WorldWideScience

Sample records for core histone tail

  1. Histone H2A mobility is regulated by its tails and acetylation of core histone tails

    International Nuclear Information System (INIS)

    Higashi, Tsunehito; Matsunaga, Sachihiro; Isobe, Keisuke; Morimoto, Akihiro; Shimada, Tomoko; Kataoka, Shogo; Watanabe, Wataru; Uchiyama, Susumu; Itoh, Kazuyoshi; Fukui, Kiichi

    2007-01-01

    Histone tail domains play important roles in cellular processes, such as replication, transcription, and chromosome condensation. Histone H2A has one central and two tail domains, and their functions have mainly been studied from a biochemical perspective. In addition, analyses based on visualization have been employed for functional analysis of some chromatin proteins. In this study, we analyzed histone H2A mobility in vivo by two-photon FRAP, and elucidated that the histone H2A N- and C-terminal tails regulate its mobility. We found that histone H2A mobility was increased following treatment of host cells with a histone deacetylase inhibitor. Our results support a model in which core histone tails directly regulate transcription by interacting with nucleosome DNA via electrostatic interactions

  2. Flexible histone tails in a new mesoscopic oligonucleosome model.

    Science.gov (United States)

    Arya, Gaurav; Zhang, Qing; Schlick, Tamar

    2006-07-01

    We describe a new mesoscopic model of oligonucleosomes that incorporates flexible histone tails. The nucleosome cores are modeled using the discrete surface-charge optimization model, which treats the nucleosome as an electrostatic surface represented by hundreds of point charges; the linker DNAs are treated using a discrete elastic chain model; and the histone tails are modeled using a bead/chain hydrodynamic approach as chains of connected beads where each bead represents five protein residues. Appropriate charges and force fields are assigned to each histone chain so as to reproduce the electrostatic potential, structure, and dynamics of the corresponding atomistic histone tails at different salt conditions. The dynamics of resulting oligonucleosomes at different sizes and varying salt concentrations are simulated by Brownian dynamics with complete hydrodynamic interactions. The analyses demonstrate that the new mesoscopic model reproduces experimental results better than its predecessors, which modeled histone tails as rigid entities. In particular, our model with flexible histone tails: correctly accounts for salt-dependent conformational changes in the histone tails; yields the experimentally obtained values of histone-tail mediated core/core attraction energies; and considers the partial shielding of electrostatic repulsion between DNA linkers as a result of the spatial distribution of histone tails. These effects are crucial for regulating chromatin structure but are absent or improperly treated in models with rigid histone tails. The development of this model of oligonucleosomes thus opens new avenues for studying the role of histone tails and their variants in mediating gene expression through modulation of chromatin structure.

  3. Dynamics of Histone Tails within Chromatin

    Science.gov (United States)

    Bernier, Morgan; North, Justin; Page, Michael; Jaroniec, Christopher; Hammel, Christopher; Poirier, Michael

    2012-02-01

    Genetic information in humans is encoded within DNA molecules that is wrapped around histone octamer proteins and compacted into a highly conserved structural polymer, chromatin. The physical and material properties of chromatin appear to influence gene expression by altering the accessibility of proteins to the DNA. The tails of the histones are flexible domains that are thought to play a role in regulating DNA accessibility and compaction; however the molecular mechanisms for these phenomena are not understood. I will present CW-EPR studies on site directed spin labeled nucleosomes that probe the structure and dynamics of these histone tails within nucleosomes.

  4. Posttranslational Modifications of the Histone 3 Tail and Their Impact on the Activity of Histone Lysine Demethylases In Vitro

    DEFF Research Database (Denmark)

    Lohse, Brian; Helgstrand, Charlotte; Andersson, Jan Legaard

    2013-01-01

    mimicking histone H3. Various combinations with other PTMs were employed to study possible cross-talk effects by comparing enzyme kinetic characteristics. We compared the kinetics of histone tail substrates for truncated histone lysine demethylases KDM4A and KDM4C containing only the catalytic core (cc...... toward bis-trimethylated substrates could be observed. Furthermore, a significant difference in the catalytic activity between dimethylated and trimethylated substrates was found for full length demethylases in line with what has been reported previously for truncated demethylases. Histone peptide...

  5. Characterization of Complete Histone Tail Proteoforms Using Differential Ion Mobility Spectrometry

    DEFF Research Database (Denmark)

    Shliaha, Pavel V; Baird, Matthew A; Nielsen, Mogens M

    2017-01-01

    Histone proteins are subject to dynamic post-translational modifications (PTMs) that cooperatively modulate the chromatin structure and function. Nearly all functional PTMs are found on the N-terminal histone domains (tails) of ∼50 residues protruding from the nucleosome core. Using high...

  6. Analysis of the histone protein tail and DNA in nucleosome using molecular dynamics simulation

    Science.gov (United States)

    Fujimori, R.; Komatsu, Y.; Fukuda, M.; Miyakawa, T.; Morikawa, R.; Takasu, M.

    2013-02-01

    We study the effect of the tails of H3 and H4 histones in the nucleosomes, where DNA and histones are packed in the form of chromatin. We perform molecular dynamics simulations of the complex of DNA and histones and calculate the mean square displacement and the gyration radius of the complex of DNA and histones for the cases with tails intact and the cases with tails missing. Our results show that the H3 tails are important for the motion of the histones. We also find that the motion of one tail is affected by other tails, although the tails are distanced apart, suggesting the correlated motion in biological systems.

  7. Removal of histone tails from nucleosome dissects the physical mechanisms of salt-induced aggregation, linker histone H1-induced compaction, and 30-nm fiber formation of the nucleosome array

    International Nuclear Information System (INIS)

    Hizume, Kohji; Nakai, Tonau; Araki, Sumiko; Prieto, Eloise; Yoshikawa, Kenichi; Takeyasu, Kunio

    2009-01-01

    In order to reveal the roles of histone tails in the formation of higher-order chromatin structures, we employed atomic force microscopy (AFM), and an in vitro reconstitution system to examine the properties of reconstituted chromatin composed of tail-less histones and a long DNA (106-kb plasmid) template. The tail-less nucleosomes did not aggregate at high salt concentrations or with an excess amount of core histones, in contrast with the behavior of nucleosomal arrays composed of nucleosomes containing normal, N-terminal tails. Analysis of our nucleosome distributions reveals that the attractive interaction between tail-less nucleosomes is weakened. Addition of linker histone H1 into the tail-less nucleosomal array failed to promote the formation of 30 nm chromatin fibers that are usually formed in the normal nucleosomal array. These results demonstrate that the attractive interaction between nucleosomes via histone tails plays a critical role in the formation of the uniform 30-nm chromatin fiber.

  8. UV laser-induced histone-DNA crosslinking proceeds via the N-terminal tails

    International Nuclear Information System (INIS)

    Stefanovski, V.; Dimitrov, S.; Angelov, D.; Keskinova, E.; Pashev, I.

    1990-01-01

    The covalent crosslinking of histones to DNA by UV laser irradiation is accomplished solely via the N-terminal part of the molecule. Irradiated isolated calfthymus nuclei are treated with clostripain. The crosslinked protein-DNA complexes are isolated and the presence of each core histone analyzed by dot-immunoassay using antibodies, specific to the central globular domain of the respective histone. The reaction is negative for all core histones i.e. the globular domain is absent. It means that this domain has not been crosslinked to DNA and, once cleaved by clostripain, it has been stripped from DNA during the centrigugation in CsCl. This peculiar property of the crosslinked procedure makes it particularly useful in addressing some yet unanswered questions concerning histone-DNA interactions, such as the interaction of the N-terminal tails with linker DNA, the effect of the transient postsynthetic histone acetylation on its interaction with DNA, etc. These questions are now under study. 1 fig., 6 refs

  9. Med5(Nut1) and Med17(Srb4) Are Direct Targets of Mediator Histone H4 Tail Interactions

    Science.gov (United States)

    Liu, Zhongle; Myers, Lawrence C.

    2012-01-01

    The Mediator complex transmits activation signals from DNA bound transcription factors to the core transcription machinery. In addition to its canonical role in transcriptional activation, recent studies have demonstrated that S. cerevisiae Mediator can interact directly with nucleosomes, and their histone tails. Mutations in Mediator subunits have shown that Mediator and certain chromatin structures mutually impact each other structurally and functionally in vivo. We have taken a UV photo cross-linking approach to further delineate the molecular basis of Mediator chromatin interactions and help determine whether the impact of certain Mediator mutants on chromatin is direct. Specifically, by using histone tail peptides substituted with an amino acid analog that is a UV activatible crosslinker, we have identified specific subunits within Mediator that participate in histone tail interactions. Using Mediator purified from mutant yeast strains we have evaluated the impact of these subunits on histone tail binding. This analysis has identified the Med5 subunit of Mediator as a target for histone tail interactions and suggests that the previously observed effect of med5 mutations on telomeric heterochromatin and silencing is direct. PMID:22693636

  10. Med5(Nut1 and Med17(Srb4 are direct targets of mediator histone H4 tail interactions.

    Directory of Open Access Journals (Sweden)

    Zhongle Liu

    Full Text Available The Mediator complex transmits activation signals from DNA bound transcription factors to the core transcription machinery. In addition to its canonical role in transcriptional activation, recent studies have demonstrated that S. cerevisiae Mediator can interact directly with nucleosomes, and their histone tails. Mutations in Mediator subunits have shown that Mediator and certain chromatin structures mutually impact each other structurally and functionally in vivo. We have taken a UV photo cross-linking approach to further delineate the molecular basis of Mediator chromatin interactions and help determine whether the impact of certain Mediator mutants on chromatin is direct. Specifically, by using histone tail peptides substituted with an amino acid analog that is a UV activatible crosslinker, we have identified specific subunits within Mediator that participate in histone tail interactions. Using Mediator purified from mutant yeast strains we have evaluated the impact of these subunits on histone tail binding. This analysis has identified the Med5 subunit of Mediator as a target for histone tail interactions and suggests that the previously observed effect of med5 mutations on telomeric heterochromatin and silencing is direct.

