showing that type 2 hub cells easily "hijack" neuronal networks to synchronization. These results underscore the fact that the degree of synchronization observed in neuronal networks is determined by a complex interplay between network structure and the dynamical properties of individual neurons, indicating that efforts to recover structural connectivity from dynamical correlations must in general take both factors into account.

CHOL-N-SOIL PCB TEST KIT, DEXSIL CORP. - INNOVATIVE TECHNOLOGY Evaluation REPORT

EPA Science Inventory

This innovative technology evaluation report (ITER) presents the evaluation of two field screening technologies for determining polychlorinated biphenyl (PCB) contamination in soil. The demonstration was conducted by PRC Environmental Management, Inc. (PRC), under contract to the...

15 CFR 748.10 - Import Certificates and End-User Statements.

Code of Federal Regulations, 2013 CFR

2013-01-01

... value. Also, if your transaction involves an export to the PRC of an item classified under ECCN 6A003... national security reasons (or, for the PRC, for any reason) in a single ECCN exceeding $50,000, an Import...

15 CFR 748.10 - Import Certificates and End-User Statements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... value. Also, if your transaction involves an export to the PRC of an item classified under ECCN 6A003... national security reasons (or, for the PRC, for any reason) in a single ECCN exceeding $50,000, an Import...

15 CFR 748.10 - Import Certificates and End-User Statements.

Code of Federal Regulations, 2011 CFR

2011-01-01

... value. Also, if your transaction involves an export to the PRC of an item classified under ECCN 6A003... national security reasons (or, for the PRC, for any reason) in a single ECCN exceeding $50,000, an Import...

15 CFR 748.10 - Import Certificates and End-User Statements.

Code of Federal Regulations, 2012 CFR

2012-01-01

... value. Also, if your transaction involves an export to the PRC of an item classified under ECCN 6A003... national security reasons (or, for the PRC, for any reason) in a single ECCN exceeding $50,000, an Import...

15 CFR 748.10 - Import Certificates and End-User Statements.

Code of Federal Regulations, 2014 CFR

2014-01-01

... value. Also, if your transaction involves an export to the PRC of an item classified under ECCN 6A003... national security reasons (or, for the PRC, for any reason) in a single ECCN exceeding $50,000, an Import...

Dual Functions of Perirhinal Cortex in Fear Conditioning

PubMed Central

Kent, Brianne A.; Brown, Thomas H.

2012-01-01

The present review examines the role of perirhinal cortex (PRC) in Pavlovian fear conditioning. The focus is on rats, partly because so much is known, behaviorally and neurobiologically, about fear conditioning in these animals. In addition, the neuroanatomy and neurophysiology of rat PRC have been described in considerable detail at the cellular and systems levels. The evidence suggests that PRC can serve at least two types of mnemonic functions in Pavlovian fear conditioning. The first function, termed "stimulus unitization," refers to the ability to treat two or more separate items or stimulus elements as a single entity. Supporting evidence for this perceptual function comes from studies of context conditioning as well as delay conditioning to discontinuous auditory cues. In a delay paradigm, the conditional stimulus (CS) and unconditional stimulus (US) overlap temporally and co-terminate. The second PRC function entails a type of "transient memory." Supporting evidence comes from studies of trace cue conditioning, where there is a temporal gap or trace interval between the CS offset and the US onset. For learning to occur, there must be a transient CS representation during the trace interval. We advance a novel neurophysiological mechanism for this transient representation. These two hypothesized functions of PRC are consistent with inferences based on non-aversive forms of learning. PMID:22903623

Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

PubMed Central

Watanabe, Yukiko; Onodera, Atsushi; Kanai, Urara; Ichikawa, Tomomi; Obata-Ninomiya, Kazushige; Wada, Tomoko; Kiuchi, Masahiro; Iwamura, Chiaki; Tumes, Damon J.; Shinoda, Kenta; Yagi, Ryoji; Motohashi, Shinichiro; Hirahara, Kiyoshi; Nakayama, Toshinori

2014-01-01

Epigenetic modifications, such as posttranslational modifications of histones, play an important role in gene expression and regulation. These modifications are in part mediated by the Trithorax group (TrxG) complex and the Polycomb group (PcG) complex, which activate and repress transcription, respectively. We herein investigate the role of Menin, a component of the TrxG complex in T helper (Th) cell differentiation and show a critical role for Menin in differentiation and maintenance of Th17 cells. Menin−/− T cells do not efficiently differentiate into Th17 cells, leaving Th1 and Th2 cell differentiation intact in in vitro cultures. Menin deficiency resulted in the attenuation of Th17-induced airway inflammation. In differentiating Th17 cells, Menin directly bound to the Il17a gene locus and was required for the deposition of permissive histone modifications and recruitment of the RNA polymerase II transcriptional complex. Interestingly, although Menin bound to the Rorc locus, Menin was dispensable for the induction of Rorc expression and permissive histone modifications in differentiating Th17 cells. In contrast, Menin was required to maintain expression of Rorc in differentiated Th17 cells, indicating that Menin is essential to stabilize expression of the Rorc gene. Thus, Menin orchestrates Th17 cell differentiation and function by regulating both the induction and maintenance of target gene expression. PMID:25136117

Neuropilin-2: Novel Biomarker and Therapeutic Target for Aggressive Prostate Cancer

DTIC Science & Technology

2013-09-01

pathways GLI1 BMI1 Perivascular niche Oncogenic stimuli Self- renewal Polycomb group Proteins that were first described in Drosophila melanogaster ...Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author...s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation

Evaluating the precision of passive sampling methods using ...

EPA Pesticide Factsheets

To assess these models, four different thicknesses of low-density polyethylene (LDPE) passive samplers were co-deployed for 28 days in the water column at three sites in New Bedford Harbor, MA, USA. Each sampler was pre-loaded with six PCB performance reference compounds (PRCs) to assess equilibrium status, such that the percent of PRC lost would range depending on PRC and LDPE thickness. These data allow subsequent Cfree comparisons to be made in two ways: (1) comparing Cfree derived from one thickness using different models and (2) comparing Cfree derived from the same model using different thicknesses of LDPE. Following the deployments, the percent of PRC lost ranged from 0-100%. As expected, fractional equilibrium decreased with increasing PRC molecular weight as well as sampler thickness. Overall, a total of 27 PCBs (log KOW ranging from 5.07 – 8.09) were measured at Cfree concentrations varying from 0.05 pg/L (PCB 206) to about 200 ng/L (PCB 28) on a single LDPE sampler. Relative standard deviations (RSDs) for total PCB measurements using the same thickness and varying model types range from 0.04-12% and increased with sampler thickness. Total PCB RSD for measurements using the same model and varying thickness ranged from: 6 – 30%. No RSD trends between models were observed but RSD did increase as Cfree decreased. These findings indicate that existing models yield precise and reproducible results when using LDPE and PRCs to measure Cfree. This work in

The Growing Complexity of Sino-Indian Ties

DTIC Science & Technology

2014-06-01

with a record of dealing with North Korea , Iran , and Libya, reflects China’s growing diplomatic confidence and underscores its view of Pakistan as a...issues. Dr. Pant’s most recent books include The US-India Nuclear Pact: Policy, Process and Great Power Politics (Oxford Univer- sity Press, 2011...membership at the United Nations (UN) but also opposed attempts to condemn the PRC for its actions in Korea . Yet, the issue of Tibet soon emerged as the

76 FR 54510 - New Postal Product

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-01

... Service request to enter into an additional agreement under the ``International Business Reply Service..., 2011. ADDRESSES: Submit comments electronically by accessing the ``Filing Online'' link in the banner... Commission's Filing Online system at https://www.prc.gov/prc-pages/filing-online/login.aspx . Commenters who...

Dysprosium complexes with mono-/di-carboxylate ligands-From simple dimers to 2D and 3D frameworks

NASA Astrophysics Data System (ADS)

Zhang, Yingjie; Bhadbhade, Mohan; Scales, Nicholas; Karatchevtseva, Inna; Price, Jason R.; Lu, Kim; Lumpkin, Gregory R.

2014-11-01

Four dysprosium (Dy) single carboxylates, a formate, a propionate, a butyrate and an oxalate have been synthesized and structurally characterized. The structure of Dy(HCO2)3 (1) contains nine-fold coordinated Dy polyhedra in perfect tricapped trigonal prisms. They are linked through trigonal O atoms forming 1D pillars which are further linked together through tricapped O atoms into a 3D pillared metal organic framework. The network structure is stable up to 360 °C. The structure of [Dy2(C2O4)3(H2O)6]·2.5H2O (2) contains nine-fold coordinated Dy polyhedra linking together through μ2-bridging oxalate anions into a 2D hexagonal layered structure. Both [Dy2(Pr)6(H2O)4]·(HPr)0.5 (3) [Pr=(C2H5CO2)-1] and [Dy2(Bu)6(H2O)4] (4) [Bu=(C3H7CO2)-1] have similar di-nuclear structures. The Raman vibration modes of the complexes have been investigated.

QMC Goes BOINC: Using Public Resource Computing to Perform Quantum Monte Carlo Calculations

NASA Astrophysics Data System (ADS)

Rainey, Cameron; Engelhardt, Larry; Schröder, Christian; Hilbig, Thomas

2008-10-01

Theoretical modeling of magnetic molecules traditionally involves the diagonalization of quantum Hamiltonian matrices. However, as the complexity of these molecules increases, the matrices become so large that this process becomes unusable. An additional challenge to this modeling is that many repetitive calculations must be performed, further increasing the need for computing power. Both of these obstacles can be overcome by using a quantum Monte Carlo (QMC) method and a distributed computing project. We have recently implemented a QMC method within the Spinhenge@home project, which is a Public Resource Computing (PRC) project where private citizens allow part-time usage of their PCs for scientific computing. The use of PRC for scientific computing will be described in detail, as well as how you can contribute to the project. See, e.g., L. Engelhardt, et. al., Angew. Chem. Int. Ed. 47, 924 (2008). C. Schröoder, in Distributed & Grid Computing - Science Made Transparent for Everyone. Principles, Applications and Supporting Communities. (Weber, M.H.W., ed., 2008). Project URL: http://spin.fh-bielefeld.de

The great Chinese fire of 1987 - A view from space

NASA Technical Reports Server (NTRS)

Cahoon, Donald R., Jr.; Levine, Joel S.; Cofer, Wesley R., III; Miller, James E.; Minnis, Patrick; Tennille, Geoffrey M.; Yip, Tommy W.; Stocks, Brian J.; Heck, Patrick W.

1991-01-01

One of the largest forest fires ever recorded burned in the People's Republic of China (PRC) and the Soviet Union in May 1987. The fire covered over 1.0 million hectares in the PRC and almost 4 million hectares in the Soviet Union. The progress and areal extent of the fire were measured using satellite images analyzed in the imaging facilities at NASA-Langley and Forestry Canada. The analyses show the utility and value of satellite measurements to assess the areal extent and geographical distribution of fires, and have important implications for future measurements to be obtained from space platforms, such as the Earth Observing System.

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

Polycomb-group protein SlMSI1 represses the expression of fruit-ripening genes to prolong shelf life in tomato.

PubMed

Liu, Dan-Dan; Zhou, Li-Jie; Fang, Mou-Jing; Dong, Qing-Long; An, Xiu-Hong; You, Chun-Xiang; Hao, Yu-Jin

2016-08-25

Polycomb-group (PcG) protein MULTICOPY SUPPRESSOR OF IRA1 (MSI1) protein is an evolutionarily conserved developmental suppressor and plays a crucial role in regulating epigenetic modulations. However, the potential role and function of MSI1 in fleshy fruits remain unknown. In this study, SlMSI1 was cloned and transformed into tomato to explore its function. The quantitative real-time PCR results showed that SlMSI1 was highly expressed in flowers and fruits and that its transcript and protein levels were significantly decreased in fruits after the breaker stage. Additionally, SlMSI1-overexpressing transgenic tomatoes displayed abnormal non-ripening fruit formation, whereas its suppression promoted fruit ripening in transgenic tomatoes. Quantitative real-time PCR assays also showed that RIN and its regulons were decreased in SlMSI1 overexpression transgenic tomato fruits. Furthermore, RNA-seq analysis demonstrated that SlMSI1 inhibits fruit ripening by negatively regulating a large set of fruit-ripening genes in addition to RIN and its regulons. Finally, genetic manipulation of SlMSI1 and RIN successfully prolonged the fruit shelf life by regulating the fruit-ripening genes in tomato. Our findings reveal a novel regulatory function of SlMSI1 in fruit ripening and provide a new regulator that may be useful for genetic engineering and modification of fruit shelf life.

Polycomb-group protein SlMSI1 represses the expression of fruit-ripening genes to prolong shelf life in tomato

PubMed Central

Liu, Dan-Dan; Zhou, Li-Jie; Fang, Mou-Jing; Dong, Qing-Long; An, Xiu-Hong; You, Chun-Xiang; Hao, Yu-Jin

2016-01-01

Polycomb-group (PcG) protein MULTICOPY SUPPRESSOR OF IRA1 (MSI1) protein is an evolutionarily conserved developmental suppressor and plays a crucial role in regulating epigenetic modulations. However, the potential role and function of MSI1 in fleshy fruits remain unknown. In this study, SlMSI1 was cloned and transformed into tomato to explore its function. The quantitative real-time PCR results showed that SlMSI1 was highly expressed in flowers and fruits and that its transcript and protein levels were significantly decreased in fruits after the breaker stage. Additionally, SlMSI1-overexpressing transgenic tomatoes displayed abnormal non-ripening fruit formation, whereas its suppression promoted fruit ripening in transgenic tomatoes. Quantitative real-time PCR assays also showed that RIN and its regulons were decreased in SlMSI1 overexpression transgenic tomato fruits. Furthermore, RNA-seq analysis demonstrated that SlMSI1 inhibits fruit ripening by negatively regulating a large set of fruit-ripening genes in addition to RIN and its regulons. Finally, genetic manipulation of SlMSI1 and RIN successfully prolonged the fruit shelf life by regulating the fruit-ripening genes in tomato. Our findings reveal a novel regulatory function of SlMSI1 in fruit ripening and provide a new regulator that may be useful for genetic engineering and modification of fruit shelf life. PMID:27558543

Interference with endogenous EZH2 reverses the chemotherapy drug resistance in cervical cancer cells partly by up-regulating Dicer expression.

PubMed

Cai, Liqiong; Wang, Zehua; Liu, Denghua

2016-05-01

Cervical cancer is one of the most common female malignancies in the world, and chemotherapeutic drug resistance is a major obstacle to cancer therapy. Enhancer of zeste homolog 2 (EZH2) is an enzymatic subunit of polycomb repressive complex 2 (PRC2) and catalyzes the repressive histone H3 lysine 27 trimethylation (H3K27me3). However, the role of EZH2 on the chemotherapy drug resistance in cervical cancers remains unclear. In the present study, the cervical carcinoma specimens and paired normal tissue specimens were obtained and the expression of EZH2 was detected by western blotting. The results showed that high levels of EZH2 were detected in cervical carcinoma tissues, compared with paired control tissues (**p < 0.01). Next, three pairs of shRNA specific to EZH2 were designed and used to interfere with endogenous EZH2 expression. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays following treatment with various concentrations of cisplatin in HeLa and HeLa/DDP cells. The MTT assay results showed that knockdown of EZH2 in HeLa/DDP cells caused a 2.29- or 1.83-fold decrease in the cisplatin IC50 values (for shRNA1-EZH2, 34.88 vs. 15.21 μg/mL; p < 0.01; for shRNA3-EZH2, 34.88 vs. 19.09 μg/mL; p < 0.01). The EZH2 activity was also suppressed by 3-deazaneplanocin A (DZNep), EZH2 inhibitor, and the results demonstrated that, meanwhile, DZNep potently inhibited cell viability of HeLa/DDP cells, partly by suppression the levels of EZH2 and H3K27me3, but not H3K27me2, which was detected by western blotting analysis. Moreover, cell migration assay results showed that knockdown of EZH2 decreased cell metastasis of cervical cancer cells. Furthermore, cell cycle was detected by fluorescence-activated cell sorting (FACS) assay and the results demonstrated that interference with EZH2 expression increased the percentage of cells at G0/G1 phase and the HeLa/DDP cells were blocked at G0/G1 phase. Interestingly, western blotting results revealed that higher expression of EZH2 was related with lower level of Dicer in HeLa/DDP cells. Finally, in vivo tumorigenicity experiments results demonstrated that interference with endogenous EZH2 by shRNA specific to EZH2 or inhibition EZH2 by DZNep could significantly increase antitumor effects in nude mice. Thus, inhibiting the levels of endogenous EZH2 effectively reversed the cisplatin resistance and increased the cisplatin sensitivity in cisplatin-resistant HeLa/DDP cells. EZH2 might be a potential target for treating chemotherapeutic drug-resistant cervical cancers.

Disruptions to women's social identity: a comparative study of workplace stress experienced by women in three geographic regions.