  11. Cell cycle-regulated oscillator coordinates core histone gene transcription through histone acetylation.

    Science.gov (United States)

    Kurat, Christoph F; Lambert, Jean-Philippe; Petschnigg, Julia; Friesen, Helena; Pawson, Tony; Rosebrock, Adam; Gingras, Anne-Claude; Fillingham, Jeffrey; Andrews, Brenda

    2014-09-30

    DNA replication occurs during the synthetic (S) phase of the eukaryotic cell cycle and features a dramatic induction of histone gene expression for concomitant chromatin assembly. Ectopic production of core histones outside of S phase is toxic, underscoring the critical importance of regulatory pathways that ensure proper expression of histone genes. Several regulators of histone gene expression in the budding yeast Saccharomyces cerevisiae are known, yet the key oscillator responsible for restricting gene expression to S phase has remained elusive. Here, we show that suppressor of Ty (Spt)10, a putative histone acetyltransferase, and its binding partner Spt21 are key determinants of S-phase-specific histone gene expression. We show that Spt21 abundance is restricted to S phase in part by anaphase promoting complex Cdc20-homologue 1 (APC(Cdh1)) and that it is recruited to histone gene promoters in S phase by Spt10. There, Spt21-Spt10 enables the recruitment of a cascade of regulators, including histone chaperones and the histone-acetyltransferase general control nonderepressible (Gcn) 5, which we hypothesize lead to histone acetylation and consequent transcription activation.

  12. Cell cycle-regulated oscillator coordinates core histone gene transcription through histone acetylation

    Science.gov (United States)

    Kurat, Christoph F.; Lambert, Jean-Philippe; Petschnigg, Julia; Friesen, Helena; Pawson, Tony; Rosebrock, Adam; Gingras, Anne-Claude; Fillingham, Jeffrey; Andrews, Brenda

    2014-01-01

    DNA replication occurs during the synthetic (S) phase of the eukaryotic cell cycle and features a dramatic induction of histone gene expression for concomitant chromatin assembly. Ectopic production of core histones outside of S phase is toxic, underscoring the critical importance of regulatory pathways that ensure proper expression of histone genes. Several regulators of histone gene expression in the budding yeast Saccharomyces cerevisiae are known, yet the key oscillator responsible for restricting gene expression to S phase has remained elusive. Here, we show that suppressor of Ty (Spt)10, a putative histone acetyltransferase, and its binding partner Spt21 are key determinants of S-phase–specific histone gene expression. We show that Spt21 abundance is restricted to S phase in part by anaphase promoting complex Cdc20-homologue 1 (APCCdh1) and that it is recruited to histone gene promoters in S phase by Spt10. There, Spt21-Spt10 enables the recruitment of a cascade of regulators, including histone chaperones and the histone-acetyltransferase general control nonderepressible (Gcn) 5, which we hypothesize lead to histone acetylation and consequent transcription activation. PMID:25228766

  13. Automated setup for characterization of intact histone tails in Suz12-/- stem cells

    DEFF Research Database (Denmark)

    Sidoli, Simone; Schwämmle, Veit; Hansen, Thomas Aarup

    Epigenetics is defined as the study of heritable changes that occur without modifying the DNA sequence. Histone proteins are crucial components of epigenetic mechanisms and regulation, since they are fundamental for chromatin structure. Mass spectrometry-based proteomics is already an integrated...... developed a high-resolving and automated LC-MS/MS setup to characterize intact histone tails (middle-down strategy)...

  14. Identification and characterization of the genes encoding the core histones and histone variants of Neurospora crassa.

    OpenAIRE

    Hays, Shan M; Swanson, Johanna; Selker, Eric U

    2002-01-01

    We have identified and characterized the complete complement of genes encoding the core histones of Neurospora crassa. In addition to the previously identified pair of genes that encode histones H3 and H4 (hH3 and hH4-1), we identified a second histone H4 gene (hH4-2), a divergently transcribed pair of genes that encode H2A and H2B (hH2A and hH2B), a homolog of the F/Z family of H2A variants (hH2Az), a homolog of the H3 variant CSE4 from Saccharomyces cerevisiae (hH3v), and a highly diverged ...

  15. The H1 linker histones: multifunctional proteins beyond the nucleosomal core particle.

    Science.gov (United States)

    Hergeth, Sonja P; Schneider, Robert

    2015-11-01

    The linker histone H1 family members are a key component of chromatin and bind to the nucleosomal core particle around the DNA entry and exit sites. H1 can stabilize both nucleosome structure and higher-order chromatin architecture. In general, H1 molecules consist of a central globular domain with more flexible tail regions at both their N- and C-terminal ends. The existence of multiple H1 subtypes and a large variety of posttranslational modifications brings about a considerable degree of complexity and makes studying this protein family challenging. Here, we review recent progress in understanding the function of linker histones and their subtypes beyond their role as merely structural chromatin components. We summarize current findings on the role of H1 in heterochromatin formation, transcriptional regulation and embryogenesis with a focus on H1 subtypes and their specific modifications. © 2015 The Authors.

  16. Destabilization of the Outer and Inner Mitochondrial Membranes by Core and Linker Histones

    Science.gov (United States)

    Cascone, Annunziata; Bruelle, Celine; Lindholm, Dan; Bernardi, Paolo; Eriksson, Ove

    2012-01-01

    Background Extensive DNA damage leads to apoptosis. Histones play a central role in DNA damage sensing and may mediate signals of genotoxic damage to cytosolic effectors including mitochondria. Methodology/Principal Findings We have investigated the effects of histones on mitochondrial function and membrane integrity. We demonstrate that both linker histone H1 and core histones H2A, H2B, H3, and H4 bind strongly to isolated mitochondria. All histones caused a rapid and massive release of the pro-apoptotic intermembrane space proteins cytochrome c and Smac/Diablo, indicating that they permeabilize the outer mitochondrial membrane. In addition, linker histone H1, but not core histones, permeabilized the inner membrane with a collapse of the membrane potential, release of pyridine nucleotides, and mitochondrial fragmentation. Conclusions We conclude that histones destabilize the mitochondrial membranes, a mechanism that may convey genotoxic signals to mitochondria and promote apoptosis following DNA damage. PMID:22523586

  17. Modulation of the functional association between the HIV-1 intasome and the nucleosome by histone amino-terminal tails.

    Science.gov (United States)

    Benleulmi, Mohamed S; Matysiak, Julien; Robert, Xavier; Miskey, Csaba; Mauro, Eric; Lapaillerie, Delphine; Lesbats, Paul; Chaignepain, Stéphane; Henriquez, Daniel R; Calmels, Christina; Oladosu, Oyindamola; Thierry, Eloïse; Leon, Oscar; Lavigne, Marc; Andreola, Marie-Line; Delelis, Olivier; Ivics, Zoltán; Ruff, Marc; Gouet, Patrice; Parissi, Vincent

    2017-11-28

    Stable insertion of the retroviral DNA genome into host chromatin requires the functional association between the intasome (integrase·viral DNA complex) and the nucleosome. The data from the literature suggest that direct protein-protein contacts between integrase and histones may be involved in anchoring the intasome to the nucleosome. Since histone tails are candidates for interactions with the incoming intasomes we have investigated whether they could participate in modulating the nucleosomal integration process. We show here that histone tails are required for an optimal association between HIV-1 integrase (IN) and the nucleosome for efficient integration. We also demonstrate direct interactions between IN and the amino-terminal tail of human histone H4 in vitro. Structure/function studies enabled us to identify amino acids in the carboxy-terminal domain of IN that are important for this interaction. Analysis of the nucleosome-binding properties of catalytically active mutated INs confirmed that their ability to engage the nucleosome for integration in vitro was affected. Pseudovirus particles bearing mutations that affect the IN/H4 association also showed impaired replication capacity due to altered integration and re-targeting of their insertion sites toward dynamic regions of the chromatin with lower nucleosome occupancy. Collectively, our data support a functional association between HIV-1 IN and histone tails that promotes anchoring of the intasome to nucleosomes and optimal integration into chromatin.