PubMed

Shaffer, M A; Joplin, J R; Bell, M P; Lau, T; Oguz, C

2000-10-01

Drawing on social identity theory (P. J. Burke, 1991) and the current status of women and equal opportunity legislation, the authors tested several factors associated with distress in working women in the People's Republic of China (PRC), Hong Kong, and the United States. Women in Hong Kong experienced significantly greater levels of life stress than PRC and U.S. women. Reports of negative attitudes toward women, gender evaluation, and avoidance coping were greater for Hong Kong and PRC women than for U.S. women. Hong Kong women reported more use of positive/confrontational coping mechanisms. Negative attitudes toward women had an important influence on life stress across regions. Moderator tests resulted in 2 significant findings: The effect of negative attitudes toward women on life stress was stronger for PRC and Hong Kong women, and the relationship between nervous/self-destructive coping and life stress was stronger for U.S. women.

Studying cross-cultural differences in the development of infant temperament: People's Republic of China, the United States of America, and Spain.

PubMed

Gartstein, Maria A; Gonzalez, Carmen; Carranza, Jose A; Ahadi, Stephan A; Ye, Renmin; Rothbart, Mary K; Yang, Suh Wen

2006-01-01

Investigated early development of temperament across three cultures: People's Republic of China (PRC), United States of America (US), and Spain, utilizing a longitudinal design (assessments at 3, 6, and 9 months of age). Selection of these countries presented an opportunity to conduct Eastern-Western/Individualistic-Collectivistic comparisons. The greatest number of significant differences (i.e., involving more temperament dimensions) was anticipated for the US (Western/Individualistic) and PRC (Eastern/Collectivistic) comparisons. The US sample included 66, the PRC group 69, and the Spanish sample, 60 mothers, all of whom completed the Infant Behavior Questionnaire (IBQ) 3 times, when their infants were 3, 6, and 9 months of age. Results related to mean group differences were generally consistent with our hypotheses, demonstrating a greater number of significant differences for US versus PRC, with fewer differences observed for US and Spain. Analyses addressing developmental changes in temperament indicated patterns consistent with a priori expectations and cross-cultural differences.

Light-Induced resetting of the circadian pacemaker: quantitative analysis of transient versus steady-state phase shifts.

PubMed

Watanabe, K; Deboer, T; Meijer, J H

2001-12-01

The suprachiasmatic nuclei of the hypothalamus contain the major circadian pacemaker in mammals, driving circadian rhythms in behavioral and physiological functions. This circadian pacemaker's responsiveness to light allows synchronization to the light-dark cycle. Phase shifting by light often involves several transient cycles in which the behavioral activity rhythm gradually shifts to its steady-state position. In this article, the authors investigate in Syrian hamsters whether a phase-advancing light pulse results in immediate shifts of the PRC at the next circadian cycle. In a first series of experiments, the authors aimed a light pulse at CT 19 to induce a phase advance. It appeared that the steady-state phase advances were highly correlated with activity onset in the first and second transient cycle. This enabled them to make a reliable estimate of the steady-state phase shift induced by a phase-advancing light pulse on the basis of activity onset in the first transient cycle. In the next series of experiments, they presented a light pulse at CT 19, which was followed by a second light pulse aimed at the delay zone of the PRC on the next circadian cycle. The immediate and steady-state phase delays induced by the second light pulse were compared with data from a third experiment in which animals received a phase-delaying light pulse only. The authors observed that the waveform of the phase-delay part of the PRC (CT 12-16) obtained in Experiment 2 was virtually identical to the phase-delay part of the PRC for a single light pulse (obtained in Experiment 3). This finding allowed for a quantitative assessment of the data. The analysis indicates that the delay part of the PRC-between CT 12 and CT 16-is rapidly reset following a light pulse at CT 19. These findings complement earlier findings in the hamster showing that after a light pulse at CT 19, the phase-advancing part of the PRC is immediately shifted. Together, the data indicate that the basis for phase advancing involves rapid resetting of both advance and delay components of the PRC.

Neural activity in the hippocampus and perirhinal cortex during encoding is associated with the durability of episodic memory.

PubMed

Carr, Valerie A; Viskontas, Indre V; Engel, Stephen A; Knowlton, Barbara J

2010-11-01

Studies examining medial temporal lobe (MTL) involvement in memory formation typically assess memory performance after a single, short delay. Thus, the relationship between MTL encoding activity and memory durability over time remains poorly characterized. To explore this relationship, we scanned participants using high-resolution functional imaging of the MTL as they encoded object pairs; using the remember/know paradigm, we then assessed memory performance for studied items both 10 min and 1 week later. Encoding trials were classified as either subsequently recollected across both delays, transiently recollected (i.e., recollected at 10 min but not after 1 week), consistently familiar, or consistently forgotten. Activity in perirhinal cortex (PRC) and a hippocampal subfield comprising the dentate gyrus and CA fields 2 and 3 reflected successful encoding only when items were recollected consistently across both delays. Furthermore, in PRC, encoding activity for items that later were consistently recollected was significantly greater than that for transiently recollected and consistently familiar items. Parahippocampal cortex, in contrast, showed a subsequent memory effect during encoding of items that were recollected after 10 min, regardless of whether they also were recollected after 1 week. These data suggest that MTL subfields contribute uniquely to the formation of memories that endure over time, and highlight a role for PRC in supporting subsequent durable episodic recollection.

15 CFR 748.9 - Support documents for license applications.

Code of Federal Regulations, 2010 CFR

2010-01-01

... agency(ies), other than the government of the People's Republic of China. To determine whether the... security reasons? Does your transaction involve items destined for the People's Republic of China (PRC)? (i... Australia Austria Belgium Bulgaria China (PRC) Czech Republic Denmark Finland France Germany Greece Hong...

15 CFR 748.9 - Support documents for license applications.

Code of Federal Regulations, 2011 CFR

2011-01-01

... agency(ies), other than the government of the People's Republic of China. To determine whether the... security reasons? Does your transaction involve items destined for the People's Republic of China (PRC)? (i... Australia Austria Belgium Bulgaria China (PRC) Czech Republic Denmark Finland France Germany Greece Hong...

Protein S Negatively Regulates Neural Stem Cell Self-Renewal through Bmi-1 Signaling

PubMed Central

Zelentsova-Levytskyi, Katya; Talmi, Ziv; Abboud-Jarrous, Ghada; Capucha, Tal; Sapir, Tamar; Burstyn-Cohen, Tal

2017-01-01

Revealing the molecular mechanisms underlying neural stem cell self-renewal is a major goal toward understanding adult brain homeostasis. The self-renewing potential of neural stem and progenitor cells (NSPCs) must be tightly regulated to maintain brain homeostasis. We recently reported the expression of Protein S (PROS1) in adult hippocampal NSPCs, and revealed its role in regulation of NSPC quiescence and neuronal differentiation. Here, we investigate the effect of PROS1 on NSPC self-renewal and show that genetic ablation of Pros1 in neural progenitors increased NSPC self-renewal by 50%. Mechanistically, we identified the upregulation of the polycomb complex protein Bmi-1 and repression of its downstream effectors p16Ink4a and p19Arf to promote NSPC self-renewal in Pros1-ablated cells. Rescuing Pros1 expression restores normal levels of Bmi-1 signaling, and reverts the proliferation and enhanced self-renewal phenotypes observed in Pros1-deleted cells. Our study identifies PROS1 as a novel negative regulator of NSPC self-renewal. We conclude PROS1 is instructive for NSPC differentiation by negatively regulating Bmi-1 signaling in adult and embryonic neural stem cells. PMID:28512399

Out of the Dragon’s Museum: Motivations for PLA Equipment Modernization

DTIC Science & Technology

1998-06-01

culture works within the constraints set by civilians; the military’s culture intervenes between civilian choices and military doctrine.Ř In the case of...PLAN, Military Modernization, KILO, FLANKER SOVREMENNY, Military-Industrial Complex, Strategic Culture . 15. NUMBER OF PAGES 100 16...20 2. The U.S. Factor 22 F. CONCLUSION 24 Vll III. THE PRC’S EVOLVING STRATEGIC CULTURE 27 A. MAO AND "PEOPLE’S WAR" 27 B. DENG, THE "FOUR

Probing the interaction between the histone methyltransferase/deacetylase subunit RBBP4/7 and the transcription factor BCL11A in epigenetic complexes.

PubMed

Moody, Rebecca Reed; Lo, Miao-Chia; Meagher, Jennifer L; Lin, Chang-Ching; Stevers, Nicholas O; Tinsley, Samantha L; Jung, Inkyung; Matvekas, Aleksas; Stuckey, Jeanne A; Sun, Duxin

2018-02-09

The transcription factor BCL11A has recently been reported to be a driving force in triple-negative breast cancer (TNBC), contributing to the maintenance of a chemoresistant breast cancer stem cell (BCSC) population. Although BCL11A was shown to suppress γ-globin and p21 and to induce MDM2 expression in the hematopoietic system, its downstream targets in TNBC are still unclear. For its role in transcriptional repression, BCL11A was found to interact with several corepressor complexes; however, the mechanisms underlying these interactions remain unknown. Here, we reveal that BCL11A interacts with histone methyltransferase (PRC2) and histone deacetylase (NuRD and SIN3A) complexes through their common subunit, RBBP4/7. In fluorescence polarization assays, we show that BCL11A competes with histone H3 for binding to the negatively charged top face of RBBP4. To define that interaction, we solved the crystal structure of RBBP4 in complex with an N-terminal peptide of BCL11A (residues 2-16, BCL11A(2-16)). The crystal structure identifies novel interactions between BCL11A and the side of the β-propeller of RBBP4 that are not seen with histone H3. We next show that BCL11A(2-16) pulls down RBBP4, RBBP7, and other components of PRC2, NuRD, and SIN3A from the cell lysate of the TNBC cell line SUM149. Furthermore, we demonstrate the therapeutic potential of targeting the RBBP4-BCL11A binding by showing that a BCL11A peptide can decrease aldehyde dehydrogenase-positive BCSCs and mammosphere formation capacity in SUM149. Together, our findings have uncovered a previously unidentified mechanism that BCL11A may use to recruit epigenetic complexes to regulate transcription and promote tumorigenesis. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Sonothrombolysis is effective with recombinant tissue-type plasminogen activator, but not with Abciximab. Results from an in vitro study with whole blood clots and platelet-rich clots.

PubMed

Eggers, Jürgen; Ossadnik, Stefan; Hütten, Heiko; Seidel, Günter

2009-12-01

Transcranial "diagnostic" ultrasound (US) has been shown to accelerate thrombolysis related to recombinant tissue-type plasminogen activator (rt-PA). In this in vitro study, we evaluated the potential of US to increase clot dissolution mediated by Abciximab (Abc) compared to rt-PA. The effect of 1.8-MHz pulsed wave (PW) Doppler US on dissolution of whole venous blood clots (WBC) and platelet-rich clots (PRC) treated with Abc and rt-PA was investigated in an in vitro model. Clot dissolution was measured by weight loss. Abc-related WBC dissolution was enhanced by additional US, but the effect was not any more detectable when the US was attenuated by a human temporal bone (US-tb). In PRC there was no additional effect of US on the Abc-related clot lysis. Rt-PA-related clot dissolution was increased by US in WBC and PRC as well, however, US-tb was only effective in WBC. The effect of insonation on WBC dissolution treated with the combination of Abc plus rt-PA was lower compared with those treated with rt-PA. In this in vitro experiment, the additional effect of "diagnostic" US in combination with Abc was only present in WBC and less strong than with rt-PA. The results do not support the use of Abc for sonothrombolysis targeting both, fibrin-rich and platelet-rich clots. In contrast, US when combined with rt-PA increases dissolution in both, WBC and PRC as well.

Engaging partners to initiate evaluation efforts: tactics used and lessons learned from the prevention research centers program.

PubMed

Wright, Demia Sundra; Anderson, Lynda A; Brownson, Ross C; Gwaltney, Margaret K; Scherer, Jennifer; Cross, Alan W; Goodman, Robert M; Schwartz, Randy; Sims, Tom; White, Carol R

2008-01-01

The Centers for Disease Control and Prevention's (CDC's) Prevention Research Centers (PRC) Program underwent a 2-year evaluation planning project using a participatory process that allowed perspectives from the national community of PRC partners to be expressed and reflected in a national logic model. The PRC Program recognized the challenge in developing a feasible, useable, and relevant evaluation process for a large, diverse program. To address the challenge, participatory and utilization-focused evaluation models were used. Four tactics guided the evaluation planning process: 1) assessing stakeholders' communication needs and existing communication mechanisms and infrastructure; 2) using existing mechanisms and establishing others as needed to inform, educate, and request feedback; 3) listening to and using feedback received; and 4) obtaining adequate resources and building flexibility into the project plan to support multifaceted mechanisms for data collection. Participatory methods resulted in buy-in from stakeholders and the development of a national logic model. Benefits included CDC's use of the logic model for program planning and development of a national evaluation protocol and increased expectations among PRC partners for involvement. Challenges included the time, effort, and investment of program resources required for the participatory approach and the identification of whom to engage and when to engage them for feedback on project decisions. By using a participatory and utilization-focused model, program partners positively influenced how CDC developed an evaluation plan. The tactics we used can guide the involvement of program stakeholders and help with decisions on appropriate methods and approaches for engaging partners.

The Role of Polycomb Group Gene Bmi-1 in the Development of Prostate Cancer

DTIC Science & Technology

2011-09-01

new tricks. Cell Div. 2006 Jul 24;1:15. 17. Fu M, Wang C, Li Z, Sakamaki T, Pestell RG. Minireview: Cyclin D1: normal and abnormal functions... Pestell RG. Signal transduction mediated by cyclin D1: from mitogens to cell proliferation: a molecular target with therapeutic potential. Cancer...Datar 22 R, Cote R, Pestell R, Albanese C. ErbB-2 induces the cyclin D1 gene in prostate epithelial cells in vitro and in vivo. Cancer Res. 2007

Therapeutic Role of Bmi-1 Inhibitors in Eliminating Prostate Tumor Stem Cells

DTIC Science & Technology

2013-10-01

collagen-adherent α2β1hi/CD44hi cells2 (see appendix). Recent experimental and clinical studies have identified BMI-1 as a member of the polycomb family of...next phase of studies will examine BMI-1 targeted therapy in combination with Taxotere and other recently approved therapies. These studies will...project, we are on track for determining which BMI-1 inhibitor(s) to be used for in vivo studies in NOD-SCID mice and fish during the second and third

LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint

PubMed Central

Dimitrova, Nadya; Zamudio, Jesse R.; Jong, Robyn M.; Soukup, Dylan; Resnick, Rebecca; Sarma, Kavitha; Ward, Amanda J.; Raj, Arjun; Lee, Jeannie; Sharp, Phillip A.; Jacks, Tyler

2014-01-01

SUMMARY The p53-regulated long non-coding RNA lincRNA-p21 has been proposed to act in trans via several mechanisms ranging from repressing genes in the p53 transcriptional network to regulating mRNA translation and protein stability. To further examine lincRNA-p21 function we generated a conditional knockout mouse model. We find that lincRNA-p21 predominantly functions in cis to activate expression of its neighboring gene, p21. Mechanistically, we show that lincRNA-p21 acts in concert with hnRNP-K as a co-activator for p53-dependent p21 transcription. Additional phenotypes of lincRNA-p21 deficiency could be attributed to diminished p21 levels, including deregulated expression and altered chromatin state of some Polycomb target genes, defective G1/S checkpoint, increased proliferation rates, and enhanced reprogramming efficiency. These findings indicate that lincRNA-p21 affects global gene expression and influences the p53 tumor suppressor pathway by acting in cis as a locus-restricted co-activator for p53-mediated p21 expression. PMID:24857549

The ASYMMETRIC LEAVES Complex Employs Multiple Modes of Regulation to Affect Adaxial-Abaxial Patterning and Leaf Complexity[OPEN

PubMed Central

Husbands, Aman Y.; Benkovics, Anna H.; Nogueira, Fabio T.S.; Lodha, Mukesh; Timmermans, Marja C.P.

2015-01-01

Flattened leaf architecture is not a default state but depends on positional information to precisely coordinate patterns of cell division in the growing primordium. This information is provided, in part, by the boundary between the adaxial (top) and abaxial (bottom) domains of the leaf, which are specified via an intricate gene regulatory network whose precise circuitry remains poorly defined. Here, we examined the contribution of the ASYMMETRIC LEAVES (AS) pathway to adaxial-abaxial patterning in Arabidopsis thaliana and demonstrate that AS1-AS2 affects this process via multiple, distinct regulatory mechanisms. AS1-AS2 uses Polycomb-dependent and -independent mechanisms to directly repress the abaxial determinants MIR166A, YABBY5, and AUXIN RESPONSE FACTOR3 (ARF3), as well as a nonrepressive mechanism in the regulation of the adaxial determinant TAS3A. These regulatory interactions, together with data from prior studies, lead to a model in which the sequential polarization of determinants, including AS1-AS2, explains the establishment and maintenance of adaxial-abaxial leaf polarity. Moreover, our analyses show that the shared repression of ARF3 by the AS and trans-acting small interfering RNA (ta-siRNA) pathways intersects with additional AS1-AS2 targets to affect multiple nodes in leaf development, impacting polarity as well as leaf complexity. These data illustrate the surprisingly multifaceted contribution of AS1-AS2 to leaf development showing that, in conjunction with the ta-siRNA pathway, AS1-AS2 keeps the Arabidopsis leaf both flat and simple. PMID:26589551

Illustrations of mathematical modeling in biology: epigenetics, meiosis, and an outlook.

PubMed

Richards, D; Berry, S; Howard, M

2012-01-01

In the past few years, mathematical modeling approaches in biology have begun to fulfill their promise by assisting in the dissection of complex biological systems. Here, we review two recent examples of predictive mathematical modeling in plant biology. The first involves the quantitative epigenetic silencing of the floral repressor gene FLC in Arabidopsis, mediated by a Polycomb-based system. The second involves the spatiotemporal dynamics of telomere bouquet formation in wheat-rye meiosis. Although both the biology and the modeling framework of the two systems are different, both exemplify how mathematical modeling can help to accelerate discovery of the underlying mechanisms in complex biological systems. In both cases, the models that developed were relatively minimal, including only essential features, but both nevertheless yielded fundamental insights. We also briefly review the current state of mathematical modeling in biology, difficulties inherent in its application, and its potential future development.

The Role of Polycomb Group Gene BMI1 in the Development of Prostate Cancer

DTIC Science & Technology

2014-03-01

SUBJECT TERMS BMI1, Wnt Signaling, Bcl-2, TCF, Prostate Cancer 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18 . NUMBER OF PAGES 19a...Status: Completed; Data presented in this report. Task 3 : Studies in athymic nude mouse xenograft model will be conducted (a) to...colon cancer cell line HT29 which is known to exhibit increased Wnt signaling and TCF-transcriptional activity ( 18 ). We first determined BMI1 levels in

Postgraduate Education in the People's Republic of China.

ERIC Educational Resources Information Center

Shiqi, Huang

The historical background and development of postgraduate education in the People's Republic of China (PRC) are discussed. Before the founding of PRC, there were only a few higher education institutions that offered postgraduate programs at the master's level. No doctoral programs were offered and no doctorates were awarded in old China. Before…

76 FR 12338 - Silicon Metal From the People's Republic of China: Rescission of Antidumping Duty Administrative...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-07

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-806] Silicon Metal From the... metal, requested an administrative review of the antidumping duty order on silicon metal from the PRC... initiation of the administrative review of the antidumping duty order on silicon metal from the PRC on July...

Revisiting the Principle of Relative Constancy: Consumer Mass Media Expenditures in Belgium.

ERIC Educational Resources Information Center

Dupagne, Michel; Green, R. Jeffery

1996-01-01

Proposes two new econometric models for testing the principle of relative constancy (PRC). Reports on regression and cointegration analyses conducted with Belgian mass media expenditure data from 1953-91. Suggests that alternative mass media expenditure models should be developed because PRC lacks of economic foundation and sound empirical…

75 FR 57441 - Aluminum Extrusions From the People's Republic of China: Alignment of Final Countervailing Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-21

... DEPARTMENT OF COMMERCE International Trade Administration [C-570-968] Aluminum Extrusions From the... countervailing duty investigation of aluminum extrusions from the People's Republic of China (PRC) with the final... antidumping duty investigations on aluminum extrusions from the PRC. See Aluminum Extrusions from the People's...

School Psychology in China (PRC), Hong Kong and Taiwan: A Cross-Regional Perspective

ERIC Educational Resources Information Center

Ding, Yi; Kuo, Yi-Lung; Van Dyke, Don C.

2008-01-01

Although China (People's Republic of China [PRC]), Hong Kong and Taiwan have many similarities in language, culture, values, Confucian traditions, family systems and other social-environmental variables, school psychological services in the three regions are distinctly different in both history and practice. Few studies in the psychology…

Adaptation to Cognitive Context and Item Information in the Medial Temporal Lobes

ERIC Educational Resources Information Center

Diana, Rachel A.; Yonelinas, Andrew P.; Ranganath, Charan

2012-01-01

The medial temporal lobes (MTL) play an essential role in episodic memory, and accumulating evidence indicates that two MTL subregions--the perirhinal (PRc) and parahippocampal (PHc) cortices--might have different functions. According to the binding of item and context theory ( [16] and [21]), PRc is involved in processing item information, the…

75 FR 17376 - Certain Preserved Mushrooms from the People's Republic of China: Amended Final Results Pursuant...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-06

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-851] Certain Preserved Mushrooms... administrative review of the antidumping duty order on certain preserved mushrooms from the PRC for the period... preserved mushrooms from the People's Republic of China (PRC). EFFECTIVE DATE: April 6, 2010. FOR FURTHER...

75 FR 28235 - Certain Frozen Warmwater Shrimp From the People's Republic of China: Extension of Final Results...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-20

... Shrimp From the People's Republic of China: Extension of Final Results of Antidumping Duty Administrative... administrative review of certain frozen warmwater shrimp from the People's Republic of China (``PRC''). The... frozen shrimp from the Socialist Republic of Vietnam and the PRC. See Notice of Initiation of...

76 FR 16460 - Mail Classification Change for Priority Mail Flat Mail

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-23

... online model and the retail model. The online model will allow customers to purchase packs from a Web...: March 23, 2011. ADDRESSES: Submit comments electronically by accessing the ``Filing Online'' link in the... Commission's Filing Online system at https://www.prc.gov/prc-pages/filing-online/login.aspx . Commenters who...

40 CFR 80.169 - Liability for violations of the detergent certification program controls and prohibitions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) REGULATION OF FUELS AND FUEL ADDITIVES... violations caused solely by the addition of misadditized ethanol or other PRC to the gasoline. In any case in...(a) caused solely by another party's addition of misadditized ethanol or other PRC to the gasoline...

77 FR 75838 - Regional Reliability Standard PRC-006-SERC-01; Automatic Underfrequency Load Shedding Requirements

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-26

... approves the related violation risk factors (VRF), with one modification, violation severity levels (VSL... assigned to Requirement R6 from ``medium'' to ``high'' to make it consistent with the Commission's VRF... Commission's VRF guidelines and the violation risk factor for Requirement R9 of NERC Reliability Standard PRC...

75 FR 10216 - Malleable Cast Iron Pipe Fittings from the People's Republic of China: Notice of Rescission of...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-05

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-881] Malleable Cast Iron Pipe... antidumping duty order on malleable cast iron pipe fittings from the People's Republic of China (``PRC''). See... malleable cast iron pipe fittings from the PRC. See Initiation of Antidumping and Countervailing Duty...

77 FR 45336 - Multilayered Wood Flooring From the People's Republic of China: Initiation of Antidumping Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-31

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-970] Multilayered Wood Flooring... on multilayered wood flooring from the People's Republic of China (``PRC'') meets the statutory and... announcing the antidumping duty order on multilayered wood flooring from the PRC was published in the Federal...

78 FR 46318 - Multilayered Wood Flooring From the People's Republic of China: Initiation of Antidumping Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-31

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-970] Multilayered Wood Flooring... antidumping duty order on multilayered wood flooring from the People's Republic of China (``PRC'') meet the...: Background The Department published the antidumping duty order on multilayered wood flooring from the PRC on...

Investigating Cantonese Speakers' Language Attitudes in Mainland China

ERIC Educational Resources Information Center

Ng, Dana Funywe; Zhao, Juanjuan

2015-01-01

The People's Republic of China (PRC) has often been considered a monolithic, monolingual state but, in fact, it is linguistically and culturally diverse. Despite the size, there is still a lack of sociolinguistic studies on the Han Chinese in the PRC. Therefore, this study focuses on the language attitudes of Cantonese-speaking students in…

75 FR 2435 - Addition to the List of Validated End-Users in the People's Republic of China (PRC)

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-15

... DEPARTMENT OF COMMERCE Bureau of Industry and Security 15 CFR Part 748 [Docket No. 0908111226... (PRC) AGENCY: Bureau of Industry and Security, Commerce. ACTION: Final rule. SUMMARY: In this final rule, the Bureau of Industry and Security (BIS) amends the Export Administration Regulations (EAR) to...

Behaviour of Plate Anchorage in Plate-Reinforced Composite Coupling Beams

PubMed Central

Lam, W. Y.; Li, Lingzhi; Su, R. K. L.; Pam, H. J.

2013-01-01

As a new alternative design, plate-reinforced composite (PRC) coupling beam achieves enhanced strength and ductility by embedding a vertical steel plate into a conventionally reinforced concrete (RC) coupling beam. Based on a nonlinear finite element model developed in the authors' previous study, a parametric study presented in this paper has been carried out to investigate the influence of several key parameters on the overall performance of PRC coupling beams. The effects of steel plate geometry, span-to-depth ratio of beams, and steel reinforcement ratios at beam spans and in wall regions are quantified. It is found that the anchorage length of the steel plate is primarily controlled by the span-to-depth ratio of the beam. Based on the numerical results, a design curve is proposed for determining the anchorage length of the steel plate. The load-carrying capacity of short PRC coupling beams with high steel ratio is found to be controlled by the steel ratio of wall piers. The maximum shear stress of PRC coupling beams should be limited to 15 MPa. PMID:24288465

The perirhinal cortex and conceptual processing: Effects of feature-based statistics following damage to the anterior temporal lobes.

PubMed

Wright, Paul; Randall, Billi; Clarke, Alex; Tyler, Lorraine K

2015-09-01

The anterior temporal lobe (ATL) plays a prominent role in models of semantic knowledge, although it remains unclear how the specific subregions within the ATL contribute to semantic memory. Patients with neurodegenerative diseases, like semantic dementia, have widespread damage to the ATL thus making inferences about the relationship between anatomy and cognition problematic. Here we take a detailed anatomical approach to ask which substructures within the ATL contribute to conceptual processing, with the prediction that the perirhinal cortex (PRc) will play a critical role for concepts that are more semantically confusable. We tested two patient groups, those with and without damage to the PRc, across two behavioural experiments - picture naming and word-picture matching. For both tasks, we manipulated the degree of semantic confusability of the concepts. By contrasting the performance of the two groups, along with healthy controls, we show that damage to the PRc results in worse performance in processing concepts with higher semantic confusability across both experiments. Further by correlating the degree of damage across anatomically defined regions of interest with performance, we find that PRc damage is related to performance for concepts with increased semantic confusability. Our results show that the PRc supports a necessary and crucial neurocognitve function that enables fine-grained conceptual processes to take place through the resolution of semantic confusability. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

VizieR Online Data Catalog: SDSS-based Polar Ring Catalogue (Moiseev+, 2011)

NASA Astrophysics Data System (ADS)

Moiseev, A. V.; Smirnova, K. I.; Smirnova, A. A.; Reshetnikov, V. P.

2012-06-01

Galaxies with polar rings (PRGs) are a unique class of extragalactic objects. Using these, we can investigate a wide range of problems, linked to the formation and evolution of galaxies, and we can study the properties of their dark haloes. The progress that has been made in the study of PRGs has been constrained by the small number of known objects of this type. The Polar Ring Catalogue (PRC) by Whitmore et al. (1990AJ....100.1489W) and their photographic atlas of PRGs and related objects includes 157 galaxies. At present, there are only about two dozen kinematically confirmed galaxies in this PRG class, mostly from the PRC. We present a new catalogue of PRGs, supplementing the PRC and significantly increasing the number of known candidate PRGs. The catalogue is based on the results of the original Galaxy Zoo project. Within this project, volunteers performed visual classifications of nearly a million galaxies from the Sloan Digital Sky Survey (SDSS). Based on the preliminary classifications of the Galaxy Zoo, we viewed more than 40000 images of the SDSS and selected 275 galaxies to include in our catalogue. (1 data file).

Impact of adaptation currents on synchronization of coupled exponential integrate-and-fire neurons.

PubMed

Ladenbauer, Josef; Augustin, Moritz; Shiau, LieJune; Obermayer, Klaus

2012-01-01

The ability of spiking neurons to synchronize their activity in a network depends on the response behavior of these neurons as quantified by the phase response curve (PRC) and on coupling properties. The PRC characterizes the effects of transient inputs on spike timing and can be measured experimentally. Here we use the adaptive exponential integrate-and-fire (aEIF) neuron model to determine how subthreshold and spike-triggered slow adaptation currents shape the PRC. Based on that, we predict how synchrony and phase locked states of coupled neurons change in presence of synaptic delays and unequal coupling strengths. We find that increased subthreshold adaptation currents cause a transition of the PRC from only phase advances to phase advances and delays in response to excitatory perturbations. Increased spike-triggered adaptation currents on the other hand predominantly skew the PRC to the right. Both adaptation induced changes of the PRC are modulated by spike frequency, being more prominent at lower frequencies. Applying phase reduction theory, we show that subthreshold adaptation stabilizes synchrony for pairs of coupled excitatory neurons, while spike-triggered adaptation causes locking with a small phase difference, as long as synaptic heterogeneities are negligible. For inhibitory pairs synchrony is stable and robust against conduction delays, and adaptation can mediate bistability of in-phase and anti-phase locking. We further demonstrate that stable synchrony and bistable in/anti-phase locking of pairs carry over to synchronization and clustering of larger networks. The effects of adaptation in aEIF neurons on PRCs and network dynamics qualitatively reflect those of biophysical adaptation currents in detailed Hodgkin-Huxley-based neurons, which underscores the utility of the aEIF model for investigating the dynamical behavior of networks. Our results suggest neuronal spike frequency adaptation as a mechanism synchronizing low frequency oscillations in local excitatory networks, but indicate that inhibition rather than excitation generates coherent rhythms at higher frequencies.

Impact of Adaptation Currents on Synchronization of Coupled Exponential Integrate-and-Fire Neurons

PubMed Central

Ladenbauer, Josef; Augustin, Moritz; Shiau, LieJune; Obermayer, Klaus

2012-01-01

The ability of spiking neurons to synchronize their activity in a network depends on the response behavior of these neurons as quantified by the phase response curve (PRC) and on coupling properties. The PRC characterizes the effects of transient inputs on spike timing and can be measured experimentally. Here we use the adaptive exponential integrate-and-fire (aEIF) neuron model to determine how subthreshold and spike-triggered slow adaptation currents shape the PRC. Based on that, we predict how synchrony and phase locked states of coupled neurons change in presence of synaptic delays and unequal coupling strengths. We find that increased subthreshold adaptation currents cause a transition of the PRC from only phase advances to phase advances and delays in response to excitatory perturbations. Increased spike-triggered adaptation currents on the other hand predominantly skew the PRC to the right. Both adaptation induced changes of the PRC are modulated by spike frequency, being more prominent at lower frequencies. Applying phase reduction theory, we show that subthreshold adaptation stabilizes synchrony for pairs of coupled excitatory neurons, while spike-triggered adaptation causes locking with a small phase difference, as long as synaptic heterogeneities are negligible. For inhibitory pairs synchrony is stable and robust against conduction delays, and adaptation can mediate bistability of in-phase and anti-phase locking. We further demonstrate that stable synchrony and bistable in/anti-phase locking of pairs carry over to synchronization and clustering of larger networks. The effects of adaptation in aEIF neurons on PRCs and network dynamics qualitatively reflect those of biophysical adaptation currents in detailed Hodgkin-Huxley-based neurons, which underscores the utility of the aEIF model for investigating the dynamical behavior of networks. Our results suggest neuronal spike frequency adaptation as a mechanism synchronizing low frequency oscillations in local excitatory networks, but indicate that inhibition rather than excitation generates coherent rhythms at higher frequencies. PMID:22511861

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

Accounting for the Confound of Meninges in Segmenting Entorhinal and Perirhinal Cortices in T1-Weighted MRI.

PubMed

Xie, Long; Wisse, Laura E M; Das, Sandhitsu R; Wang, Hongzhi; Wolk, David A; Manjón, Jose V; Yushkevich, Paul A

2016-10-01

Quantification of medial temporal lobe (MTL) cortices, including entorhinal cortex (ERC) and perirhinal cortex (PRC), from in vivo MRI is desirable for studying the human memory system as well as in early diagnosis and monitoring of Alzheimer's disease. However, ERC and PRC are commonly over-segmented in T1-weighted (T1w) MRI because of the adjacent meninges that have similar intensity to gray matter in T1 contrast. This introduces errors in the quantification and could potentially confound imaging studies of ERC/PRC. In this paper, we propose to segment MTL cortices along with the adjacent meninges in T1w MRI using an established multi-atlas segmentation framework together with super-resolution technique. Experimental results comparing the proposed pipeline with existing pipelines support the notion that a large portion of meninges is segmented as gray matter by existing algorithms but not by our algorithm. Cross-validation experiments demonstrate promising segmentation accuracy. Further, agreement between the volume and thickness measures from the proposed pipeline and those from the manual segmentations increase dramatically as a result of accounting for the confound of meninges. Evaluated in the context of group discrimination between patients with amnestic mild cognitive impairment and normal controls, the proposed pipeline generates more biologically plausible results and improves the statistical power in discriminating groups in absolute terms comparing to other techniques using T1w MRI. Although the performance of the proposed pipeline is inferior to that using T2-weighted MRI, which is optimized to image MTL sub-structures, the proposed pipeline could still provide important utilities in analyzing many existing large datasets that only have T1w MRI available.