  18. Dengue Virus Capsid Protein Binds Core Histones and Inhibits Nucleosome Formation in Human Liver Cells

    Science.gov (United States)

    Colpitts, Tonya M.; Barthel, Sebastian; Wang, Penghua; Fikrig, Erol

    2011-01-01

    Dengue virus (DENV) is a member of the Flaviviridae and a globally (re)emerging pathogen that causes serious human disease. There is no specific antiviral or vaccine for dengue virus infection. Flavivirus capsid (C) is a structural protein responsible for gathering the viral RNA into a nucleocapsid that forms the core of a mature virus particle. Flaviviral replication is known to occur in the cytoplasm yet a large portion of capsid protein localizes to the nucleus during infection. The reasons for the nuclear presences of capsid are not completely understood. Here, we expressed mature DENV C in a tandem affinity purification assay to identify potential binding partners in human liver cells. DENV C targeted the four core histones, H2A, H2B, H3 and H4. DENV C bound recombinant histones in solution and colocalized with histones in the nucleus and cytoplasm of liver cells during DENV infection. We show that DENV C acts as a histone mimic, forming heterodimers with core histones, binding DNA and disrupting nucleosome formation. We also demonstrate that DENV infection increases the amounts of core histones in livers cells, which may be a cellular response to C binding away the histone proteins. Infection with DENV additionally alters levels of H2A phosphorylation in a time-dependent manner. The interactions of C and histones add an interesting new role for the presence of C in the nucleus during DENV infection. PMID:21909430

  19. Acetylation-Mediated Proteasomal Degradation of Core Histones during DNA Repair and Spermatogenesis

    Science.gov (United States)

    Qian, Min-Xian; Pang, Ye; Liu, Cui Hua; Haratake, Kousuke; Du, Bo-Yu; Ji, Dan-Yang; Wang, Guang-Fei; Zhu, Qian-Qian; Song, Wei; Yu, Yadong; Zhang, Xiao-Xu; Huang, Hai-Tao; Miao, Shiying; Chen, Lian-Bin; Zhang, Zi-Hui; Liang, Ya-Nan; Liu, Shan; Cha, Hwangho; Yang, Dong; Zhai, Yonggong; Komatsu, Takuo; Tsuruta, Fuminori; Li, Haitao; Cao, Cheng; Li, Wei; Li, Guo-Hong; Cheng, Yifan; Chiba, Tomoki; Wang, Linfang; Goldberg, Alfred L.; Shen, Yan; Qiu, Xiao-Bo

    2013-01-01

    SUMMARY Histone acetylation plays critical roles in chromatin remodeling, DNA repair, and epigenetic regulation of gene expression, but the underlying mechanisms are unclear. Proteasomes usually catalyze ATP- and polyubiquitin-dependent proteolysis. Here we show that the proteasomes containing the activator PA200 catalyze the polyubiquitin-independent degradation of histones. Most proteasomes in mammalian testes (“spermatoproteasomes”) contain a spermatid/sperm-specific α-subunit α4s/PSMA8 and/or the catalytic β-subunits of immunoproteasomes in addition to PA200. Deletion of PA200 in mice abolishes acetylation-dependent degradation of somatic core histones during DNA double-strand breaks, and delays core histone disappearance in elongated spermatids. Purified PA200 greatly promotes ATP-independent proteasomal degradation of the acetylated core histones, but not polyubiquitinated proteins. Furthermore, acetylation on histones is required for their binding to the bromodomain-like regions in PA200 and its yeast ortholog, Blm10. Thus, PA200/Blm10 specifically targets the core histones for acetylation-mediated degradation by proteasomes, providing mechanisms by which acetylation regulates histone degradation, DNA repair, and spermatogenesis. PMID:23706739

  20. Core nucleosomes by digestion of reconstructed histone-DNA complexes

    Energy Technology Data Exchange (ETDEWEB)

    Bryan, P N; Wright, E B; Olins, D E

    1979-04-01

    Reconstructed complexes of the inner histones (H2A, H2B, H3, H4) and a variety of DNAs were digested with micrococcal nuclease to yield very homogeneous populations of core nucleosomes (..nu../sub 1/). Nucleosomes containing Micrococcus luteus DNA (72% G+C); chicken DNA (43% G+C), Clostridium perfringens DNA (29% G+C); or poly(dA-dT).poly(dA-dT) have been examined by circular dichroism, thermal denaturation, electron microscopy, and DNAse I digestion. Circular dichroism spectra of all particles show a typically suppressed ellipticity at 260 to 280 nm and a prominent ..cap alpha..-helix signal at 222 nm. All particles show biphasic melting except ..nu../sub 1/(dA-dT), which show three prominent melting transitions at ionic strength less than or equal to 1 mM. DNAse I digestion of ..nu../sub 1/ (dA-dT) produces a ladder of DNA fragments differing in length by one base residue. ..nu../sub 1/ (dA-dT) contain 146 base pairs of DNA and exhibit an average DNA helix pitch of 10.4 to 10.5 bases per turn. There appear to be two regions of different DNA pitch within ..nu../sub 1/ (dA-dT). It is suggested that the two regions of DNA pitch might correspond to the two regions of the melting profiles.

  1. Modulations of DNA Contacts by Linker Histones and Post-translational Modifications Determine the Mobility and Modifiability of Nucleosomal H3 Tails.

    Science.gov (United States)

    Stützer, Alexandra; Liokatis, Stamatios; Kiesel, Anja; Schwarzer, Dirk; Sprangers, Remco; Söding, Johannes; Selenko, Philipp; Fischle, Wolfgang

    2016-01-21

    Post-translational histone modifications and linker histone incorporation regulate chromatin structure and genome activity. How these systems interface on a molecular level is unclear. Using biochemistry and NMR spectroscopy, we deduced mechanistic insights into the modification behavior of N-terminal histone H3 tails in different nucleosomal contexts. We find that linker histones generally inhibit modifications of different H3 sites and reduce H3 tail dynamics in nucleosomes. These effects are caused by modulations of electrostatic interactions of H3 tails with linker DNA and largely depend on the C-terminal domains of linker histones. In agreement, linker histone occupancy and H3 tail modifications segregate on a genome-wide level. Charge-modulating modifications such as phosphorylation and acetylation weaken transient H3 tail-linker DNA interactions, increase H3 tail dynamics, and, concomitantly, enhance general modifiability. We propose that alterations of H3 tail-linker DNA interactions by linker histones and charge-modulating modifications execute basal control mechanisms of chromatin function. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Stabilization of Nucleosomes by Histone Tails and by FACT Revealed by spFRET Microscopy

    Directory of Open Access Journals (Sweden)

    Maria E. Valieva

    2017-01-01

    Full Text Available A correct chromatin structure is important for cell viability and is tightly regulated by numerous factors. Human protein complex FACT (facilitates chromatin transcription is an essential factor involved in chromatin transcription and cancer development. Here FACT-dependent changes in the structure of single nucleosomes were studied with single-particle Förster resonance energy transfer (spFRET microscopy using nucleosomes labeled with a donor-acceptor pair of fluorophores, which were attached to the adjacent gyres of DNA near the contact between H2A-H2B dimers. Human FACT and its version without the C-terminal domain (CTD and the high mobility group (HMG domain of the structure-specific recognition protein 1 (SSRP1 subunit did not change the structure of the nucleosomes, while FACT without the acidic C-terminal domains of the suppressor of Ty 16 (Spt16 and the SSRP1 subunits caused nucleosome aggregation. Proteolytic removal of histone tails significantly disturbed the nucleosome structure, inducing partial unwrapping of nucleosomal DNA. Human FACT reduced DNA unwrapping and stabilized the structure of tailless nucleosomes. CTD and/or HMG domains of SSRP1 are required for this FACT activity. In contrast, previously it has been shown that yeast FACT unfolds (reorganizes nucleosomes using the CTD domain of SSRP1-like Pol I-binding protein 3 subunit (Pob3. Thus, yeast and human FACT complexes likely utilize the same domains for nucleosome reorganization and stabilization, respectively, and these processes are mechanistically similar.

  3. Nucleosome–nucleosome interactions via histone tails and linker DNA regulate nuclear rigidity

    Science.gov (United States)

    Shimamoto, Yuta; Tamura, Sachiko; Masumoto, Hiroshi; Maeshima, Kazuhiro

    2017-01-01

    Cells, as well as the nuclei inside them, experience significant mechanical stress in diverse biological processes, including contraction, migration, and adhesion. The structural stability of nuclei must therefore be maintained in order to protect genome integrity. Despite extensive knowledge on nuclear architecture and components, however, the underlying physical and molecular mechanisms remain largely unknown. We address this by subjecting isolated human cell nuclei to microneedle-based quantitative micromanipulation with a series of biochemical perturbations of the chromatin. We find that the mechanical rigidity of nuclei depends on the continuity of the nucleosomal fiber and interactions between nucleosomes. Disrupting these chromatin features by varying cation concentration, acetylating histone tails, or digesting linker DNA results in loss of nuclear rigidity. In contrast, the levels of key chromatin assembly factors, including cohesin, condensin II, and CTCF, and a major nuclear envelope protein, lamin, are unaffected. Together with in situ evidence using living cells and a simple mechanical model, our findings reveal a chromatin-based regulation of the nuclear mechanical response and provide insight into the significance of local and global chromatin structures, such as those associated with interdigitated or melted nucleosomal fibers. PMID:28428255

  4. Phylogenetic analysis of the core histone doublet and DNA topo II genes of Marseilleviridae: evidence of proto-eukaryotic provenance.