78 FR 13321 - Silicon Metal From the People's Republic of China: Preliminary Results of Antidumping Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-27

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-806] Silicon Metal From the... administrative review of the antidumping duty order on silicon metal from the People's Republic of China (``PRC... administrative review of the antidumping duty order on silicon metal from the PRC.\\2\\ On June 29, 2012, Globe...

77 FR 10477 - Silicon Metal From the People's Republic of China: Final Results of the Expedited Third Sunset...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-22

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-806] Silicon Metal From the... review of the antidumping duty order on silicon metal from the People's Republic of China (``PRC...) sunset review of the antidumping duty order on silicon metal from the PRC, pursuant to section 751(c)(3...

78 FR 40101 - Certain Tissue Paper Products from the People's Republic of China: Affirmative Final...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-03

... CONTACT: Brian Smith or Gemal Brangman, AD/CVD Operations, Office 2, Import Administration, International... Antidumping Duty Order'' section, which are produced in India from PRC-origin jumbo rolls and/or cut sheets of tissue paper, and exported from India to the United States. This inquiry only covers such PRC-origin...

75 FR 37382 - Notice of Antidumping Duty Order: Prestressed Concrete Steel Wire Strand from the People's...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-29

... strand (``PC strand'') from the People's Republic of China (``PRC''). On June 22, 2010, the ITC notified... investigation of PC strand from the PRC. See Prestressed Concrete Steel Wire Strand From the People's Republic... Determination''). Scope of the Order The scope of this investigation consists of PC strand, produced from wire...

77 FR 17439 - Crystalline Silicon Photovoltaic Cells, Whether or Not Assembled Into Modules, From the People's...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-26

... silicon photovoltaic cells, whether or not assembled into modules (solar cells) from the People's Republic... History The Department initiated a countervailing duty (CVD) investigation of solar cells from the PRC on.... Customs and Border Protection (CBP) entry data for U.S. imports of solar cells from the PRC for the period...

76 FR 11758 - Drill Pipe From the People's Republic of China: Countervailing Duty Order

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-03

... DEPARTMENT OF COMMERCE International Trade Administration [C-570-966] Drill Pipe From the People's... countervailing duty order on drill pipe from the People's Republic of China (PRC). DATES: Effective Date: March 3... producers and exporters of drill pipe from the PRC. See Drill Pipe from the People's Republic of China...

75 FR 75964 - Non-Malleable Cast Iron Pipe Fittings From the People's Republic of China: Extension of Time...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-07

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-875] Non-Malleable Cast Iron Pipe...-malleable cast iron pipe fittings from the People's Republic of China (``PRC''). See Initiation of...-malleable cast iron pipe fittings from the PRC within the time limits mandated by section 751(a)(3)(A) of...

78 FR 37205 - Freshwater Crawfish Tail Meat From the People's Republic of China: Rescission of Antidumping Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-20

... Meat From the People's Republic of China: Rescission of Antidumping Duty New Shipper Review AGENCY... freshwater crawfish tail meat from the People's Republic of China (PRC) with respect to Hubei Nature... Department initiated an antidumping duty new shipper review of freshwater crawfish tail meat from the PRC...

Gender Differences in Career Perceptions in the People's Republic of China

ERIC Educational Resources Information Center

Granrose, Cherlyn Skromme

2007-01-01

Purpose: This paper seeks to review gender differences in career goals and career tactics of men and women in the People's Republic of China (PRC). Design/methodology/approach: Survey results were used to identify empirical differences in career beliefs of 233 managers employed in 16 organizations in the PRC. Findings: Women and men were equally…

76 FR 44575 - Paper Clips From the People's Republic of China: Continuation of the Antidumping Duty Order

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-26

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-826] Paper Clips From the People... the antidumping duty order on paper clips from the People's Republic of China (``PRC'') would likely... of the antidumping duty order on paper clips from the PRC pursuant to section 751(c) of the Tariff...

78 FR 15703 - Certain Hot-Rolled Carbon Steel Flat Products From India, Indonesia, the People's Republic of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-12

...-835, A-549-817, A-823-811] Certain Hot-Rolled Carbon Steel Flat Products From India, Indonesia, the... steel flat products from India, Indonesia, the People's Republic of China (PRC), Taiwan, Thailand, and... steel flat products from India, Indonesia, the PRC, Taiwan, Thailand, and Ukraine, pursuant to section...

Educational Development in China: Characteristics and Trends.

ERIC Educational Resources Information Center

Lamontagne, Jacques

Some characteristics and trends of the educational development in the People's Republic of China (PRC) are analyzed on the basis of statistical data covering the period 1949 to 1985. During the 1950s, 1960s, and 1970s, the educational development of the PRC displayed a trend toward the reduction of educational disparities among regions and among…

The Role of Polycomb Group Gene BMI1 in the Development of Prostate Cancer

DTIC Science & Technology

2012-07-01

16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18 . NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a. REPORT U b...Completed; Data presented in this report. 11 Task 3 (OF SOW): Sub-task: (3A) Studies in athymic nude mouse xenograft model will be conducted (a) to...to exhibit increased Wnt signaling and TCF-transcriptional activity ( 18 ). We first determined BMI1 levels in HT29 cells and then generated BMI1

A phase response curve to single bright light pulses in human subjects

NASA Technical Reports Server (NTRS)

Khalsa, Sat Bir S.; Jewett, Megan E.; Cajochen, Christian; Czeisler, Charles A.

2003-01-01

The circadian pacemaker is differentially sensitive to the resetting effects of retinal light exposure, depending upon the circadian phase at which the light exposure occurs. Previously reported human phase response curves (PRCs) to single bright light exposures have employed small sample sizes, and were often based on relatively imprecise estimates of circadian phase and phase resetting. In the present study, 21 healthy, entrained subjects underwent pre- and post-stimulus constant routines (CRs) in dim light (approximately 2-7 lx) with maintained wakefulness in a semi-recumbent posture. The 6.7 h bright light exposure stimulus consisted of alternating 6 min fixed gaze (approximately 10 000 lx) and free gaze (approximately 5000-9000 lx) exposures. Light exposures were scheduled across the circadian cycle in different subjects so as to derive a PRC. Plasma melatonin was used to determine the phase of the onset, offset, and midpoint of the melatonin profiles during the CRs. Phase shifts were calculated as the difference in phase between the pre- and post-stimulus CRs. The resultant PRC of the midpoint of the melatonin rhythm revealed a characteristic type 1 PRC with a significant peak-to-trough amplitude of 5.02 h. Phase delays occurred when the light stimulus was centred prior to the critical phase at the core body temperature minimum, phase advances occurred when the light stimulus was centred after the critical phase, and no phase shift occurred at the critical phase. During the subjective day, no prolonged 'dead zone' of photic insensitivity was apparent. Phase shifts derived using the melatonin onsets showed larger magnitudes than those derived from the melatonin offsets. These data provide a comprehensive characterization of the human PRC under highly controlled laboratory conditions.

The Role of Polycomb Group Gene BMI-1 in the Development of Prostate Cancer

DTIC Science & Technology

2010-09-01

2006 Jul 24;1:15. 17. Fu M, Wang C, Li Z, Sakamaki T, Pestell RG. Minireview: Cyclin D1: normal and abnormal functions. Endocrinology. 2004 Dec;145...and cyclin D1:connecting development to breast cancer. Cell Cycle. 2004 Feb;3(2):145-8. 32. Wang C, Li Z, Fu M, Bouras T, Pestell RG. Signal... Pestell R, Albanese C. ErbB-2 induces the cyclin D1 gene in prostate epithelial cells in vitro and in vivo. Cancer Res. 2007 May 1;67(9):4364-72. 36

Implication of SUMO E3 ligases in nucleotide excision repair.

PubMed

Tsuge, Maasa; Kaneoka, Hidenori; Masuda, Yusuke; Ito, Hiroki; Miyake, Katsuhide; Iijima, Shinji

2015-08-01

Post-translational modifications alter protein function to mediate complex hierarchical regulatory processes that are crucial to eukaryotic cellular function. The small ubiquitin-like modifier (SUMO) is an important post-translational modification that affects transcriptional regulation, nuclear localization, and the maintenance of genome stability. Nucleotide excision repair (NER) is a very versatile DNA repair system that is essential for protection against ultraviolet (UV) irradiation. The deficiencies in NER function remarkably increase the risk of skin cancer. Recent studies have shown that several NER factors are SUMOylated, which influences repair efficiency. However, how SUMOylation modulates NER has not yet been elucidated. In the present study, we performed RNAi knockdown of SUMO E3 ligases and found that, in addition to PIASy, the polycomb protein Pc2 affected the repair of cyclobutane pyrimidine dimers. PIAS1 affected both the removal of 6-4 pyrimidine pyrimidone photoproducts and cyclobutane pyrimidine dimers, whereas other SUMO E3 ligases did not affect the removal of either UV lesion.

Characterization and corrosion property of nano-rod-like HA on fluoride coating supported on Mg-Zn-Ca alloy.

PubMed

Feng, Yashan; Zhu, Shijie; Wang, Liguo; Chang, Lei; Yan, Bingbing; Song, Xiaozhe; Guan, Shaokang

2017-06-01

The poor corrosion resistance of biodegradable magnesium alloys is the dominant factor that limits their clinical application. In this study, to deal with this challenge, fluoride coating was prepared on Mg-Zn-Ca alloy as the inner coating and then hydroxyapatite (HA) coating as the outer coating was deposited on fluoride coating by pulse reverse current electrodeposition (PRC-HA/MgF 2 ). As a comparative study, the microstructure and corrosion properties of the composite coating with the outer coating fabricated by traditional constant current electrodeposition (TED-HA/MgF 2 ) were also investigated. Scanning electron microscopy (SEM) images of the coatings show that the morphology of PRC-HA/MgF 2 coating is dense and uniform, and presents nano-rod-like structure. Compared with that of TED-HA/MgF 2 , the corrosion current density of Mg alloy coated with PRC-HA/MgF 2 coatings decreases from 5.72 × 10 -5 A/cm 2 to 4.32 × 10 -7 A/cm 2 , and the corrosion resistance increases by almost two orders of magnitude. In immersion tests, samples coated with PRC-HA/MgF 2 coating always show the lowest hydrogen evolution amount, and could induce deposition of the hexagonal structure-apatite on the surface rapidly. The results show that the corrosion resistance and the bioactivity of the coatings have been improved by adopting double-pulse current mode in the process of preparing HA on fluoride coating, and the PRC-HA/MgF 2 coating is worth of further investigation.

Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells.

PubMed

Lyons, Amy; Coleman, Michael; Riis, Sarah; Favre, Cedric; O'Flanagan, Ciara H; Zhdanov, Alexander V; Papkovsky, Dmitri B; Hursting, Stephen D; O'Connor, Rosemary

2017-10-13

Mitochondrial activity and metabolic reprogramming influence the phenotype of cancer cells and resistance to targeted therapy. We previously established that an insulin-like growth factor 1 (IGF-1)-inducible mitochondrial UTP carrier (PNC1/SLC25A33) promotes cell growth. This prompted us to investigate whether IGF signaling is essential for mitochondrial maintenance in cancer cells and whether this contributes to therapy resistance. Here we show that IGF-1 stimulates mitochondrial biogenesis in a range of cell lines. In MCF-7 and ZR75.1 breast cancer cells, IGF-1 induces peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) and PGC-1α-related coactivator (PRC). Suppression of PGC-1β and PRC with siRNA reverses the effects of IGF-1 and disrupts mitochondrial morphology and membrane potential. IGF-1 also induced expression of the redox regulator nuclear factor-erythroid-derived 2-like 2 (NFE2L2 alias NRF-2). Of note, MCF-7 cells with acquired resistance to an IGF-1 receptor (IGF-1R) tyrosine kinase inhibitor exhibited reduced expression of PGC-1β, PRC, and mitochondrial biogenesis. Interestingly, these cells exhibited mitochondrial dysfunction, indicated by reactive oxygen species expression, reduced expression of the mitophagy mediators BNIP3 and BNIP3L, and impaired mitophagy. In agreement with this, IGF-1 robustly induced BNIP3 accumulation in mitochondria. Other active receptor tyrosine kinases could not compensate for reduced IGF-1R activity in mitochondrial protection, and MCF-7 cells with suppressed IGF-1R activity became highly dependent on glycolysis for survival. We conclude that IGF-1 signaling is essential for sustaining cancer cell viability by stimulating both mitochondrial biogenesis and turnover through BNIP3 induction. This core mitochondrial protective signal is likely to strongly influence responses to therapy and the phenotypic evolution of cancer. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

From neural development to cognition: unexpected roles for chromatin

PubMed Central

Ronan, Jehnna L.; Wu, Wei

2014-01-01

Recent genome-sequencing studies in human neurodevelopmental and psychiatric disorders have uncovered mutations in many chromatin regulators. These human genetic studies, along with studies in model organisms, are providing insight into chromatin regulatory mechanisms in neural development and how alterations to these mechanisms can cause cognitive deficits, such as intellectual disability. We discuss several implicated chromatin regulators, including BAF (also known as SWI/SNF) and CHD8 chromatin remodellers, HDAC4 and the Polycomb component EZH2. Interestingly, mutations in EZH2 and certain BAF complex components have roles in both neurodevelopmental disorders and cancer, and overlapping point mutations are suggesting functionally important residues and domains. We speculate on the contribution of these similar mutations to disparate disorders. PMID:23568486

The Challenge of English Language Collocation Learning in an ES/FL Environment: PRC Students in Singapore

ERIC Educational Resources Information Center

Ying, Yang

2015-01-01

This study aimed to seek an in-depth understanding about English collocation learning and the development of learner autonomy through investigating a group of English as a Second Language (ESL) learners' perspectives and practices in their learning of English collocations using an AWARE approach. A group of 20 PRC students learning English in…

15 CFR 744.21 - Restrictions on certain military end-uses in the People's Republic of China (PRC).

Code of Federal Regulations, 2014 CFR

2014-01-01

... PRC without a license if, at the time of the export, reexport, or transfer, you know, meaning either... the license requirements for “600 series” items specified on the Commerce Control List (CCL), you may not export, reexport, or transfer any “600 series” item, including .y items described in a “600 series...

76 FR 21331 - Certain Carbon Steel Butt-Weld Pipe Fittings From Brazil, Japan, Taiwan, Thailand, and the People...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-15

...-807, A-570-814] Certain Carbon Steel Butt-Weld Pipe Fittings From Brazil, Japan, Taiwan, Thailand, and... butt-weld pipe fittings from Brazil, Japan, Taiwan, Thailand, and the People's Republic of China (PRC... duty orders on carbon steel butt-weld pipe fittings from Brazil, Japan, Taiwan, Thailand, and the PRC...

Chinese Students' Social Integration into the University Community: Hearing the Students' Voices

ERIC Educational Resources Information Center

Spencer-Oatey, Helen; Dauber, Daniel; Jing, Jing; Lifei, Wang

2017-01-01

According to UNESCO statistics, the People's Republic of China (PRC) sends far more students to study overseas than any other country in the world. Similarly, from the receiving countries' point of view, PRC students form by far the highest proportion of international students. In many respects, this is a success story, but it also poses a number…

A Reemerging China: The Time for Hasty Predictions is Past

ERIC Educational Resources Information Center

Zheng, Shiping

2010-01-01

In recent years, there has been much talk in the media and the academic world about the "rise of China," as if China were a young country. Because the People's Republic of China (PRC) celebrated its sixtieth birthday only last October--and because the PRC was not admitted into the United Nations until 1971 and did not become a member of…

Education and Economics, People's Republic of China, 1983: Document of a Lecturer.

ERIC Educational Resources Information Center

Kavich, Lawrence L.

Educational and economic factors in evidence in the People's Republic of China (PRC) that indicate it will become a major power by the year 2000 are described. The factors were observed during a lecture tour from December 1982 to January 1983. Following a description of the lecture tour, four characteristics of the PRC's educational system are…

What I Wish My College Students Already Knew about PRC History

ERIC Educational Resources Information Center

Stapleton, Kristin

2010-01-01

Different generations of Americans understand China quite differently. This, of course, is true of many topics. However, the turbulence of Chinese history and U.S.-China relations in the 60 years since the founding of the People's Republic of China (PRC) in 1949 has deepened the gaps in generational thinking about China. Those who came of age in…

The PRC Decision-Making Process

DTIC Science & Technology

2002-03-01

REPORT DATE March 2002 3. REPORT TYPE AND DATES COVERED Master’s Thesis 4. TITLE AND SUBTITLE The PRC Decision - Making ...of crisis. It explores who has the authority to make decisions in China today and who will have this authority as new leaders...security and foreign policy decision - making during times of crisis. The April 2001 EP-3 incident is examined to assess high-level

76 FR 23543 - Floor-Standing, Metal-Top Ironing Tables and Certain Parts Thereof From the People's Republic of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-27

... separate rate, the cash deposit rate will be the PRC-wide rate of 157.68 percent; and (5) for all non-PRC... that in the calculation of brokerage and handling expense, the Department incorrectly applied the... antidumping duties on all appropriate entries covered by this review. Cash Deposit Requirements The following...

Education Abroad, Human Capital Development, and National Competitiveness: China's Brain Gain Strategies

ERIC Educational Resources Information Center

Pan, Su-Yan

2011-01-01

This is a documentary study of education abroad policy in the People's Republic of China (PRC) between 1978 and 2009. By examining the dynamics underpinning the PRC state's efforts to shape the flow of Chinese students and scholars from and into China, this article reveals the major strategies that have enabled education abroad to become a source…

75 FR 51004 - Drill Pipe From the People's Republic of China: Preliminary Determination of Sales at Less Than...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-18

....; Jiangsu Shuguang Huayang Drilling Tool Co., Ltd.; and Jiangyin Long-Bright Drill Pipe Manufacturing Co..., Ukraine, and Peru are countries comparable to the PRC in terms of economic development. See April 20, 2010... countries comparable to the PRC in terms of economic development. See Surrogate Country List. The sources of...

Tactile Object Familiarity in the Blind Brain Reveals the Supramodal Perceptual-Mnemonic Nature of the Perirhinal Cortex

PubMed Central

Cacciamani, Laura; Likova, Lora T.

2016-01-01

This study is the first to investigate the neural underpinnings of tactile object familiarity in the blind during both perception and memory. In the sighted, the perirhinal cortex (PRC) has been implicated in the assessment of visual object familiarity—a crucial everyday task—as evidenced by reduced activation when an object becomes familiar. Here, to examine the PRC’s role in tactile object familiarity in the absence of vision, we trained blind participants on a unique memory-guided drawing technique and measured brain activity while they perceptually explored raised-line drawings, drew them from tactile memory, and scribbled (control). Functional magnetic resonance imaging (fMRI) before and after a week of training revealed a significant decrease in PRC activation from pre- to post-training (i.e., from unfamiliar to familiar) during perceptual exploration as well as memory-guided drawing, but not scribbling. This familiarity-based reduction is the first evidence that the PRC represents tactile object familiarity in the blind. Furthermore, the finding of this effect during both tactile perception and tactile memory provides the critical link in establishing the PRC as a structure whose representations are supramodal for both perception and memory. PMID:27148002

Synergetic Organization in Speech Rhythm

NASA Astrophysics Data System (ADS)

Cummins, Fred

The Speech Cycling Task is a novel experimental paradigm developed together with Robert Port and Keiichi Tajima at Indiana University. In a task of this sort, subjects repeat a phrase containing multiple prominent, or stressed, syllables in time with an auditory metronome, which can be simple or complex. A phase-based collective variable is defined in the acoustic speech signal. This paper reports on two experiments using speech cycling which together reveal many of the hallmarks of hierarchically coupled oscillatory processes. The first experiment requires subjects to place the final stressed syllable of a small phrase at specified phases within the overall Phrase Repetition Cycle (PRC). It is clearly demonstrated that only three patterns, characterized by phases around 1/3, 1/2 or 2/3 are reliably produced, and these points are attractors for other target phases. The system is thus multistable, and the attractors correspond to stable couplings between the metrical foot and the PRC. A second experiment examines the behavior of these attractors at increased rates. Faster rates lead to mode jumps between attractors. Previous experiments have also illustrated hysteresis as the system moves from one mode to the next. The dynamical organization is particularly interesting from a modeling point of view, as there is no single part of the speech production system which cycles at the level of either the metrical foot or the phrase repetition cycle. That is, there is no continuous kinematic observable in the system. Nonetheless, there is strong evidence that the oscopic behavior of the entire production system is correctly described as hierarchically coupled oscillators. There are many parallels between this organization and the forms of inter-limb coupling observed in locomotion and rhythmic manual tasks.

Ase1/Prc1-dependent spindle elongation corrects merotely during anaphase in fission yeast

PubMed Central

Courtheoux, Thibault; Gay, Guillaume; Tournier, Sylvie

2009-01-01

Faithful segregation of sister chromatids requires the attachment of each kinetochore (Kt) to microtubules (MTs) that extend from opposite spindle poles. Merotelic Kt orientation is a Kt–MT misattachment in which a single Kt binds MTs from both spindle poles rather than just one. Genetic induction of merotelic Kt attachment during anaphase in fission yeast resulted in intra-Kt stretching followed by either correction or Kt disruption. Laser ablation of spindle MTs revealed that intra-Kt stretching and merotelic correction were dependent on MT forces. The presence of multiple merotelic chromosomes linearly antagonized the spindle elongation rate, and this phenomenon could be solved numerically using a simple force balance model. Based on the predictions of our mechanical model, we provide in vivo evidence that correction of merotelic attachment in anaphase is tension dependent and requires an Ase1/Prc1-dependent mechanism that prevents spindle collapse and thus asymmetric division and/or the appearance of the cut phenotype. PMID:19948483

New Partners in Regulation of Gene Expression: The Enhancer of Trithorax and Polycomb Corto Interacts with Methylated Ribosomal Protein L12 Via Its Chromodomain

PubMed Central

Coléno-Costes, Anne; Jang, Suk Min; de Vanssay, Augustin; Rougeot, Julien; Bouceba, Tahar; Randsholt, Neel B.; Gibert, Jean-Michel; Le Crom, Stéphane; Mouchel-Vielh, Emmanuèle

2012-01-01

Chromodomains are found in many regulators of chromatin structure, and most of them recognize methylated lysines on histones. Here, we investigate the role of the Drosophila melanogaster protein Corto's chromodomain. The Enhancer of Trithorax and Polycomb Corto is involved in both silencing and activation of gene expression. Over-expression of the Corto chromodomain (CortoCD) in transgenic flies shows that it is a chromatin-targeting module, critical for Corto function. Unexpectedly, mass spectrometry analysis reveals that polypeptides pulled down by CortoCD from nuclear extracts correspond to ribosomal proteins. Furthermore, real-time interaction analyses demonstrate that CortoCD binds with high affinity RPL12 tri-methylated on lysine 3. Corto and RPL12 co-localize with active epigenetic marks on polytene chromosomes, suggesting that both are involved in fine-tuning transcription of genes in open chromatin. RNA–seq based transcriptomes of wing imaginal discs over-expressing either CortoCD or RPL12 reveal that both factors deregulate large sets of common genes, which are enriched in heat-response and ribosomal protein genes, suggesting that they could be implicated in dynamic coordination of ribosome biogenesis. Chromatin immunoprecipitation experiments show that Corto and RPL12 bind hsp70 and are similarly recruited on gene body after heat shock. Hence, Corto and RPL12 could be involved together in regulation of gene transcription. We discuss whether pseudo-ribosomal complexes composed of various ribosomal proteins might participate in regulation of gene expression in connection with chromatin regulators. PMID:23071455

Collective phase response curves for heterogeneous coupled oscillators

NASA Astrophysics Data System (ADS)

Hannay, Kevin M.; Booth, Victoria; Forger, Daniel B.

2015-08-01

Phase response curves (PRCs) have become an indispensable tool in understanding the entrainment and synchronization of biological oscillators. However, biological oscillators are often found in large coupled heterogeneous systems and the variable of physiological importance is the collective rhythm resulting from an aggregation of the individual oscillations. To study this phenomena we consider phase resetting of the collective rhythm for large ensembles of globally coupled Sakaguchi-Kuramoto oscillators. Making use of Ott-Antonsen theory we derive an asymptotically valid analytic formula for the collective PRC. A result of this analysis is a characteristic scaling for the change in the amplitude and entrainment points for the collective PRC compared to the individual oscillator PRC. We support the analytical findings with numerical evidence and demonstrate the applicability of the theory to large ensembles of coupled neuronal oscillators.

The ASYMMETRIC LEAVES Complex Employs Multiple Modes of Regulation to Affect Adaxial-Abaxial Patterning and Leaf Complexity.

PubMed

Husbands, Aman Y; Benkovics, Anna H; Nogueira, Fabio T S; Lodha, Mukesh; Timmermans, Marja C P

2015-12-01

Flattened leaf architecture is not a default state but depends on positional information to precisely coordinate patterns of cell division in the growing primordium. This information is provided, in part, by the boundary between the adaxial (top) and abaxial (bottom) domains of the leaf, which are specified via an intricate gene regulatory network whose precise circuitry remains poorly defined. Here, we examined the contribution of the ASYMMETRIC LEAVES (AS) pathway to adaxial-abaxial patterning in Arabidopsis thaliana and demonstrate that AS1-AS2 affects this process via multiple, distinct regulatory mechanisms. AS1-AS2 uses Polycomb-dependent and -independent mechanisms to directly repress the abaxial determinants MIR166A, YABBY5, and AUXIN RESPONSE FACTOR3 (ARF3), as well as a nonrepressive mechanism in the regulation of the adaxial determinant TAS3A. These regulatory interactions, together with data from prior studies, lead to a model in which the sequential polarization of determinants, including AS1-AS2, explains the establishment and maintenance of adaxial-abaxial leaf polarity. Moreover, our analyses show that the shared repression of ARF3 by the AS and trans-acting small interfering RNA (ta-siRNA) pathways intersects with additional AS1-AS2 targets to affect multiple nodes in leaf development, impacting polarity as well as leaf complexity. These data illustrate the surprisingly multifaceted contribution of AS1-AS2 to leaf development showing that, in conjunction with the ta-siRNA pathway, AS1-AS2 keeps the Arabidopsis leaf both flat and simple. © 2015 American Society of Plant Biologists. All rights reserved.

76 FR 19325 - 1-Hydroxyethylidene-1, 1-Diphosphonic Acid From the People's Republic of China: Preliminary...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-07

...-Diphosphonic Acid From the People's Republic of China: Preliminary Results of Antidumping Duty Administrative... People's Republic of China (``PRC''). The period of review (``POR'') is April 23, 2009, through March 31....\\4\\ \\1\\ See 1-Hydroxyethylidene-1, 1-Diphosphonic Acid from India and the People's Republic of China...

78 FR 18956 - Sodium Hexametaphosphate from the People's Republic of China: Final Results of Antidumping Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-28

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-908] Sodium Hexametaphosphate... third administrative review of sodium hexametaphosphate from the People's Republic of China (``PRC'').\\1... on the Preliminary Results. \\1\\ See Sodium Hexametaphosphate from the People's Republic of China...

China/Taiwan: Evolution of the One China Policy - Key Statements from Washington, Beijing, and Taipei

DTIC Science & Technology

2006-09-07

Statements During Clinton Administration . . . . . . . . . . . . . . . . . . . . . . . . . 48 PRC Premier Li Peng Warns Taiwan...Soviet Union/Russia and built up its theater missile force.48 In December 1992 and March 1993, PRC President Jiang Zemin and Premier Li Peng began to...Ye Jianying Explains Policy Concerning Return of Taiwan to Motherland and Peaceful Unification,” Xinhua [New China News Agency], September 30, 1981

Approaches Japan Can Adopt to Deter China’s Assertive Behavior in the International Arena

DTIC Science & Technology

2016-06-10

REVIEW AND RESEACH METHODOLOGY ...............11 Theories of International Relations and UNCLOS ....................................................... 11...China, the People’s Republic of China (PRC) was established in 1949. PRC succeeded in its nuclear test in 1964 and became a permanent member of the...LITERATURE REVIEW AND RESEACH METHODOLOGY This chapter reviews existing literature to provide information, perspectives, and insights on this

Survey Summary: Students and Scholars from the People's Republic of China in the United States, August 1981.

ERIC Educational Resources Information Center

Fingar, Thomas; Reed, Linda A.

A survey of 313 American colleges and universities thought to have accepted students and/or scholars from the People's Republic of China (PRC) was conducted in March 1981 by the U.S.-China Education Clearinghouse. Usable responses were received from 164 institutions. The responses indicated that a total of 3,467 PRC students and scholars were…

75 FR 62504 - Certain New Pneumatic Off-the-Road Tires From the People's Republic of China: Notice of Decision...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-12

...-the-Road Tires From the People's Republic of China: Notice of Decision of the Court of International...-road tires (``OTR tires'') from the People's Republic of China (``PRC''). See GPX Int'l Tire Corp. v... tires from the PRC. The final judgment in this case was not in harmony with the Department's July 2008...

77 FR 6536 - Certain New Pneumatic Off-the-Road Tires From the People's Republic of China: Notice of Extension...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-08

...-the-Road Tires From the People's Republic of China: Notice of Extension of Time Limit for the Final... pneumatic off-the-road tires (``off-the-road tires'') from the People's Republic of China (``PRC'') for the... preliminary results of the administrative review of the antidumping order on off- the-road tires from the PRC...

Military Power of the People’s Republic of China 2007

DTIC Science & Technology

2007-01-01

in the Asia-Pacifi c Economic Cooperation ( APEC ) group, the Association of Southeast Asian Nations ( ASEAN ), and...China and ASEAN . In November 2006, PRC President Hu Jintao made the fi rst visit to India by a PRC head of state in ten years, demonstrating the ...country, two systems” framework that would provide Taiwan a degree of autonomy in exchange for its unifi cation with

A three pulse phase response curve to three milligrams of melatonin in humans

PubMed Central

Burgess, Helen J; Revell, Victoria L; Eastman, Charmane I

2008-01-01

Exogenous melatonin is increasingly used for its phase shifting and soporific effects. We generated a three pulse phase response curve (PRC) to exogenous melatonin (3 mg) by administering it to free-running subjects. Young healthy subjects (n = 27) participated in two 5 day laboratory sessions, each preceded by at least a week of habitual, but fixed sleep. Each 5 day laboratory session started and ended with a phase assessment to measure the circadian rhythm of endogenous melatonin in dim light using 30 min saliva samples. In between were three days in an ultradian dim light (< 150 lux)–dark cycle (LD 2.5 : 1.5) during which each subject took one pill per day at the same clock time (3 mg melatonin or placebo, double blind, counterbalanced). Each individual's phase shift to exogenous melatonin was corrected by subtracting their phase shift to placebo (a free-run). The resulting PRC has a phase advance portion peaking about 5 h before the dim light melatonin onset, in the afternoon. The phase delay portion peaks about 11 h after the dim light melatonin onset, shortly after the usual time of morning awakening. A dead zone of minimal phase shifts occurred around the first half of habitual sleep. The fitted maximum advance and delay shifts were 1.8 h and 1.3 h, respectively. This new PRC will aid in determining the optimal time to administer exogenous melatonin to achieve desired phase shifts and demonstrates that using exogenous melatonin as a sleep aid at night has minimal phase shifting effects. PMID:18006583

Association of Dyslipidemia and Sex With Coronary Artery Calcium Assessed by Coronary Computed Tomography Angiography.

PubMed

Asami, Masahiko; Yamaji, Kyohei; Aoki, Jiro; Tanimoto, Shuzou; Watanabe, Mika; Horiuchi, Yu; Furui, Koichi; Kato, Nahoko; Hara, Kazuhiro; Tanabe, Kengo

2017-10-21

Previous studies reporting that statin increases coronary artery calcium (CAC) were conducted exclusively on patients with statin as a prevention, regardless of the presence or absence of dyslipidemia. The impact of sex on CAC has not been fully evaluated. We aimed to determine the association of dyslipidemia and sex with CAC using 320-row multi-detector computed tomography (MDCT).Of the 356 consecutive patients who underwent coronary MDCT, 251 patients were enrolled, after excluding those with prior stenting and/or coronary bypass grafting or images showing motion artifacts. The primary outcome measures were the percent calcium volume (PCV) and percent atheroma volume (PAV) per coronary vessel.Multivariable analyses indicated that PCV was significantly higher in dyslipidemia patients without statins than in the subjects without dyslipidemia [partial regression coefficient (PRC): 2.59, 95% confidence interval (CI): 0.83 to 4.34, P = 0.004]. In contrast, PCV was similar in dyslipidemia patients taking statins and those without dyslipidemia (PRC: -1.09, 95% CI: -2.82 to 0.65, P = 0.22). There was no significant difference in PCV between men and women, although women exhibited a significantly lower PAV (PRC: -2.87, 95% CI: -4.54 to -1.20, P = 0.001).In low-risk patients, these results could be translated into hypotheses, which should be tested in future prospective studies. Furthermore, there was no significant difference in CAC between men and women, but women had lower PAV than men.

Substance abuse and criminal thinking: testing the countervailing, mediation, and specificity hypotheses.

PubMed

Walters, Glenn D

2012-12-01

The purpose of this study was to determine (a) which of 2 dimensions of criminal thinking (proactive and/or reactive) correlates with prior substance abuse; (b) whether criminal thinking mediates the relationship between prior substance abuse and recidivism; (c) if a direct relationship exists between specific drugs of abuse and specific criminal thinking styles. First, the reconstructed Proactive (Prc) and Reactive (Rrc) Criminal Thinking scores from the Psychological Inventory of Criminal Thinking Styles (PICTS; Walters, 1995) were correlated with a dichotomous measure of prior substance abuse and a continuous measure of the number of substances abused in a sample of 2877 male federal prisoners (age: M = 34.96, SD = 9.89, range = 18-84; race: 63.6% Black, 17.3% White, 17.6% Hispanic, 1.4% other). The results indicated that only the Rrc score correlated significantly with prior substance abuse when the effect of the alternative measure (Prc in the case of Rrc and Rrc in the case of the Prc) was controlled through partial correlations. Second, reactive criminal thinking was found to mediate the relationship between a history of prior substance abuse and subsequent recidivism in a subsample of 1101 inmates who were released from prison during a 1- to 76-month follow-up. Third, both specific (alcohol with cutoff; marijuana with cognitive indolence) and global (heroin, cocaine, and amphetamine with cutoff, cognitive indolence, and discontinuity) drug-criminal thinking correlations were obtained. These results suggest that reactive criminal thinking plays a potentially important role in the drug-crime relationship.