    Science.gov (United States)

    Erives, Albert J

    2017-11-28

    While the genomes of eukaryotes and Archaea both encode the histone-fold domain, only eukaryotes encode the core histone paralogs H2A, H2B, H3, and H4. With DNA, these core histones assemble into the nucleosomal octamer underlying eukaryotic chromatin. Importantly, core histones for H2A and H3 are maintained as neofunctionalized paralogs adapted for general bulk chromatin (canonical H2 and H3) or specialized chromatin (H2A.Z enriched at gene promoters and cenH3s enriched at centromeres). In this context, the identification of core histone-like "doublets" in the cytoplasmic replication factories of the Marseilleviridae (MV) is a novel finding with possible relevance to understanding the origin of eukaryotic chromatin. Here, we analyze and compare the core histone doublet genes from all known MV genomes as well as other MV genes relevant to the origin of the eukaryotic replisome. Using different phylogenetic approaches, we show that MV histone domains encode obligate H2B-H2A and H4-H3 dimers of possible proto-eukaryotic origin. MV core histone moieties form sister clades to each of the four eukaryotic clades of canonical and variant core histones. This suggests that MV core histone moieties diverged prior to eukaryotic neofunctionalizations associated with paired linear chromosomes and variant histone octamer assembly. We also show that MV genomes encode a proto-eukaryotic DNA topoisomerase II enzyme that forms a sister clade to eukaryotes. This is a relevant finding given that DNA topo II influences histone deposition and chromatin compaction and is the second most abundant nuclear protein after histones. The combined domain architecture and phylogenomic analyses presented here suggest that a primitive origin for MV histone genes is a more parsimonious explanation than horizontal gene transfers + gene fusions + sufficient divergence to eliminate relatedness to eukaryotic neofunctionalizations within the H2A and H3 clades without loss of relatedness to each of

  5. Structural basis for site-specific reading of unmodified R2 of histone H3 tail by UHRF1 PHD finger

    Institute of Scientific and Technical Information of China (English)

    Chengkun Wang; Jie Shen; Zhongzheng Yang; Ping Chen; Bin Zhao; Wei Hu; Wenxian Lan

    2011-01-01

    Dear Editor,We report two NMR complex structures of PHDUHRF1 binding to unmodified or K9 trimethylated histone tails,which clarify a controversy regarding how the binding of UHRF1 to H3 tails is mediated.Based on our structures,H3R2,not H3K9,mediates PHD binding.

  6. Interactions of acetylated histones with DNA as revealed by UV laser induced histone-DNA crosslinking

    International Nuclear Information System (INIS)

    Stefanovsky, V.Yu.; Dimitrov, S.I.; Angelov, D.; Pashev, I.G.

    1989-01-01

    The interaction of acetylated histones with DNA in chromatin has been studied by UV laser-induced crosslinking histones to DNA. After irradiation of the nuclei, the covalently linked protein-DNA complexes were isolated and the presence of histones in them demonstrated immunochemically. When chromatin from irradiated nuclei was treated with clostripain, which selectively cleaved the N-terminal tails of core histones, no one of them was found covalently linked to DNA, thus showing that crosslinking proceeded solely via the N-terminal regions. However, the crosslinking ability of the laser was preserved both upon physiological acetylation of histones, known to be restricted to the N-terminal tails, and with chemically acetylated chromatin. This finding is direct evidence that the postsynthetic histone acetylation does not release the N-terminal tails from interaction with DNA

  7. TRF2 Protein Interacts with Core Histones to Stabilize Chromosome Ends*

    Science.gov (United States)

    Izumi, Takashi; Shimizu, Shigeomi

    2016-01-01

    Mammalian chromosome ends are protected by a specialized nucleoprotein complex called telomeres. Both shelterin, a telomere-specific multi-protein complex, and higher order telomeric chromatin structures combine to stabilize the chromosome ends. Here, we showed that TRF2, a component of shelterin, binds to core histones to protect chromosome ends from inappropriate DNA damage response and loss of telomeric DNA. The N-terminal Gly/Arg-rich domain (GAR domain) of TRF2 directly binds to the globular domain of core histones. The conserved arginine residues in the GAR domain of TRF2 are required for this interaction. A TRF2 mutant with these arginine residues substituted by alanine lost the ability to protect telomeres and induced rapid telomere shortening caused by the cleavage of a loop structure of the telomeric chromatin. These findings showed a previously unnoticed interaction between the shelterin complex and nucleosomal histones to stabilize the chromosome ends. PMID:27514743

  8. Core Histones H2B and H4 Are Mobilized during Infection with Herpes Simplex Virus 1 ▿

    Science.gov (United States)

    Conn, Kristen L.; Hendzel, Michael J.; Schang, Luis M.

    2011-01-01

    The infecting genomes of herpes simplex virus 1 (HSV-1) are assembled into unstable nucleosomes soon after nuclear entry. The source of the histones that bind to these genomes has yet to be addressed. However, infection inhibits histone synthesis. The histones that bind to HSV-1 genomes are therefore most likely those previously bound in cellular chromatin. In order for preexisting cellular histones to associate with HSV-1 genomes, however, they must first disassociate from cellular chromatin. Consistently, we have shown that linker histones are mobilized during HSV-1 infection. Chromatinization of HSV-1 genomes would also require the association of core histones. We therefore evaluated the mobility of the core histones H2B and H4 as measures of the mobilization of H2A-H2B dimers and the more stable H3-H4 core tetramer. H2B and H4 were mobilized during infection. Their mobilization increased the levels of H2B and H4 in the free pools and decreased the rate of H2B fast chromatin exchange. The histones in the free pools would then be available to bind to HSV-1 genomes. The mobilization of H2B occurred independently from HSV-1 protein expression or DNA replication although expression of HSV-1 immediate-early (IE) or early (E) proteins enhanced it. The mobilization of core histones H2B and H4 supports a model in which the histones that associate with HSV-1 genomes are those that were previously bound in cellular chromatin. Moreover, this mobilization is consistent with the assembly of H2A-H2B and H3-H4 dimers into unstable nucleosomes with HSV-1 genomes. PMID:21994445

  9. TRF2 Protein Interacts with Core Histones to Stabilize Chromosome Ends.

    Science.gov (United States)

    Konishi, Akimitsu; Izumi, Takashi; Shimizu, Shigeomi

    2016-09-23

    Mammalian chromosome ends are protected by a specialized nucleoprotein complex called telomeres. Both shelterin, a telomere-specific multi-protein complex, and higher order telomeric chromatin structures combine to stabilize the chromosome ends. Here, we showed that TRF2, a component of shelterin, binds to core histones to protect chromosome ends from inappropriate DNA damage response and loss of telomeric DNA. The N-terminal Gly/Arg-rich domain (GAR domain) of TRF2 directly binds to the globular domain of core histones. The conserved arginine residues in the GAR domain of TRF2 are required for this interaction. A TRF2 mutant with these arginine residues substituted by alanine lost the ability to protect telomeres and induced rapid telomere shortening caused by the cleavage of a loop structure of the telomeric chromatin. These findings showed a previously unnoticed interaction between the shelterin complex and nucleosomal histones to stabilize the chromosome ends. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Identification of distinct SET/TAF-Ibeta domains required for core histone binding and quantitative characterisation of the interaction.

    Science.gov (United States)

    Karetsou, Zoe; Emmanouilidou, Anastasia; Sanidas, Ioannis; Liokatis, Stamatis; Nikolakaki, Eleni; Politou, Anastasia S; Papamarcaki, Thomais

    2009-04-09

    The assembly of nucleosomes to higher-order chromatin structures is finely tuned by the relative affinities of histones for chaperones and nucleosomal binding sites. The myeloid leukaemia protein SET/TAF-Ibeta belongs to the NAP1 family of histone chaperones and participates in several chromatin-based mechanisms, such as chromatin assembly, nucleosome reorganisation and transcriptional activation. To better understand the histone chaperone function of SET/TAF-Ibeta, we designed several SET/TAF-Ibeta truncations, examined their structural integrity by circular Dichroism and assessed qualitatively and quantitatively the histone binding properties of wild-type protein and mutant forms using GST-pull down experiments and fluorescence spectroscopy-based binding assays. Wild type SET/TAF-Ibeta binds to histones H2B and H3 with Kd values of 2.87 and 0.15 microM, respectively. The preferential binding of SET/TAF-Ibeta to histone H3 is mediated by its central region and the globular part of H3. On the contrary, the acidic C-terminal tail and the amino-terminal dimerisation domain of SET/TAF-Ibeta, as well as the H3 amino-terminal tail, are dispensable for this interaction. This type of analysis allowed us to assess the relative affinities of SET/TAF-Ibeta for different histones and identify the domains of the protein required for effective histone recognition. Our findings are consistent with recent structural studies of SET/TAF-Ibeta and can be valuable to understand the role of SET/TAF-Ibeta in chromatin function.