Japanese encephalitis vaccines: current vaccines and future prospects.

PubMed

Monath, T P

2002-01-01

Vaccination against JE ideally should be practiced in all areas of Asia where the virus is responsible for human disease. The WHO has placed a high priority on the development of a new vaccine for prevention of JE. Some countries in Asia (Japan, South Korea, North Korea, Taiwan, Vietnam, Thailand, and the PRC) manufacture JE vaccines and practice childhood immunization, while other countries suffering endemic or epidemic disease (India, Nepal, Laos, Cambodia, Bangladesh, Myanmar, Malaysia, Indonesia and the Philippines) have no JE vaccine manufacturing or policy for use. With the exception of the PRC, all countries practicing JE vaccination use formalin inactivated mouse brain vaccines, which are relatively expensive and are associated with rare but clinically significant allergic and neurological adverse events. New inactivated JE vaccines manufactured in Vero cells are in advanced preclinical or early clinical development in Japan, South Korea, Taiwan, and the PRC. An empirically derived, live attenuated vaccine (SA14-14-2) is widely used in the PRC. Trials in the PRC have shown SA14-14-2 to be safe and effective when administered in a two-dose regimen, but regulatory concerns over manufacturing and control have restricted international distribution. The genetic basis of attenuation of SA14-14-2 has been partially defined. A new live attenuated vaccine (ChimeriVax-JE) that uses a reliable flavivirus vaccine--yellow fever 17D--as a live vector for the envelope genes of SA14-14-2 virus is in early clinical trials and appears to be well tolerated and immunogenic after a single dose. Vaccinia and avipox vectored vaccines have also been tested clinically, but are no longer being pursued due to restricted effectiveness mediated by anti-vector immunity. Other approaches to JE vaccines--including naked DNA, oral vaccination, and recombinant subunit vaccines--have been reviewed.

How landmark suitability shapes recognition memory signals for objects in the medial temporal lobes.

PubMed

Martin, Chris B; Sullivan, Jacqueline A; Wright, Jessey; Köhler, Stefan

2018-02-01

A role of perirhinal cortex (PrC) in recognition memory for objects has been well established. Contributions of parahippocampal cortex (PhC) to this function, while documented, remain less well understood. Here, we used fMRI to examine whether the organization of item-based recognition memory signals across these two structures is shaped by object category, independent of any difference in representing episodic context. Guided by research suggesting that PhC plays a critical role in processing landmarks, we focused on three categories of objects that differ from each other in their landmark suitability as confirmed with behavioral ratings (buildings > trees > aircraft). Participants made item-based recognition-memory decisions for novel and previously studied objects from these categories, which were matched in accuracy. Multi-voxel pattern classification revealed category-specific item-recognition memory signals along the long axis of PrC and PhC, with no sharp functional boundaries between these structures. Memory signals for buildings were observed in the mid to posterior extent of PhC, signals for trees in anterior to posterior segments of PhC, and signals for aircraft in mid to posterior aspects of PrC and the anterior extent of PhC. Notably, item-based memory signals for the category with highest landmark suitability ratings were observed only in those posterior segments of PhC that also allowed for classification of landmark suitability of objects when memory status was held constant. These findings provide new evidence in support of the notion that item-based memory signals for objects are not limited to PrC, and that the organization of these signals along the longitudinal axis that crosses PrC and PhC can be captured with reference to landmark suitability. Copyright © 2017 Elsevier Inc. All rights reserved.

Soil actinomycetes in the National Forest Park in northeastern China

NASA Astrophysics Data System (ADS)

Shirokikh, I. G.; Shirokikh, A. A.

2017-01-01

The taxonomic and functional structure of actinomycete complexes in the litters and upper horizons of the soils under an artificial coniferous-broad-leaved forest located around the town of Chanchun (Tszilin province, PRC). The complex of actinomycetes included representatives of the Streptomyces, Micromonospora, Streptosporangium, and Streptoverticillium genera and oligosporous forms. In the actinomycete complexes, streptomycetes prevailed in the abundance (61-95%) and frequency of occurrence (100%). In the parcels of Korean pine ( Pinus koraiensis) and Mongolian oak ( Quercus mongolica), streptomycetes of 19 species from 8 series and 4 sections were isolated. The most representative, as in European forest biomes, was the Cinereus Achromogenes series. A distinguishing feature of the streptomycete complex in the biomes studied was the high participation of species from the Imperfectus series. The verification of the functional activity of natural isolates made it possible to reveal strains with high antagonistic and cellulolytic abilities. A high similarity of actinomycete complexes was found in Eurasian forest ecosystems remote from each other, probably due to the similarity of plant polymers decomposable by actinomycetes.

75 FR 16913 - Transmission Relay Loadability Reliability Standard

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-02

... B. Approval of PRC-023-1 13 C. Applicability 20 D. Generator Step-Up and Auxiliary Transformers......... 98 1. Omission From the Reliability Standard 98 2. Generator Step-Up Transformer Relays as Back-up... series elements such as transformers) that emanates from the remote buses. All transmission owners shall...

78 FR 56864 - Small Diameter Graphite Electrodes From the People's Republic of China: Affirmative Final...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-16

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-929] Small Diameter Graphite... (Department) determines that imports from the People's Republic of China (PRC) of graphite electrodes... Act of 1930, as amended (the Act).\\1\\ \\1\\ See Antidumping Duty Order: Small Diameter Graphite...

39 CFR 3060.22 - Financial status report.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Postal Service POSTAL REGULATORY COMMISSION PERSONNEL ACCOUNTING PRACTICES AND TAX RULES FOR THE... Products Financials—PRC Form CP-02 [$ in 000s] Beginning value Change from prior year Ending value (1... Value: Sum total of Net Income (Loss) as of October 1 of Reportable Fiscal Year. Change from Prior Year...

The Role of Polycomb Group Gene BMI-1 in the Development of Prostate Cancer

DTIC Science & Technology

2013-07-01

cyclin D1 (Wnt target) and Bcl-2 (Sonic Hedgehog -SHH target). The novel finding in presented in the 2nd annual report was that regulation of Bcl-2... hedgehog (SHH) pathway that is very well know to regulate Bcl-2. For this purpose we determined the expression level of Bcl-2 in BMI1- overexpressing and...2006; 15: 217-27. 16. Hegde GV, Munger CM, Emanuel K, Joshi AD, Greiner TC, Weisenburger DD, Vose JM, et al. Targeting of sonic hedgehog -GLI signaling

Impeccable Timing: The Political Efficiency of Prc-U.S. Surveillance Confrontations

DTIC Science & Technology

2014-06-01

for the PRC, stating that the scope of its naval operations will not exceed “China’s self- defense needs,”16 and its... The Department of Defense of the United States of America and the Ministry of National Defense of the People’s Republic of China on Establishing a...08/29/ the -u- s -china- incidents-at-sea-agreement-a-recipe- for -disaster/. 19 changed

China Report, Agriculture, No. 260.

DTIC Science & Technology

1983-06-09

Deep- Sea , Coastal Fishing (XINHUA, 2U May 83) 32 World Food Program To Aid PRC Dairy Industry (XINHUA, 28 May 83) 33 More on WFP Aid...PRC TO EXPAND DEEP- SEA , COASTAL FISHING OW241245 Beijing XINHUA in English 1159 GMT 24 May 83 [Text] Beijing, May 24 (XINHUA)—China will expand...fishing in the open seas while protecting, cultivating and rationally exploiting coastal resources, said Meng Xiande, director of the Aquatic

JPRS Report, Science & Technology, Europe & Latin America

DTIC Science & Technology

1988-02-23

Space Cooperation With USSR, PRC ( ESPACIAL , May 87) 121 - c - Brazil’s SMAR May Sell Automation Equipment to Cuba (0 GLOBO, 16 Nov 87) 124...Edson Fregni, president of Scopus Tecnologia and former president of Abicomp, expects that the process of mergers or takeovers among domestic data...its equipment. 5058 CSO: 3699/0013 120 TECHNOLOGY TRANSFER LATIN AMERICA BRAZILIAN SPACE COOPERATION WITH USSR, PRC San Jose dos Campos ESPACIAL

Multivariate fMRI and Eye Tracking Reveal Differential Effects of Visual Interference on Recognition Memory Judgments for Objects and Scenes.

PubMed

O'Neil, Edward B; Watson, Hilary C; Dhillon, Sonya; Lobaugh, Nancy J; Lee, Andy C H

2015-09-01

Recent work has demonstrated that the perirhinal cortex (PRC) supports conjunctive object representations that aid object recognition memory following visual object interference. It is unclear, however, how these representations interact with other brain regions implicated in mnemonic retrieval and how congruent and incongruent interference influences the processing of targets and foils during object recognition. To address this, multivariate partial least squares was applied to fMRI data acquired during an interference match-to-sample task, in which participants made object or scene recognition judgments after object or scene interference. This revealed a pattern of activity sensitive to object recognition following congruent (i.e., object) interference that included PRC, prefrontal, and parietal regions. Moreover, functional connectivity analysis revealed a common pattern of PRC connectivity across interference and recognition conditions. Examination of eye movements during the same task in a separate study revealed that participants gazed more at targets than foils during correct object recognition decisions, regardless of interference congruency. By contrast, participants viewed foils more than targets for incorrect object memory judgments, but only after congruent interference. Our findings suggest that congruent interference makes object foils appear familiar and that a network of regions, including PRC, is recruited to overcome the effects of interference.

Characterization of new regulatory elements within the Drosophila bithorax complex.

PubMed

Pérez-Lluch, Sílvia; Cuartero, Sergi; Azorín, Fernando; Espinàs, M Lluïsa

2008-12-01

The homeotic Abdominal-B (Abd-B) gene expression depends on a modular cis-regulatory region divided into discrete functional domains (iab) that control the expression of the gene in a particular segment of the fly. These domains contain regulatory elements implicated in both initiation and maintenance of homeotic gene expression and elements that separate the different domains. In this paper we have performed an extensive analysis of the iab-6 regulatory region, which regulates Abd-B expression at abdominal segment A6 (PS11), and we have characterized two new polycomb response elements (PREs) within this domain. We report that PREs at Abd-B cis-regulatory domains present a particular chromatin structure which is nuclease accessible all along Drosophila development and both in active and repressed states. We also show that one of these regions contains a dCTCF and CP190 dependent activity in transgenic enhancer-blocking assays, suggesting that it corresponds to the Fab-6 boundary element of the Drosophila bithorax complex.

ASXL1 mutation correction by CRISPR/Cas9 restores gene function in leukemia cells and increases survival in mouse xenografts

PubMed Central

Valletta, Simona; Dolatshad, Hamid; Bartenstein, Matthias; Yip, Bon Ham; Bello, Erica; Gordon, Shanisha; Yu, Yiting; Shaw, Jacqueline; Roy, Swagata; Scifo, Laura; Schuh, Anna; Pellagatti, Andrea; Fulga, Tudor A.; Verma, Amit; Boultwood, Jacqueline

2015-01-01

Recurrent somatic mutations of the epigenetic modifier and tumor suppressor ASXL1 are common in myeloid malignancies, including chronic myeloid leukemia (CML), and are associated with poor clinical outcome. CRISPR/Cas9 has recently emerged as a powerful and versatile genome editing tool for genome engineering in various species. We have used the CRISPR/Cas9 system to correct the ASXL1 homozygous nonsense mutation present in the CML cell line KBM5, which lacks ASXL1 protein expression. CRISPR/Cas9-mediated ASXL1 homozygous correction resulted in protein re-expression with restored normal function, including down-regulation of Polycomb repressive complex 2 target genes. Significantly reduced cell growth and increased myeloid differentiation were observed in ASXL1 mutation-corrected cells, providing new insights into the role of ASXL1 in human myeloid cell differentiation. Mice xenografted with mutation-corrected KBM5 cells showed significantly longer survival than uncorrected xenografts. These results show that the sole correction of a driver mutation in leukemia cells increases survival in vivo in mice. This study provides proof-of-concept for driver gene mutation correction via CRISPR/Cas9 technology in human leukemia cells and presents a strategy to illuminate the impact of oncogenic mutations on cellular function and survival. PMID:26623729

ASXL1 mutation correction by CRISPR/Cas9 restores gene function in leukemia cells and increases survival in mouse xenografts.

PubMed

Valletta, Simona; Dolatshad, Hamid; Bartenstein, Matthias; Yip, Bon Ham; Bello, Erica; Gordon, Shanisha; Yu, Yiting; Shaw, Jacqueline; Roy, Swagata; Scifo, Laura; Schuh, Anna; Pellagatti, Andrea; Fulga, Tudor A; Verma, Amit; Boultwood, Jacqueline

2015-12-29

Recurrent somatic mutations of the epigenetic modifier and tumor suppressor ASXL1 are common in myeloid malignancies, including chronic myeloid leukemia (CML), and are associated with poor clinical outcome. CRISPR/Cas9 has recently emerged as a powerful and versatile genome editing tool for genome engineering in various species. We have used the CRISPR/Cas9 system to correct the ASXL1 homozygous nonsense mutation present in the CML cell line KBM5, which lacks ASXL1 protein expression. CRISPR/Cas9-mediated ASXL1 homozygous correction resulted in protein re-expression with restored normal function, including down-regulation of Polycomb repressive complex 2 target genes. Significantly reduced cell growth and increased myeloid differentiation were observed in ASXL1 mutation-corrected cells, providing new insights into the role of ASXL1 in human myeloid cell differentiation. Mice xenografted with mutation-corrected KBM5 cells showed significantly longer survival than uncorrected xenografts. These results show that the sole correction of a driver mutation in leukemia cells increases survival in vivo in mice. This study provides proof-of-concept for driver gene mutation correction via CRISPR/Cas9 technology in human leukemia cells and presents a strategy to illuminate the impact of oncogenic mutations on cellular function and survival.

An Automatic Segmentation Method Combining an Active Contour Model and a Classification Technique for Detecting Polycomb-group Proteinsin High-Throughput Microscopy Images.

PubMed

Gregoretti, Francesco; Cesarini, Elisa; Lanzuolo, Chiara; Oliva, Gennaro; Antonelli, Laura

2016-01-01

The large amount of data generated in biological experiments that rely on advanced microscopy can be handled only with automated image analysis. Most analyses require a reliable cell image segmentation eventually capable of detecting subcellular structures.We present an automatic segmentation method to detect Polycomb group (PcG) proteins areas isolated from nuclei regions in high-resolution fluorescent cell image stacks. It combines two segmentation algorithms that use an active contour model and a classification technique serving as a tool to better understand the subcellular three-dimensional distribution of PcG proteins in live cell image sequences. We obtained accurate results throughout several cell image datasets, coming from different cell types and corresponding to different fluorescent labels, without requiring elaborate adjustments to each dataset.

The role of epigenetics and long noncoding RNA MIAT in neuroendocrine prostate cancer.

PubMed

Crea, Francesco; Venalainen, Erik; Ci, Xinpei; Cheng, Hongwei; Pikor, Larissa; Parolia, Abhijit; Xue, Hui; Nur Saidy, Nur Ridzwan; Lin, Dong; Lam, Wan; Collins, Colin; Wang, Yuzhuo

2016-05-01

Neuroendocrine prostate cancer (NEPC) is the most lethal prostatic neoplasm. NEPC is thought to originate from the transdifferentiation of AR-positive adenocarcinoma cells. We have previously shown that an epigenetic/noncoding interactome (ENI) orchestrates cancer cells' plasticity, thereby allowing the emergence of metastatic, drug-resistant neoplasms. The primary objective of this manuscript is to discuss evidence indicating that some components of the ENI (Polycomb genes, miRNAs) play a key role in NEPC initiation and progression. Long noncoding RNAs represent vast and largely unexplored component of the ENI. Their role in NEPC has not been investigated. We show preliminary evidence indicating that a lncRNA (MIAT) is selectively upregulated in NEPCs and might interact with Polycomb genes. Our results indicate that long noncoding RNAs can be exploited as new biomarkers and therapeutic targets for NEPC.

Effects of rearrangement and allelic exclusion of JJAZ1/SUZ12 on cell proliferation and survival

PubMed Central

Li, Hui; Ma, XianYong; Wang, Jinglan; Koontz, Jason; Nucci, Marisa; Sklar, Jeffrey

2007-01-01

Polycomb group genes (PcGs) have been implicated in cancer based on altered levels of expression observed in certain tumors and the behavior of cultured cells containing inserted PcG transgenes. Endometrial stromal tumors provide evidence for a direct causal relationship because they contain several chromosomal translocations and resultant gene fusions involving PcGs, the most common of which joins portions of theJAZF1 gene to the PcGJJAZ1/SUZ12. We show here that both benign and malignant forms of this tumor have theJAZF1–JJAZ1 fusion but only the malignant form also exhibits exclusion of the unrearrangedJJAZ1 allele. To evaluate the effects of both theJJAZ1/SUZ12 fusion and allelic exclusion on functions related to cell growth, we studied HEK293 cells that were modified with respect toJJAZ1 expression. We found that theJAZF1–JJAZ1 fusion restored levels of the polycomb protein EZH2 and histone 3 lysine 27 trimethylation, which were reduced by knockdown of endogenous JJAZ1. At the same time, the presence ofJAZF1–JJAZ1 markedly inhibited apoptosis and induced above normal proliferation rates, although the latter effect occurred only when normalJJAZ1 was suppressed. Our findings suggest a genetic pathway for progression of a benign precursor to a sarcoma involving increased cell survival associated with acquisition of a PcG rearrangement, followed by accelerated cellular proliferation upon allelic exclusion of the unrearranged copy of that gene. Furthermore, these results indicate the likely functional importance of allelic exclusion of genes disrupted by chromosomal translocations, as seen in a variety of other cancers. PMID:18077430

Assessing Maritime Aspects of the AirSea Battle Concept

DTIC Science & Technology

2012-03-23

AirSea Battle centered on the assessment that in hostilities the PRC would conduct a rapid preemptive attack to knock back U.S. and allied forces in...these factors provide the foundational need for a clear maritime strategy backed by strong naval power. ! The core of PRC maritime security strategy...Law Enforcement Command. This direct and indirect approach hearkens back to the theories of Sunzi and Mao Tse-tung. ! China’s 2010 National Defense

China/Taiwan: Evolution of the One China Policy - Key Statements from Washington, Beijing, and Taipei

DTIC Science & Technology

2007-07-09

48 PRC Premier Li Peng Warns Taiwan . . . . . . . . . . . . . . . . . . . . . . . . . 48 Mainland-Taiwan “Koo-Wang...and March 1993, PRC President Jiang Zemin and Premier Li Peng began to warn of having to use “drastic” or “resolute” measures to prevent Taiwan...commitment in its referral to Quemoy and Matsu.” (Wolff and Simon, p. 282-283.) 95 “Ye Jianying Explains Policy Concerning Return of Taiwan to Motherland and

Parallel resonant converter with LLC-type commutation

NASA Astrophysics Data System (ADS)

Lee, C. Q.; Liu, Rui; Batarseh, Issa

1989-11-01

It is shown that by using a proper transformation of state variables, the third-order system of the parallel resonant converter (PRC) with LLC-type commutation can be analyzed by means of a two-dimensional state-plane diagram. A set of characteristic curves which can be used for the converter design is derived from the analysis. It is shown from these curves that the converter possesses more desirable features than the conventional PRC.

The CWF pipeline system from Shen mu to the Yellow Sea

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

Ercolani, D.

1993-12-31

A feasibility study on the applicability of coal-water fuel (CWF) technology in the People`s Republic of China (PRC) is in progress. This study, awarded to Snamprogetti by the International Centre for Scientific Culture (World Laboratory) of Geneva, Switzerland, is performed on behalf of Chinese Organizations led by the Ministry of Energy Resources and the Academy of Sciences of the People`s Republic of China. Slurry pipelines appear to be a solution for solving the logistic problems created by a progressively increasing coal consumption and a limited availability of conventional transport infrastructures in the PRC. Within this framework, CWF pipelines are themore » most innovative technological option in consideration of the various advantages the technology offers with respect to conventional slurry pipelines. The PRC CWF pipeline system study evaluates two alternative transport streams, but originating from the same slurry production plant, located at Shachuanguo, about 100 km from Sheng Mu.« less

78 FR 49475 - Certain Oil Country Tubular Goods From the People's Republic of China: Final Results of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-14

... (``PRC''). The period of review is January 1, 2011, through December 31, 2011. We find that Wuxi Seamless Oil Pipe Co., Ltd. (``Wuxi'') and Jiangsu Chengde Steel Tube Share Co., Ltd. (``Jiangsu Chengde...

78 FR 29322 - Silicon Metal From the People's Republic of China: Final Results and Final No Shipments...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-20

... People's Republic of China: Final Results and Final No Shipments Determination of Antidumping Duty... the People's Republic of China (``PRC'').\\1\\ The period of review (``POR'') is June 1, 2011, through... any reviewable transactions during the POR. \\1\\ See Silicon Metal From the People's Republic of China...

77 FR 67337 - Certain Activated Carbon From the People's Republic of China; 2010-2011; Final Results of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-09

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-904] Certain Activated Carbon... on certain activated carbon from the People's Republic of China (``PRC'') on May 4, 2012,\\1\\ and we...'') is April 1, 2010, through March 31, 2011. \\1\\ See Certain Activated Carbon From the People's Republic...

76 FR 1404 - Pure Magnesium in Granular Form From the People's Republic of China: Rescission of Changed...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-10

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-864] Pure Magnesium in Granular... duty order \\1\\ on pure magnesium in granular form from the People's Republic of China (``PRC'') to... circumstances review. The Department is now rescinding this CCR. \\1\\ See Antidumping Duty Order: Pure Magnesium...

77 FR 55808 - Certain Preserved Mushrooms From the People's Republic of China: Final Results of Antidumping...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-11

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-851] Certain Preserved Mushrooms... preserved mushrooms from the People's Republic of China (PRC).\\1\\ Based upon our analysis of comments... is listed in the ``Final Results of Review'' section below. \\1\\ See Certain Preserved Mushrooms From...

78 FR 19209 - Laminated Woven Sacks From the People's Republic of China: Final Results of Antidumping Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-29

... the People's Republic of China: Final Results of Antidumping Duty Administrative Review; 2011-2012...'') from the People's Republic of China (``PRC''). The period of review (``POR'') is August 1, 2011... the ``Final Results of Review'' section below. \\1\\ See Laminated Woven Sacks From the People's...

75 FR 76699 - Chlorinated Isocyanurates From the People's Republic of China: Notice of Correction to the Final...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-09

... DEPARTMENT OF COMMERCE International Trade Administration [A-570-898] Chlorinated Isocyanurates... antidumping duty order on chlorinated isocyanurates from the People's Republic of China (``PRC'').\\1\\ The... final results margin for Jiheng for the 2008-2009 period of review is 2.66 percent. \\1\\ See Chlorinated...

78 FR 4386 - Chlorinated Isocyanurates From the People's Republic of China: Final Results of Antidumping Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-22

... From the People's Republic of China: Final Results of Antidumping Duty Administrative Review; 2010-2011... People's Republic of China (PRC).\\1\\ The period of review (POR) for this administrative review was June 1... Isocyanurates From the People's Republic of China: Preliminary Results of Antidumping Duty Administrative Review...

The lipodystrophic hotspot lamin A p.R482W mutation deregulates the mesodermal inducer T/Brachyury and early vascular differentiation gene networks.

PubMed

Briand, Nolwenn; Guénantin, Anne-Claire; Jeziorowska, Dorota; Shah, Akshay; Mantecon, Matthieu; Capel, Emilie; Garcia, Marie; Oldenburg, Anja; Paulsen, Jonas; Hulot, Jean-Sebastien; Vigouroux, Corinne; Collas, Philippe

2018-04-15

The p.R482W hotspot mutation in A-type nuclear lamins causes familial partial lipodystrophy of Dunnigan-type (FPLD2), a lipodystrophic syndrome complicated by early onset atherosclerosis. Molecular mechanisms underlying endothelial cell dysfunction conferred by the lamin A mutation remain elusive. However, lamin A regulates epigenetic developmental pathways and mutations could perturb these functions. Here, we demonstrate that lamin A R482W elicits endothelial differentiation defects in a developmental model of FPLD2. Genome modeling in fibroblasts from patients with FPLD2 caused by the lamin A R482W mutation reveals repositioning of the mesodermal regulator T/Brachyury locus towards the nuclear center relative to normal fibroblasts, suggesting enhanced activation propensity of the locus in a developmental model of FPLD2. Addressing this issue, we report phenotypic and transcriptional alterations in mesodermal and endothelial differentiation of induced pluripotent stem cells we generated from a patient with R482W-associated FPLD2. Correction of the LMNA mutation ameliorates R482W-associated phenotypes and gene expression. Transcriptomics links endothelial differentiation defects to decreased Polycomb-mediated repression of the T/Brachyury locus and over-activation of T target genes. Binding of the Polycomb repressor complex 2 to T/Brachyury is impaired by the mutated lamin A network, which is unable to properly associate with the locus. This leads to a deregulation of vascular gene expression over time. By connecting a lipodystrophic hotspot lamin A mutation to a disruption of early mesodermal gene expression and defective endothelial differentiation, we propose that the mutation rewires the fate of several lineages, resulting in multi-tissue pathogenic phenotypes.

Effects of hypo-O-GlcNAcylation on Drosophila development.

PubMed

Mariappa, Daniel; Ferenbach, Andrew T; van Aalten, Daan M F

2018-05-11

Post-translational modification of serine/threonine residues in nucleocytoplasmic proteins with GlcNAc ( O -GlcNAcylation) is an essential regulatory mechanism in many cellular processes. In Drosophila , null mutants of the Polycomb gene O -GlcNAc transferase ( OGT ; also known as super sex combs ( sxc )) display homeotic phenotypes. To dissect the requirement for O -GlcNAc signaling in Drosophila development, we used CRISPR/Cas9 gene editing to generate rationally designed sxc catalytically hypomorphic or null point mutants. Of the fertile males derived from embryos injected with the CRISPR/Cas9 reagents, 25% produced progeny carrying precise point mutations with no detectable off-target effects. One of these mutants, the catalytically inactive sxc K872M , was recessive lethal, whereas a second mutant, the hypomorphic sxc H537A , was homozygous viable. We observed that reduced total protein O -GlcNAcylation in the sxc H537A mutant is associated with a wing vein phenotype and temperature-dependent lethality. Genetic interaction between sxc H537A and a null allele of Drosophila host cell factor ( dHcf ), encoding an extensively O -GlcNAcylated transcriptional coactivator, resulted in abnormal scutellar bristle numbers. A similar phenotype was also observed in sxc H537A flies lacking a copy of skuld ( skd ), a Mediator complex gene known to affect scutellar bristle formation. Interestingly, this phenotype was independent of OGT Polycomb function or dHcf downstream targets. In conclusion, the generation of the endogenous OGT hypomorphic mutant sxc H537A enabled us to identify pleiotropic effects of globally reduced protein O -GlcNAc during Drosophila development. The mutants generated and phenotypes observed in this study provide a platform for discovery of OGT substrates that are critical for Drosophila development. © 2018 Mariappa et al.

Discharge disposition of adolescents admitted to medical hospitals after attempting suicide.

PubMed

Levine, Leonard J; Schwarz, Donald F; Argon, Jesse; Mandell, David S; Feudtner, Chris

2005-09-01

To test the hypothesis that discharge disposition for adolescents admitted to medical hospitals after attempting suicide varies as a function of hospital type and geographic region. Retrospective cohort analysis. The nationally representative Kids' Inpatient Database for 2000. Patients aged 10 to 19 years with a diagnosis of suicide attempt or self-inflicted injury.Main Outcome Measure Likelihood of transfer to another facility vs discharge to home. Care for 32 655 adolescents who attempted suicide was provided in adult hospitals (83% of hospitalizations), children's units in general hospitals (10%), and children's hospitals (4%). More than half (66%) of medical hospitalizations ended with discharge to home, 21% with transfer to a psychiatric, rehabilitation, or chronic care (P/R/C) facility, 10% with transfer to a skilled nursing facility, intermediate care facility, or short-term acute care hospital facility, and 2% with death or departure against medical advice. After adjustment for individual patient characteristics, children's units were 44% more likely than adult hospitals to transfer adolescent patients to a P/R/C facility (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.07-1.94). Patients cared for outside the Northeast were significantly less likely to be transferred to a P/R/C facility (South: OR, 0.79; 95% CI, 0.65-0.97; Midwest: OR, 0.63; 95% CI, 0.49-0.80; West: OR, 0.29; 95% CI, 0.22-0.38). Most adolescents admitted to a medical hospital after a suicide attempt are discharged to home, and the likelihood of transfer to another facility appears to be influenced by the geographic location of the admitting hospital and whether it caters to children.

Trends in worldwide nanotechnology patent applications: 1991 to 2008

NASA Astrophysics Data System (ADS)

Dang, Yan; Zhang, Yulei; Fan, Li; Chen, Hsinchun; Roco, Mihail C.

2010-03-01

Nanotechnology patent applications published during 1991-2008 have been examined using the "title-abstract" keyword search on esp@cenet "worldwide" database. The longitudinal evolution of the number of patent applications, their topics, and their respective patent families have been evaluated for 15 national patent offices covering 98% of the total global activity. The patent offices of the United States (USA), People's Republic of China (PRC), Japan, and South Korea have published the largest number of nanotechnology patent applications, and experienced significant but different growth rates after 2000. In most repositories, the largest numbers of nanotechnology patent applications originated from their own countries/regions, indicating a significant "home advantage." The top applicant institutions are from different sectors in different countries (e.g., from industry in the US and Canada patent offices, and from academe or government agencies at the PRC office). As compared to 2000, the year before the establishment of the US National Nanotechnology Initiative (NNI), numerous new invention topics appeared in 2008, in all 15 patent repositories. This is more pronounced in the USA and PRC. Patent families have increased among the 15 patent offices, particularly after 2005. Overlapping patent applications increased from none in 1991 to about 4% in 2000 and to about 27% in 2008. The largest share of equivalent nanotechnology patent applications (1,258) between two repositories was identified between the US and Japan patent offices.

Trends in worldwide nanotechnology patent applications: 1991 to 2008.

PubMed

Dang, Yan; Zhang, Yulei; Fan, Li; Chen, Hsinchun; Roco, Mihail C

2010-03-01

Nanotechnology patent applications published during 1991-2008 have been examined using the "title-abstract" keyword search on esp@cenet "worldwide" database. The longitudinal evolution of the number of patent applications, their topics, and their respective patent families have been evaluated for 15 national patent offices covering 98% of the total global activity. The patent offices of the United States (USA), People's Republic of China (PRC), Japan, and South Korea have published the largest number of nanotechnology patent applications, and experienced significant but different growth rates after 2000. In most repositories, the largest numbers of nanotechnology patent applications originated from their own countries/regions, indicating a significant "home advantage." The top applicant institutions are from different sectors in different countries (e.g., from industry in the US and Canada patent offices, and from academe or government agencies at the PRC office). As compared to 2000, the year before the establishment of the US National Nanotechnology Initiative (NNI), numerous new invention topics appeared in 2008, in all 15 patent repositories. This is more pronounced in the USA and PRC. Patent families have increased among the 15 patent offices, particularly after 2005. Overlapping patent applications increased from none in 1991 to about 4% in 2000 and to about 27% in 2008. The largest share of equivalent nanotechnology patent applications (1,258) between two repositories was identified between the US and Japan patent offices.

Uptake and release of polar compounds in SDB-RPS Empore disks; implications for their use as passive samplers.

PubMed

Shaw, Melanie; Eaglesham, Geoff; Mueller, Jochen F

2009-03-01

Demand for sensitive monitoring tools to detect trace levels of pollutants in aquatic environments has led to investigation of sorbents to complement the suite of passive sampling phases currently in use. Styrenedivinylbenzene-reverse phase sulfonated (SDB-RPS) sorbents have a high affinity for polar organic compounds such as herbicides. However, the applicability of the performance reference compound (PRC) concept as an in situ calibration method for passive samplers that use this or similar sampling phases has yet to be validated. In this study, laboratory based calibration experiments were conducted to compare the uptake kinetics of several key pesticides with the release of three pre-loaded PRCs in Chemcatchers using SDB-RPS Empore disks deployed with a membrane and without (naked). For compounds with log K(OW) values ranging from 1.8 to 4.0, uptake into samplers with a membrane and without was linear over 30d and 10d, respectively. While uptake was linear and reproducible, PRC loss was not linear, meaning that the dissipation rates of these PRCs cannot be used to estimate field exposure conditions on uptake rates. An alternative in situ calibration technique using PRC loaded polydimethylsiloxane (PDMS) disks deployed alongside the Empore disk samplers as a surrogate calibration phase has been tested in the current study and shows promise for future applications.

Trends in worldwide nanotechnology patent applications: 1991 to 2008

PubMed Central

Zhang, Yulei; Fan, Li; Chen, Hsinchun; Roco, Mihail C.