  11. Identification of distinct SET/TAF-Iβ domains required for core histone binding and quantitative characterisation of the interaction

    Science.gov (United States)

    Karetsou, Zoe; Emmanouilidou, Anastasia; Sanidas, Ioannis; Liokatis, Stamatis; Nikolakaki, Eleni; Politou, Anastasia S; Papamarcaki, Thomais

    2009-01-01

    Background The assembly of nucleosomes to higher-order chromatin structures is finely tuned by the relative affinities of histones for chaperones and nucleosomal binding sites. The myeloid leukaemia protein SET/TAF-Iβ belongs to the NAP1 family of histone chaperones and participates in several chromatin-based mechanisms, such as chromatin assembly, nucleosome reorganisation and transcriptional activation. To better understand the histone chaperone function of SET/TAF-Iβ, we designed several SET/TAF-Iβ truncations, examined their structural integrity by circular Dichroism and assessed qualitatively and quantitatively the histone binding properties of wild-type protein and mutant forms using GST-pull down experiments and fluorescence spectroscopy-based binding assays. Results Wild type SET/TAF-Iβ binds to histones H2B and H3 with Kd values of 2.87 and 0.15 μM, respectively. The preferential binding of SET/TAF-Iβ to histone H3 is mediated by its central region and the globular part of H3. On the contrary, the acidic C-terminal tail and the amino-terminal dimerisation domain of SET/TAF-Iβ, as well as the H3 amino-terminal tail, are dispensable for this interaction. Conclusion This type of analysis allowed us to assess the relative affinities of SET/TAF-Iβ for different histones and identify the domains of the protein required for effective histone recognition. Our findings are consistent with recent structural studies of SET/TAF-Iβ and can be valuable to understand the role of SET/TAF-Iβ in chromatin function. PMID:19358706

  12. Different reaction of core histones H2A and H2B to the red laser radiation

    Directory of Open Access Journals (Sweden)

    Brill G.E.

    2017-09-01

    Full Text Available Aim: to investigate the influence of red laser irradiation on the processes of self-assembly of core histones H2A and H2B. Material and Methods. Solutions of human histone proteins were used in the work. Self-assembly was studied by the method of wedge dehydration. Image facies analysis consisted in their qualitative characterization and calculation of quantitative indicators with subsequent statistical processing. Results. It was established that linearly polarized laser light of the red region of the spectrum (A=660 nm, 1 J/cm2 significantly modifies the process of self-assembly of core histone H2B, while the structure of the facies of H2A histone changing to a lesser extent. Conclusion. Red laser radiation influences on the on the processes of self-assembly of core histones H2A and H2B. There is a differential sensitivity of different classes of histones to laser action. Histone proteins used in the experiments are present in the form of aqueous salt solutions. Red light realizes the effect seems to be due to the formation of singlet oxygen by direct laser excitation of molecular oxygen.

  13. Different reaction of the core histones H2A and H2B to red laser irradiation

    Science.gov (United States)

    Brill, G. E.; Egorova, A. V.; Bugaeva, I. O.; Postnov, D. E.; Ushakova, O. V.

    2017-03-01

    Analysis of the influence of red laser irradiation on the processes of self-assembly of the core histones H2A and H2B was performed using a wedge dehydration method. Image-analysis of facies included their qualitative characteristics and calculation of quantitative parameters with subsequent statistical processing. It was established that linearly polarized red laser light (λ - 660 nm, 1 J/cm2) significantly modified the process of self-assembly of core histone H2B, whereas the structure of the facies of H2A histone changed to a lesser extent. Histones were used in the form of aqueous salt solutions. The effect of red light seems to result from the formation of singlet oxygen by direct laser excitation of molecular oxygen.

  14. Anticancer drug mithramycin interacts with core histones: An additional mode of action of the DNA groove binder

    Directory of Open Access Journals (Sweden)

    Amrita Banerjee

    2014-01-01

    Full Text Available Mithramycin (MTR is a clinically approved DNA-binding antitumor antibiotic currently in Phase 2 clinical trials at National Institutes of Health for treatment of osteosarcoma. In view of the resurgence in the studies of this generic antibiotic as a human medicine, we have examined the binding properties of MTR with the integral component of chromatin – histone proteins – as a part of our broad objective to classify DNA-binding molecules in terms of their ability to bind chromosomal DNA alone (single binding mode or both histones and chromosomal DNA (dual binding mode. The present report shows that besides DNA, MTR also binds to core histones present in chromatin and thus possesses the property of dual binding in the chromatin context. In contrast to the MTR–DNA interaction, association of MTR with histones does not require obligatory presence of bivalent metal ion like Mg2+. As a consequence of its ability to interact with core histones, MTR inhibits histone H3 acetylation at lysine 18, an important signature of active chromatin, in vitro and ex vivo. Reanalysis of microarray data of Ewing sarcoma cell lines shows that upon MTR treatment there is a significant down regulation of genes, possibly implicating a repression of H3K18Ac-enriched genes apart from DNA-binding transcription factors. Association of MTR with core histones and its ability to alter post-translational modification of histone H3 clearly indicates an additional mode of action of this anticancer drug that could be implicated in novel therapeutic strategies.

  15. Molecular recognition of H3/H4 histone tails by the tudor domains of JMJD2A: a comparative molecular dynamics simulations study.

    Directory of Open Access Journals (Sweden)

    Musa Ozboyaci

    Full Text Available BACKGROUND: Histone demethylase, JMJD2A, specifically recognizes and binds to methylated lysine residues at histone H3 and H4 tails (especially trimethylated H3K4 (H3K4me3, trimethylated H3K9 (H3K9me3 and di,trimethylated H4K20 (H4K20me2, H4K20me3 via its tandem tudor domains. Crystal structures of JMJD2A-tudor binding to H3K4me3 and H4K20me3 peptides are available whereas the others are not. Complete picture of the recognition of the four histone peptides by the tandem tudor domains yet remains to be clarified. METHODOLOGY/PRINCIPAL FINDINGS: We report a detailed molecular dynamics simulation and binding energy analysis of the recognition of JMJD2A-tudor with four different histone tails. 25 ns fully unrestrained molecular dynamics simulations are carried out for each of the bound and free structures. We investigate the important hydrogen bonds and electrostatic interactions between the tudor domains and the peptide molecules and identify the critical residues that stabilize the complexes. Our binding free energy calculations show that H4K20me2 and H3K9me3 peptides have the highest and lowest affinity to JMJD2A-tudor, respectively. We also show that H4K20me2 peptide adopts the same binding mode with H4K20me3 peptide, and H3K9me3 peptide adopts the same binding mode with H3K4me3 peptide. Decomposition of the enthalpic and the entropic contributions to the binding free energies indicate that the recognition of the histone peptides is mainly driven by favourable van der Waals interactions. Residue decomposition of the binding free energies with backbone and side chain contributions as well as their energetic constituents identify the hotspots in the binding interface of the structures. CONCLUSION: Energetic investigations of the four complexes suggest that many of the residues involved in the interactions are common. However, we found two receptor residues that were related to selective binding of the H3 and H4 ligands. Modifications or mutations

  16. Precision mapping of coexisting modifications in histone H3 tails from embryonic stem cells by ETD-MS/MS

    DEFF Research Database (Denmark)

    Jung, Hye Ryung; Sidoli, Simone; Haldbo, Simon

    2013-01-01

    Post-translational modifications (PTMs) of histones play a major role in regulating chromatin dynamics and influence processes such as transcription and DNA replication. Here, we report 114 distinct combinations of coexisting PTMs of histone H3 obtained from mouse embryonic stem (ES) cells. Histo...

  17. Histone modifications influence mediator interactions with chromatin

    Science.gov (United States)

    Zhu, Xuefeng; Zhang, Yongqiang; Bjornsdottir, Gudrun; Liu, Zhongle; Quan, Amy; Costanzo, Michael; Dávila López, Marcela; Westholm, Jakub Orzechowski; Ronne, Hans; Boone, Charles; Gustafsson, Claes M.; Myers, Lawrence C.

    2011-01-01

    The Mediator complex transmits activation signals from DNA bound transcription factors to the core transcription machinery. Genome wide localization studies have demonstrated that Mediator occupancy not only correlates with high levels of transcription, but that the complex also is present at transcriptionally silenced locations. We provide evidence that Mediator localization is guided by an interaction with histone tails, and that this interaction is regulated by their post-translational modifications. A quantitative, high-density genetic interaction map revealed links between Mediator components and factors affecting chromatin structure, especially histone deacetylases. Peptide binding assays demonstrated that pure wild-type Mediator forms stable complexes with the tails of Histone H3 and H4. These binding assays also showed Mediator—histone H4 peptide interactions are specifically inhibited by acetylation of the histone H4 lysine 16, a residue critical in transcriptional silencing. Finally, these findings were validated by tiling array analysis that revealed a broad correlation between Mediator and nucleosome occupancy in vivo, but a negative correlation between Mediator and nucleosomes acetylated at histone H4 lysine 16. Our studies show that chromatin structure and the acetylation state of histones are intimately connected to Mediator localization. PMID:21742760

  18. Biochemical reconstitution and phylogenetic comparison of human SET1 family core complexes involved in histone methylation.