2009-01-01

Nanotechnology patent applications published during 1991–2008 have been examined using the “title–abstract” keyword search on esp@cenet “worldwide” database. The longitudinal evolution of the number of patent applications, their topics, and their respective patent families have been evaluated for 15 national patent offices covering 98% of the total global activity. The patent offices of the United States (USA), People’s Republic of China (PRC), Japan, and South Korea have published the largest number of nanotechnology patent applications, and experienced significant but different growth rates after 2000. In most repositories, the largest numbers of nanotechnology patent applications originated from their own countries/regions, indicating a significant “home advantage.” The top applicant institutions are from different sectors in different countries (e.g., from industry in the US and Canada patent offices, and from academe or government agencies at the PRC office). As compared to 2000, the year before the establishment of the US National Nanotechnology Initiative (NNI), numerous new invention topics appeared in 2008, in all 15 patent repositories. This is more pronounced in the USA and PRC. Patent families have increased among the 15 patent offices, particularly after 2005. Overlapping patent applications increased from none in 1991 to about 4% in 2000 and to about 27% in 2008. The largest share of equivalent nanotechnology patent applications (1,258) between two repositories was identified between the US and Japan patent offices. PMID:21170123

Community Health Partnerships for Chronic Disease Prevention Among Latinos: The San Diego Prevention Research Center

PubMed Central

Elder, John P.; Ayala, Guadalupe X.; Arredondo, Elva M.; Talavera, Gregory A.; McKenzie, Thomas L.; Hoffman, Lisa; Cuestas, Lisa; Molina, Marisa; Patrick, Kevin

2017-01-01

Over 20 years ago, university–community partnerships (i.e., Prevention Research Centers [PRCs]) across the United States were funded by the Centers for Disease Control and Prevention to conduct research and training in order to promote health and prevent disease in underserved populations. In 2004, the San Diego PRC (SDPRC) became the first PRC to focus on obesity prevention and control in a community of mostly Mexican Americans/Mexican immigrants. The SDPRC was also the first PRC to comprise a university–community partnership with a school of public health, a school of medicine, and a federally qualified health center. In conjunction with two additional funded community partners and involvement of a community advisory board, the SDPRC seeks to develop effective intervention strategies that ultimately lead to behavior change. Now in its second cycle of funding, the SDPRC has identified three primary principles that are important for these and similar efforts: (1) developing culturally appropriate interventions requires community engagement; (2) building the evidence in a systematic and rigorous way yields meaningful strategies for translation to practice; and (3) translating evidence-based interventions to practice involves capacity building for both researchers and community partners. This article describes these principles to help others involved in similar intervention efforts identify the best approach for promoting health in their own communities. PMID:23355255

Isotopic exchange on solid-phase micro extraction fiber in sediment under stagnant conditions: Implications for field application of performance reference compound calibration.

PubMed

Bao, Lian-Jun; Wu, Xiaoqin; Jia, Fang; Zeng, Eddy Y; Gan, Jay

2016-08-01

An overlooked issue for field application of in situ performance reference compound (PRC) calibration methods is the validity of the assumption that both the sorption of a target compound and desorption of its corresponding PRC follow the first-order kinetics with the same rate constants under stagnant conditions. In the present study, disposable polydimethylsiloxane fibers of 2 sizes (7 and 35 µm) impregnated with 8 (13) C-labeled or deuterated PRCs were statically deployed into different marine sediments, from which the kinetics for sorption of the target compounds and desorption of the PRCs were characterized. Nonsymmetrical profiles were observed for exchange of the target analytes and their corresponding PRCs in sediment under stagnant conditions. The hysteretic desorption of PRCs in the kinetic regime may be ascribed to the low chemical potential between the fiber and sediment porewater, which reflects the inability of water molecules to rapidly diffuse through sediment to solvate the PRCs in the aqueous layer around the fiber surface. A moderate correlation (r = 0.77 and r = 0.57, p < 0.05 for both regressions) between the PRC-calibrated equilibrium concentrations of 1,1-dichloro-2,2-bis-(chlorophenyl) ethylene (p,p'-DDE) and polychlorinated biphenyl (PCB)-153 and the lipid normalized levels in worms (Neanthes arenaceodentata) was obtained in co-exposure tests under simulating field conditions, probably resulting from slightly overestimated bioavailability because of the hysteretic desorption of PRCs and toxic effects. Environ Toxicol Chem 2016;35:1978-1985. © 2015 SETAC. © 2015 SETAC.

Keratoconus: The ABCD Grading System.

PubMed

Belin, M W; Duncan, J K

2016-06-01

To propose a new keratoconus classification/staging system that utilises current tomographic data and better reflects the anatomical and functional changes seen in keratoconus. A previously published normative database was reanalysed to generate both anterior and posterior average radii of curvature (ARC and PRC) taken from a 3.0 mm optical zone centred on the thinnest point of the cornea. Mean and standard deviations were recorded and anterior data were compared to the existing Amsler-Krumeich (AK) Classification. ARC, PRC, thinnest pachymetry and distance visual acuity were then used to construct a keratoconus classification. 672 eyes of 336 patients were analysed. Anterior and posterior values were 7.65 ± 0.236 mm and 6.26 ± 0.214 mm, respectively, and thinnest pachymetry values were 534.2 ± 30.36 µm. The ARC values were 2.63, 5.47 and 6.44 standard deviations from the mean values of stages 1-3 in the AK classification, respectively. PRC staging uses the same standard deviation gates. The pachymetric values differed by 4.42 and 7.72 standard deviations for stages 2 and 3, respectively. A new keratoconus staging incorporates anterior and posterior curvature, thinnest pachymetric values, and distance visual acuity and consists of stages 0-4 (5 stages). The proposed system closely matches the existing AK classification stages 1-4 on anterior curvature. As it incorporates posterior curvature and thickness measurements based on the thinnest point, rather than apical measurements, the new staging system better reflects the anatomical changes seen in keratoconus. Georg Thieme Verlag KG Stuttgart · New York.

Individuality and epigenetics in obesity.

PubMed

Campión, J; Milagro, F I; Martínez, J A

2009-07-01

Excessive weight gain arises from the interactions among environmental factors, genetic predisposition and the individual behavior. However, it is becoming evident that interindividual differences in obesity susceptibility depend also on epigenetic factors. Epigenetics studies the heritable changes in gene expression that do not involve changes to the underlying DNA sequence. These processes include DNA methylation, covalent histone modifications, chromatin folding and, more recently described, the regulatory action of miRNAs and polycomb group complexes. In this review, we focus on experimental evidences concerning dietary factors influencing obesity development by epigenetic mechanisms, reporting treatment doses and durations. Moreover, we present a bioinformatic analysis of promoter regions for the search of future epigenetic biomarkers of obesity, including methylation pattern analyses of several obesity-related genes (epiobesigenes), such as FGF2, PTEN, CDKN1A and ESR1, implicated in adipogenesis, SOCS1/SOCS3, in inflammation, and COX7A1 LPL, CAV1, and IGFBP3, in intermediate metabolism and insulin signalling. The identification of those individuals that at an early age could present changes in the methylation profiles of specific genes could help to predict their susceptibility to later develop obesity, which may allow to prevent and follow-up its progress, as well as to research and develop newer therapeutic approaches.

ASXL2 mutations are frequently found in pediatric AML patients with t(8;21)/ RUNX1-RUNX1T1 and associated with a better prognosis.

PubMed

Yamato, Genki; Shiba, Norio; Yoshida, Kenichi; Shiraishi, Yuichi; Hara, Yusuke; Ohki, Kentaro; Okubo, Jun; Okuno, Haruna; Chiba, Kenichi; Tanaka, Hiroko; Kinoshita, Akitoshi; Moritake, Hiroshi; Kiyokawa, Nobutaka; Tomizawa, Daisuke; Park, Myoung-Ja; Sotomatsu, Manabu; Taga, Takashi; Adachi, Souichi; Tawa, Akio; Horibe, Keizo; Arakawa, Hirokazu; Miyano, Satoru; Ogawa, Seishi; Hayashi, Yasuhide

2017-05-01

ASXL2 is an epigenetic regulator involved in polycomb repressive complex regulation or recruitment. Clinical features of pediatric acute myeloid leukemia (AML) patients with ASXL2 mutations remain unclear. Thus, we investigated frequencies of ASXL1 and ASXL2 mutations, clinical features of patients with these mutations, correlations of these mutations with other genetic alterations including BCOR/BCORL1 and cohesin complex component genes, and prognostic impact of these mutations in 369 pediatric patients with de novo AML (0-17 years). We identified 9 (2.4%) ASXL1 and 17 (4.6%) ASXL2 mutations in 25 patients. These mutations were more common in patients with t(8;21)(q22;q22)/RUNX1-RUNX1T1 (ASXL1, 6/9, 67%, P = 0.02; ASXL2, 10/17, 59%, P = 0.01). Among these 25 patients, 4 (27%) of 15 patients with t(8;21) and 6 (60%) of 10 patients without t(8;21) relapsed. However, most patients with relapse were rescued using stem cell transplantation irrespective of t(8;21). The overall survival (OS) and event-free survival (EFS) rates showed no differences among pediatric AML patients with t(8;21) and ASXL1 or ASXL2 mutations and ASXL wild-type (5-year OS, 75% vs. 100% vs. 91% and 5-year EFS, 67% vs. 80% vs. 67%). In 106 patients with t(8;21) AML, the coexistence of mutations in tyrosine kinase pathways and chromatin modifiers and/or cohesin complex component genes had no effect on prognosis. These results suggest that ASXL1 and ASXL2 mutations play key roles as cooperating mutations that induce leukemogenesis, particularly in pediatric AML patients with t(8;21), and these mutations might be associated with a better prognosis than that reported previously. © 2017 Wiley Periodicals, Inc.

The Role of Polycomb Group Gene BMI-1 in the Development of Prostate Cancer

DTIC Science & Technology

2009-09-01

17. Fu M, Wang C, Li Z, Sakamaki T, Pestell RG. Minireview: Cyclin D1: normal and abnormal functions. Endocrinology. 2004 Dec;145(12):5439-47. 18...connecting development to breast cancer. Cell Cycle. 2004 Feb;3(2):145-8. 32. Wang C, Li Z, Fu M, Bouras T, Pestell RG. Signal transduction mediated by...Ferzli G, Johnson K, Fricke S, Diba F, Kallakury B, Ohanyerenwa C, Chen M, Ostrowski M, Hung MC, Rabbani SA, Datar R, Cote R, Pestell R, Albanese C

Evaluation of the use of performance reference compounds in an oasis-HLB adsorbent based passive sampler for improving water concentration estimates of polar herbicides in freshwater

USGS Publications Warehouse

Mazzella, N.; Lissalde, S.; Moreira, S.; Delmas, F.; Mazellier, P.; Huckins, J.N.

2010-01-01

Passive samplers such as the Polar Organic Chemical Integrative Sampler (POCIS) are useful tools for monitoring trace levels of polar organic chemicals in aquatic environments. The use of performance reference compounds (PRC) spiked into the POCIS adsorbent for in situ calibration may improve the semiquantitative nature of water concentration estimates based on this type of sampler. In this work, deuterium labeled atrazine-desisopropyl (DIA-d5) was chosen as PRC because of its relatively high fugacity from Oasis HLB (the POCIS adsorbent used) and our earlier evidence of its isotropic exchange. In situ calibration of POCIS spiked with DIA-d5was performed, and the resulting time-weighted average concentration estimates were compared with similar values from an automatic sampler equipped with Oasis HLB cartridges. Before PRC correction, water concentration estimates based on POCIS data sampling ratesfrom a laboratory calibration exposure were systematically lower than the reference concentrations obtained with the automatic sampler. Use of the DIA-d5 PRC data to correct POCIS sampling rates narrowed differences between corresponding values derived from the two methods. Application of PRCs for in situ calibration seems promising for improving POCIS-derived concentration estimates of polar pesticides. However, careful attention must be paid to the minimization of matrix effects when the quantification is performed by HPLC-ESI-MS/MS. ?? 2010 American Chemical Society.

Function of YY1 in Long-Distance DNA Interactions

PubMed Central

Atchison, Michael L.

2014-01-01

During B cell development, long-distance DNA interactions are needed for V(D)J somatic rearrangement of the immunoglobulin (Ig) loci to produce functional Ig genes, and for class switch recombination (CSR) needed for antibody maturation. The tissue-specificity and developmental timing of these mechanisms is a subject of active investigation. A small number of factors are implicated in controlling Ig locus long-distance interactions including Pax5, Yin Yang 1 (YY1), EZH2, IKAROS, CTCF, cohesin, and condensin proteins. Here we will focus on the role of YY1 in controlling these mechanisms. YY1 is a multifunctional transcription factor involved in transcriptional activation and repression, X chromosome inactivation, Polycomb Group (PcG) protein DNA recruitment, and recruitment of proteins required for epigenetic modifications (acetylation, deacetylation, methylation, ubiquitination, sumoylation, etc.). YY1 conditional knock-out indicated that YY1 is required for B cell development, at least in part, by controlling long-distance DNA interactions at the immunoglobulin heavy chain and Igκ loci. Our recent data show that YY1 is also required for CSR. The mechanisms implicated in YY1 control of long-distance DNA interactions include controlling non-coding antisense RNA transcripts, recruitment of PcG proteins to DNA, and interaction with complexes involved in long-distance DNA interactions including the cohesin and condensin complexes. Though common rearrangement mechanisms operate at all Ig loci, their distinct temporal activation along with the ubiquitous nature of YY1 poses challenges for determining the specific mechanisms of YY1 function in these processes, and their regulation at the tissue-specific and B cell stage-specific level. The large numbers of post-translational modifications that control YY1 functions are possible candidates for regulation. PMID:24575094

A Novel YY1-miR-1 Regulatory Circuit in Skeletal Myogenesis Revealed by Genome-Wide Prediction of YY1-miRNA Network

PubMed Central

Lu, Leina; Zhou, Liang; Chen, Eric Z.; Sun, Kun; Jiang, Peiyong; Wang, Lijun; Su, Xiaoxi; Sun, Hao; Wang, Huating

2012-01-01

microRNAs (miRNAs) are non-coding RNAs that regulate gene expression post-transcriptionally, and mounting evidence supports the prevalence and functional significance of their interplay with transcription factors (TFs). Here we describe the identification of a regulatory circuit between muscle miRNAs (miR-1, miR-133 and miR-206) and Yin Yang 1 (YY1), an epigenetic repressor of skeletal myogenesis in mouse. Genome-wide identification of potential down-stream targets of YY1 by combining computational prediction with expression profiling data reveals a large number of putative miRNA targets of YY1 during skeletal myoblasts differentiation into myotubes with muscle miRs ranking on top of the list. The subsequent experimental results demonstrate that YY1 indeed represses muscle miRs expression in myoblasts and the repression is mediated through multiple enhancers and recruitment of Polycomb complex to several YY1 binding sites. YY1 regulating miR-1 is functionally important for both C2C12 myogenic differentiation and injury-induced muscle regeneration. Furthermore, we demonstrate that miR-1 in turn targets YY1, thus forming a negative feedback loop. Together, these results identify a novel regulatory circuit required for skeletal myogenesis and reinforce the idea that regulatory circuitries involving miRNAs and TFs are prevalent mechanisms. PMID:22319554

Segregating Variation in the Polycomb Group Gene cramped Alters the Effect of Temperature on Multiple Traits

PubMed Central

Gibert, Jean-Michel; Karch, François; Schlötterer, Christian

2011-01-01

The phenotype produced by a given genotype can be strongly modulated by environmental conditions. Therefore, natural populations continuously adapt to environment heterogeneity to maintain optimal phenotypes. It generates a high genetic variation in environment-sensitive gene networks, which is thought to facilitate evolution. Here we analyze the chromatin regulator crm, identified as a candidate for adaptation of Drosophila melanogaster to northern latitudes. We show that crm contributes to environmental canalization. In particular, crm modulates the effect of temperature on a genomic region encoding Hedgehog and Wingless signaling effectors. crm affects this region through both constitutive heterochromatin and Polycomb silencing. Furthermore, we show that crm European and African natural variants shift the reaction norms of plastic traits. Interestingly, traits modulated by crm natural variants can differ markedly between Drosophila species, suggesting that temperature adaptation facilitates their evolution. PMID:21283785

Academic-health department collaborative relationships are reciprocal and strengthen public health practice: results from a study of academic research centers.

PubMed

Neri, Elizabeth M; Ballman, Marie R; Lu, Hua; Greenlund, Kurt J; Grunbaum, Jo Anne

2014-01-01

Collaborations between academic institutions and state and local health departments have been shown to enhance the public health core functions of Assurance by improving the public health workforce's knowledge and skills. Few studies have analyzed how academic-health department collaborations enhance Assessment and Policy Development core functions. This qualitative study explores types of collaborations between health departments and Prevention Research Centers (PRCs) and how they align with the core functions. Prevention Research Centers are academic institutions funded by the Centers for Disease Control and Prevention to conduct public health research and translate research results for policies and practices. We reviewed each PRC's annual report from fiscal year 2011 and abstracted descriptions of PRC-health department collaborations. We identified 14 themes of PRC-health department collaborations and conducted a qualitative analysis to describe the dimensions and distribution of themes. Of the 37 PRCs, 36 reported 215 collaborations with 19 city, 97 county, 31 state, and 46 tribal health departments. Themes of research, survey, and surveillance aligned with the Assessment core function and evaluation, strategic planning, technical assistance, and program implementation supported the Policy Development and Assurance core functions. Overall, health departments provided on-the-ground expertise to inform PRC research, ensuring its applicability to public health practice. Reciprocally, PRCs improved data quality, increased the scientific rigor of health department processes and programs, and filled knowledge gaps within health departments. Both PRCs and health departments enhanced the relevance of public health programs and practices by grounding implementation and evaluation in community needs and views. Findings from this study demonstrate that PRC-health department collaborations often enhanced multiple core functions that could lead to implementation of evidence-based interventions and continuous quality improvement of public health administration at the local, state, and tribal levels. This study highlights the value and importance of reciprocal academic-health department partnerships.