    Science.gov (United States)

    Shinsky, Stephen A; Monteith, Kelsey E; Viggiano, Susan; Cosgrove, Michael S

    2015-03-06

    Mixed lineage leukemia protein-1 (MLL1) is a member of the SET1 family of histone H3 lysine 4 (H3K4) methyltransferases that are required for metazoan development. MLL1 is the best characterized human SET1 family member, which includes MLL1-4 and SETd1A/B. MLL1 assembles with WDR5, RBBP5, ASH2L, DPY-30 (WRAD) to form the MLL1 core complex, which is required for H3K4 dimethylation and transcriptional activation. Because all SET1 family proteins interact with WRAD in vivo, it is hypothesized they are regulated by similar mechanisms. However, recent evidence suggests differences among family members that may reflect unique regulatory inputs in the cell. Missing is an understanding of the intrinsic enzymatic activities of different SET1 family complexes under standard conditions. In this investigation, we reconstituted each human SET1 family core complex and compared subunit assembly and enzymatic activities. We found that in the absence of WRAD, all but one SET domain catalyzes at least weak H3K4 monomethylation. In the presence of WRAD, all SET1 family members showed stimulated monomethyltransferase activity but differed in their di- and trimethylation activities. We found that these differences are correlated with evolutionary lineage, suggesting these enzyme complexes have evolved to accomplish unique tasks within metazoan genomes. To understand the structural basis for these differences, we employed a "phylogenetic scanning mutagenesis" assay and identified a cluster of amino acid substitutions that confer a WRAD-dependent gain-of-function dimethylation activity on complexes assembled with the MLL3 or Drosophila trithorax proteins. These results form the basis for understanding how WRAD differentially regulates SET1 family complexes in vivo. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. Measurement of magnetic susceptibility on tailings cores report on cores obtained from the Ontario Research Foundation lysimeter experiment

    International Nuclear Information System (INIS)

    1984-10-01

    Bulk susceptibility and induced magnetic remanence results are reported for 40 cores obtained from the uranium tailings lysimeter experiment at the Ontario Research Foundation. Both methods indicate a broad threefold subdivision of the tailings pile. An upper zone is characterized by an enhanced susceptibility level, which is related to enhanced concentration of both magnetite and hematite. Depletion zones, where present, are of limited areal extent and strongly developed. An intermediate zone is characterized by a mixture of large areas of reduced susceptibility that separate smaller regions of slightly enhanced susceptibility. The zones of susceptibility depletion appear to define a dendritic drainage pattern. Locally in this zone magnetite is enhanced and hematite depleted. In the lowermost zone susceptibility levels are reduced over most of the tailings bed. Only in the upper most right hand corner is there any vestige of a positive susceptibility concentration. Both magnetite and hematite are strongly depleted in this lower zone. Visually it is apparent that this lowermost depleted zone correlates to the zones of strongest 'yellowcake' development

  20. Characterization of Chlamydomonas reinhardtii Core Histones by Top-Down Mass Spectrometry Reveals Unique Algae-Specific Variants and Post-Translational Modifications.

    Science.gov (United States)

    Khan, Aliyya; Eikani, Carlo K; Khan, Hana; Iavarone, Anthony T; Pesavento, James J

    2018-01-05

    The unicellular microalga Chlamydomonas reinhardtii has played an instrumental role in the development of many new fields (bioproducts, biofuels, etc.) as well as the advancement of basic science (photosynthetic apparati, flagellar function, etc.). Chlamydomonas' versatility ultimately derives from the genes encoded in its genome and the way that the expression of these genes is regulated, which is largely influenced by a family of DNA binding proteins called histones. We characterize C. reinhardtii core histones, both variants and their post-translational modifications, by chromatographic separation, followed by top-down mass spectrometry (TDMS). Because TDMS has not been previously used to study Chlamydomonas proteins, we show rampant artifactual protein oxidation using established nuclei purification and histone extraction methods. After addressing oxidation, both histones H3 and H4 are found to each have a single polypeptide sequence that is minimally acetylated and methylated. Surprisingly, we uncover a novel monomethylation at lysine 79 on histone H4 present on all observed molecules. Histone H2B and H2A are found to have two and three variants, respectively, and both are minimally modified. This study provides an updated assessment of the core histone proteins in the green alga C. reinhardtii by top-down mass spectrometry and lays the foundation for further investigation of these essential proteins.

  1. Specific modifications of histone tails, but not DNA methylation, mirror the temporal variation of mammalian recombination hotspots.

    Science.gov (United States)

    Zeng, Jia; Yi, Soojin V

    2014-10-16

    Recombination clusters nonuniformly across mammalian genomes at discrete genomic loci referred to as recombination hotspots. Despite their ubiquitous presence, individual hotspots rapidly lose their activities, and the molecular and evolutionary mechanisms underlying such frequent hotspot turnovers (the so-called "recombination hotspot paradox") remain unresolved. Even though some sequence motifs are significantly associated with hotspots, multiple lines of evidence indicate that factors other than underlying sequences, such as epigenetic modifications, may affect the evolution of recombination hotspots. Thus, identifying epigenetic factors that covary with recombination at fine-scale is a promising step for this important research area. It was previously reported that recombination rates correlate with indirect measures of DNA methylation in the human genome. Here, we analyze experimentally determined DNA methylation and histone modification of human sperms, and show that the correlation between DNA methylation and recombination in long-range windows does not hold with respect to the spatial and temporal variation of recombination at hotspots. On the other hand, two histone modifications (H3K4me3 and H3K27me3) overlap extensively with recombination hotspots. Similar trends were observed in mice. These results indicate that specific histone modifications rather than DNA methylation are associated with the rapid evolution of recombination hotspots. Furthermore, many human recombination hotspots occupy "bivalent" chromatin regions that harbor both active (H3K4me3) and repressive (H3K27me3) marks. This may explain why human recombination hotspots tend to occur in nongenic regions, in contrast to yeast and Arabidopsis hotspots that are characterized by generally active chromatins. Our results highlight the dynamic epigenetic underpinnings of recombination hotspot evolution. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for

  2. Solution structure of the second bromodomain of Brd2 and its specific interaction with acetylated histone tails

    Directory of Open Access Journals (Sweden)

    Wu Jihui

    2007-09-01

    Full Text Available Abstract Background Brd2 is a transcriptional regulator and belongs to BET family, a less characterized novel class of bromodomain-containing proteins. Brd2 contains two tandem bromodomains (BD1 and BD2, 46% sequence identity in the N-terminus and a conserved motif named ET (extra C-terminal domain at the C-terminus that is also present in some other bromodomain proteins. The two bromodomains have been shown to bind the acetylated histone H4 and to be responsible for mitotic retention on chromosomes, which is probably a distinctive feature of BET family proteins. Although the crystal structure of Brd2 BD1 is reported, no structure features have been characterized for Brd2 BD2 and its interaction with acetylated histones. Results Here we report the solution structure of human Brd2 BD2 determined by NMR. Although the overall fold resembles the bromodomains from other proteins, significant differences can be found in loop regions, especially in the ZA loop in which a two amino acids insertion is involved in an uncommon π-helix, termed πD. The helix πD forms a portion of the acetyl-lysine binding site, which could be a structural characteristic of Brd2 BD2 and other BET bromodomains. Unlike Brd2 BD1, BD2 is monomeric in solution. With NMR perturbation studies, we have mapped the H4-AcK12 peptide binding interface on Brd2 BD2 and shown that the binding was with low affinity (2.9 mM and in fast exchange. Using NMR and mutational analysis, we identified several residues important for the Brd2 BD2-H4-AcK12 peptide interaction and probed the potential mechanism for the specific recognition of acetylated histone codes by Brd2 BD2. Conclusion Brd2 BD2 is monomeric in solution and dynamically interacts with H4-AcK12. The additional secondary elements in the long ZA loop may be a common characteristic of BET bromodomains. Surrounding the ligand-binding cavity, five aspartate residues form a negatively charged collar that serves as a secondary binding site

  3. Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer

    Directory of Open Access Journals (Sweden)

    David Corujo

    2018-02-01

    Full Text Available Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and exchanged more easily than the stable H3-H4 core. The unstructured N-terminal histone tails of all histones, but also the C-terminal tails of H2A histones protrude out of the compact structure of the nucleosome core. These accessible tails are the preferential target sites for a large number of post-translational modifications (PTMs. While some PTMs are shared between replication-coupled H2A and H2A variants, many modifications are limited to a specific histone variant. The present review focuses on the H2A variants H2A.Z, H2A.X, and macroH2A, and summarizes their functions in chromatin and how these are linked to cancer development and progression. H2A.Z primarily acts as an oncogene and macroH2A and H2A.X as tumour suppressors. We further focus on the regulation by PTMs, which helps to understand a degree of context dependency.

  4. High mobility group protein number17 cross-links primarily to histone H2A in the reconstituted HMG 17 - nucleosome core particle complex

    International Nuclear Information System (INIS)

    Cook, G.R.; Yau, P.; Yasuda, H.; Traut, R.R.; Bradbury, E.M.

    1986-01-01

    The neighbor relationship of lamb thymus High Mobility Group (HMG) protein 17 to native HeLa nucleosome core particle histones in the reconstituted complex has been studied. 125 I-labeled HMG 17 was cross-linking to core histones using the protein-protein cross-linking reagent 2-iminothiolane. Specific cross-linked products were separated on a two-dimensional Triton-acid-urea/SDS gel system, located by autoradiography, excised and quantified. Disulfide bonds in the cross links were then cleaved and the protein constituents were identified by SDS gel electrophoresis. HMG 17 cross-linked primarily to histone H2A while lower levels of cross-linking occurred between HMG 17 and the other histones. In contrast, cross-linking between two HMG 17 molecules bound on the same nucleosome was relatively rare. It is concluded that the same nucleosome was relatively rare. It is concluded that H2A comprises part of the HMG 17 binding site but that HMG 17 is sufficiently elongated and mobile to permit cross-linking to the other histones and to a second HMG 17 molecule. These results are in agreement with the current model for the structure of the nucleosome and the proposed binding sites for HMG 17

  5. Saccharomyces cerevisiae Linker Histone Hho1p Functionally Interacts with Core Histone H4 and Negatively Regulates the Establishment of Transcriptionally Silent Chromatin*

    OpenAIRE

    Yu, Qun; Kuzmiak, Holly; Zou, Yanfei; Olsen, Lars; Defossez, Pierre-Antoine; Bi, Xin

    2009-01-01

    Saccharomyces cerevisiae linker histone Hho1p is not essential for cell viability, and very little is known about its function in vivo. We show that deletion of HHO1 (hho1Δ) suppresses the defect in transcriptional silencing caused by a mutation in the globular domain of histone H4. hho1Δ also suppresses the reduction in HML silencing by the deletion of SIR1 that is involved in the establishment of silent chromatin at HML. We further show that hho1Δ suppresses chan...

  6. Structural analysis of the core COMPASS family of histone H3K4 methylases from yeast to human.

    Science.gov (United States)

    Takahashi, Yoh-hei; Westfield, Gerwin H; Oleskie, Austin N; Trievel, Raymond C; Shilatifard, Ali; Skiniotis, Georgios

    2011-12-20

    Histone H3 lysine 4 (H3K4) methylation is catalyzed by the highly evolutionarily conserved multiprotein complex known as Set1/COMPASS or MLL/COMPASS-like complexes from yeast to human, respectively. Here we have reconstituted fully functional yeast Set1/COMPASS and human MLL/COMPASS-like complex in vitro and have identified the minimum subunit composition required for histone H3K4 methylation. These subunits include the methyltransferase C-terminal SET domain of Set1/MLL, Cps60/Ash2L, Cps50/RbBP5, Cps30/WDR5, and Cps25/Dpy30, which are all common components of the COMPASS family from yeast to human. Three-dimensional (3D) cryo-EM reconstructions of the core yeast complex, combined with immunolabeling and two-dimensional (2D) EM analysis of the individual subcomplexes reveal a Y-shaped architecture with Cps50 and Cps30 localizing on the top two adjacent lobes and Cps60-Cps25 forming the base at the bottom. EM analysis of the human complex reveals a striking similarity to its yeast counterpart, suggesting a common subunit organization. The SET domain of Set1 is located at the juncture of Cps50, Cps30, and the Cps60-Cps25 module, lining the walls of a central channel that may act as the platform for catalysis and regulative processing of various degrees of H3K4 methylation. This structural arrangement suggested that COMPASS family members function as exo-methylases, which we have confirmed by in vitro and in vivo studies.

  7. Histone deacetylase inhibitors promote the tumoricidal effect of HAMLET.

    Science.gov (United States)

    Brest, Patrick; Gustafsson, Mattias; Mossberg, Ann-Kristin; Gustafsson, Lotta; Duringer, Caroline; Hamiche, Ali; Svanborg, Catharina

    2007-12-01

    Histone deacetylase inhibitors (HDIs) and HAMLET (human alpha-lactalbumin made lethal to tumor cells) interact with histones, modify the structure of chromatin, and trigger tumor cell death. This study investigated how the combination of HDIs and HAMLET influences cell viability, histone acetylation, and DNA integrity. The pretreatment of tumor cells with HDIs was shown to enhance the lethal effect of HAMLET and the histone hyperacetylation response to HDIs increased even further after HAMLET treatment. HDIs and HAMLET were shown to target different histone domains as HAMLET bound tailless core histones, whereas HDIs modify the acetylation of the histone tail. DNA damage in response to HAMLET was increased by HDIs. The DNA repair response (p21WAFI expression) was induced by both agonists but abolished when the two agonists were combined. The results suggest that the synergy of HDIs and HAMLET is based on different but converging death pathways, both involving chromatin alterations. We speculate that HAMLET and HDIs might be combined to promote tumor cell death in vivo.

  8. Equation of state of a hard core fluid with a two-Yukawa tail: toward a simple analytic theory

    International Nuclear Information System (INIS)

    Jedrzejek, C.

    1980-01-01

    Thermodynamic properties of simple fluids are calculated using variational theory for a system of hard-core potential with a two-Yukawa tail. Likewise one Yukawa-tail case the working formulas are analytic. Five parameters of the two Yukawa system are chosen so as to get the best fit to a real argon potential or an ''argon-like'' Lennard-Jones potential. The results are fairly good in light of the extreme simplicity of the method. The discrepancies result from using the variational method and a different shape of Yukawa type potential in comparision to the real argon and Lennard-Jones potentials. (author)

  9. The PR-Set7 binding domain of Riz1 is required for the H4K20me1-H3K9me1 trans-tailhistone code’ and Riz1 tumor suppressor function

    Science.gov (United States)

    Congdon, Lauren M.; Sims, Jennifer K.; Tuzon, Creighton T.; Rice, Judd C.

    2014-01-01

    PR-Set7/Set8/KMT5a is the sole histone H4 lysine 20 monomethyltransferase (H4K20me1) in metazoans and is essential for proper cell division and genomic stability. We unexpectedly discovered that normal cellular levels of monomethylated histone H3 lysine 9 (H3K9me1) were also dependent on PR-Set7, but independent of its catalytic activity. This observation suggested that PR-Set7 interacts with an H3K9 monomethyltransferase to establish the previously reported H4K20me1-H3K9me1 trans-tailhistone code’. Here we show that PR-Set7 specifically and directly binds the C-terminus of the Riz1/PRDM2/KMT8 tumor suppressor and demonstrate that the N-terminal PR/SET domain of Riz1 preferentially monomethylates H3K9. The PR-Set7 binding domain was required for Riz1 nuclear localization and maintenance of the H4K20me1-H3K9me1 trans-tailhistone code’. Although Riz1 can function as a repressor, Riz1/H3K9me1 was dispensable for the repression of genes regulated by PR-Set7/H4K20me1. Frameshift mutations resulting in a truncated Riz1 incapable of binding PR-Set7 occur frequently in various aggressive cancers. In these cancer cells, expression of wild-type Riz1 restored tumor suppression by decreasing proliferation and increasing apoptosis. These phenotypes were not observed in cells expressing either the Riz1 PR/SET domain or PR-Set7 binding domain indicating that Riz1 methyltransferase activity and PR-Set7 binding domain are both essential for Riz1 tumor suppressor function. PMID:24423864

  10. Large scale analysis of co-existing post-translational modifications in histone tails reveals global fine structure of cross-talk

    DEFF Research Database (Denmark)

    Schwämmle, Veit; Aspalter, Claudia-Maria; Sidoli, Simone

    2014-01-01

    Mass spectrometry (MS) is a powerful analytical method for the identification and quantification of co-existing post-translational modifications in histone proteins. One of the most important challenges in current chromatin biology is to characterize the relationships between co-existing histone...... sample-specific patterns for the co-frequency of histone post-translational modifications. We implemented a new method to identify positive and negative interplay between pairs of methylation and acetylation marks in proteins. Many of the detected features were conserved between different cell types...... sites but negative cross-talk for distant ones, and for discrete methylation states at Lys-9, Lys-27, and Lys-36 of histone H3, suggesting a more differentiated functional role of methylation beyond the general expectation of enhanced activity at higher methylation states....

  11. A Ribbon-like Structure in the Ejective Organelle of the Green Microalga Pyramimonas parkeae (Prasinophyceae) Consists of Core Histones and Polymers Containing N-acetyl-glucosamine.

    Science.gov (United States)

    Yamagishi, Takahiro; Kurihara, Akira; Kawai, Hiroshi

    2015-11-01

    The green microalga, Pyramimonas parkeae (Prasinophyceae) has an ejective organelle containing a coiled ribbon structure resembling the ejectisome in Cryptophyta. This structure is discharged from the cell by a stimulus and extends to form a tube-like structure, but the molecular components of the structure have not been identified. Tricine-SDS-PAGE analysis indicated that the ribbon-like structure of P. parkeae contains some proteins and low molecular acidic polymers. Edman degradation, LC/MS/MS analyses and immunological studies demonstrated that their proteins are core histones (H3, H2A, H2B and H4). In addition, monosaccharide composition analysis of the ribbon-like structures and degradation by lysozyme strongly indicated that the ribbon-like structure consist of β (1-4) linked polymers containing N-acetyl-glucosamine. Purified polymers and recombinant histones formed glob-like or filamentous structures. Therefore we conclude that the ribbon-like structure of P. parkeae mainly consists of a complex of core histones (H3, H2A, H2B and H4) and polymers containing N-acetyl-glucosamine, and suggest to name the ejective organelle in P. parkeae the "histrosome" to distinguish it from the ejectisome in Cryptophyta. Copyright © 2015 Elsevier GmbH. All rights reserved.

  12. Synthesis and in vitro transfection efficiency of spermine-based cationic lipids with different central core structures and lipophilic tails.

    Science.gov (United States)

    Niyomtham, Nattisa; Apiratikul, Nuttapon; Suksen, Kanoknetr; Opanasopit, Praneet; Yingyongnarongkul, Boon-Ek

    2015-02-01

    Twelve spermine-based cationic lipids with four different central core structures (di(oxyethyl)amino, di(oxyethyl)amino carboxy, 3-amino-1,2-dioxypropyl and 2-amino-1,3-dioxypropyl) and three hydrophobic tails (lauric acid, myristic acid and palmitic acid) were synthesized. The liposomes containing lipids and DOPE showed moderate to good in vitro DNA delivery into HeLa cells. GFP expression experiments revealed that liposomes composed of lipids with 3-amino-1,2-dioxypropyl as a central core structure exhibited highest transfection efficiency under serum-free condition. Whereas, lipid with 2-amino-1,3-dioxypropyl core structure showed highest transfection under 10% serum condition. Moreover, the liposomes and lipoplexes composted of these cationic lipids exhibited low cytotoxicity. Copyright © 2015. Published by Elsevier Ltd.

  13. Site-specific quantification of lysine acetylation in the N-terminal tail of histone H4 using a double-labelling, targeted UHPLC MS/MS approach

    NARCIS (Netherlands)

    D'Urzo, Annalisa; Boichenko, Alexander P.; van den Bosch, Thea; Hermans, Jos; Dekker, Frank; Andrisano, Vincenza; Bischoff, Rainer

    We developed a targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the site-specific quantification of lysine acetylation in the N-terminal region of histone H4 by combining chemical derivatization at the protein and peptide levels with digestion using chymotrypsin and

  14. Global turnover of histone post-translational modifications and variants in human cells

    Directory of Open Access Journals (Sweden)

    Zee Barry M

    2010-12-01

    Full Text Available Abstract Background Post-translational modifications (PTMs on the N-terminal tails of histones and histone variants regulate distinct transcriptional states and nuclear events. Whereas the functional effects of specific PTMs are the current subject of intense investigation, most studies characterize histone PTMs/variants in a non-temporal fashion and very few studies have reported kinetic information about these histone forms. Previous studies have used radiolabeling, fluorescence microscopy and chromatin immunoprecipitation to determine rates of histone turnover, and have found interesting correlations between increased turnover and increased gene expression. Therefore, histone turnover is an understudied yet potentially important parameter that may contribute to epigenetic regulation. Understanding turnover in the context of histone modifications and sequence variants could provide valuable additional insight into the function of histone replacement. Results In this study, we measured the metabolic rate of labeled isotope incorporation into the histone proteins of HeLa cells by combining stable isotope labeling of amino acids in cell culture (SILAC pulse experiments with quantitative mass spectrometry-based proteomics. In general, we found that most core histones have similar turnover rates, with the exception of the H2A variants, which exhibit a wider range of rates, potentially consistent with their epigenetic function. In addition, acetylated histones have a significantly faster turnover compared with general histone protein and methylated histones, although these rates vary considerably, depending on the site and overall degree of methylation. Histones containing transcriptionally active marks have been consistently found to have faster turnover rates than histones containing silent marks. Interestingly, the presence of both active and silent marks on the same peptide resulted in a slower turnover rate than either mark alone on that same

  15. Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail.

    Science.gov (United States)

    Brasacchio, Daniella; Okabe, Jun; Tikellis, Christos; Balcerczyk, Aneta; George, Prince; Baker, Emma K; Calkin, Anna C; Brownlee, Michael; Cooper, Mark E; El-Osta, Assam

    2009-05-01

    Results from the Diabetes Control Complications Trial (DCCT) and the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) Study and more recently from the U.K. Prospective Diabetes Study (UKPDS) have revealed that the deleterious end-organ effects that occurred in both conventional and more aggressively treated subjects continued to operate >5 years after the patients had returned to usual glycemic control and is interpreted as a legacy of past glycemia known as "hyperglycemic memory." We have hypothesized that transient hyperglycemia mediates persistent gene-activating events attributed to changes in epigenetic information. Models of transient hyperglycemia were used to link NFkappaB-p65 gene expression with H3K4 and H3K9 modifications mediated by the histone methyltransferases (Set7 and SuV39h1) and the lysine-specific demethylase (LSD1) by the immunopurification of soluble NFkappaB-p65 chromatin. The sustained upregulation of the NFkappaB-p65 gene as a result of ambient or prior hyperglycemia was associated with increased H3K4m1 but not H3K4m2 or H3K4m3. Furthermore, glucose was shown to have other epigenetic effects, including the suppression of H3K9m2 and H3K9m3 methylation on the p65 promoter. Finally, there was increased recruitment of the recently identified histone demethylase LSD1 to the p65 promoter as a result of prior hyperglycemia. These studies indicate that the active transcriptional state of the NFkappaB-p65 gene is linked with persisting epigenetic marks such as enhanced H3K4 and reduced H3K9 methylation, which appear to occur as a result of effects of the methyl-writing and methyl-erasing histone enzymes.

  16. Nematic-isotropic transition in some lattice models for rigid cores having semiflexible tails: segmental Lennard-Jones interactions

    International Nuclear Information System (INIS)

    Dowell, F.

    1983-01-01

    Two average-environment simple cubic lattice models: a refined model and a simple model, both having site-site (segmental) pair Lennard-Jones (LJ) interactions: for molecules composed of rigid cores having semiflexible tails are presented. The calculated values of the following properties at the nematic-isotropic transition for rigid rods of varying length are compared with relevant experimental data for PAA (p-azoxyanisole, or 4,4'-dimethoxyazoxybenzene): temperature, core orientational order parameter, nematic density and volume, relative density change, and relative entropy change. The temperature change as a function of volume change at constant order parameter is also discussed. In general, both LJ models give considerably better quantitative agreement with experiment, especially for the temperature and the relative density change, than do the earlier lattice models with hard repulsions, with or without constant segmental pair interaction energies. In most aspects, these LJ models give good quantitative agreement with experiment. These LJ models elucidate the importance of realistic intermolecular potentials, especially the role of soft repulsions, in describing an order-disorder transition between two condensed phases

  17. Edge-core interaction of ITG turbulence in Tokamaks: Is the Tail Wagging the Dog?

    Science.gov (United States)

    Ku, S.; Chang, C. S.; Dif-Pradalier, G.; Diamond, P. H.

    2010-11-01

    A full-f XGC1 gyrokinetic simulation of ITG turbulence, together with the neoclassical dynamics without scale separation, has been performed for the whole-volume plasma in realistic diverted DIII-D geometry. The simulation revealed that the global structure of the turbulence and transport in tokamak plasmas results from a synergy between edge-driven inward propagation of turbulence intensity and the core-driven outward heat transport. The global ion confinement and the ion temperature gradient then self-organize quickly at turbulence propagation time scale. This synergy results in inward-outward pulse scattering leading to spontaneous production of strong internal shear layers in which the turbulent transport is almost suppressed over several radial correlation lengths. Co-existence of the edge turbulence source and the strong internal shear layer leads to radially increasing turbulence intensity and ion thermal transport profiles.

  18. DNA and factor VII-activating protease protect against the cytotoxicity of histones

    NARCIS (Netherlands)

    Marsman, Gerben; von Richthofen, Helen; Bulder, Ingrid; Lupu, Florea; Hazelzet, Jan; Luken, Brenda M.; Zeerleder, Sacha

    2017-01-01

    Circulating histones have been implicated as major mediators of inflammatory disease because of their strong cytotoxic effects. Histones form the protein core of nucleosomes; however, it is unclear whether histones and nucleosomes are equally cytotoxic. Several plasma proteins that neutralize

  19. Open and Closed: The Roles of Linker Histones in Plants and Animals

    OpenAIRE

    Over, Ryan S.; Michaels, Scott D.

    2014-01-01

    Linker histones play key roles alongside core histones in the regulation and maintenance of chromatin. Here, we illustrate our current understanding of the contributions of linker histones to the cell cycle, development, and chromatin structure in plants and animals.

  20. Study of a model Fermi liquid interacting via a hard-core repulsive potential and an attractive tail

    International Nuclear Information System (INIS)

    Ng, Tai Kai; Singwi, K.S.

    1986-02-01

    In this paper we present an extensive microscopic study of the collective and single-particle properties of a model Fermi liquid whose particles interact via a repulsive hard-core potential and an attractive tail. The model system is intended to simulate liquid 3 He. The study is based on an approximate scheme of Singwi, Tosi, Land and Sjoelander (STLS) which was devised to treat correlations in Coulomb Fermi liquids. The primary aim of this study is to learn whether the model system is capable of reproducing some of the salient features observed in normal liquid 3 He, and about the role of the repulsive and attractive parts of the potential. We have calculated the Landau parameters F 0 /sup s/ and F 0 /sup a/ and their variation with pressure, the wave number and pressure dependence of the spin-symmetric and spin-anti-symmetric polarization potentials, pressure dependence of the dispersion of the zero sound, the static structure factors and the quasiparticle mass. Although we make no quantitative claims when comparing our calculations with experiments in real liquid 3 He, we do conclude that our model system within the framework of the STLS scheme can account qualitatively for the latter. Besides, since the theory is microscopic in nature and is parameter free, it has enabled us to understand better the role of the repulsive and the attractive parts of the bare potential in determining the properties of liquid 3 He. 27 figs., 2 tabs

  1. Calamitic Smectic A-Polar Smectic APA Transition Observed in Bent Molecules with Large Bent-Angle Central Core of 4,6-Dichlorobenzene and Alkylthio Terminal Tail

    Science.gov (United States)

    Nguyen, Ha; Kang, Sungmin; Tokita, Masatoshi; Watanabe, Junji

    2011-07-01

    New homologs of bent molecules with a large bent-angle central core of 4,6-dichloro benzene and an alkylthio terminal tail have been synthesized. Although the corresponding alkoxy-tail homologs show only the calamitic phases because of its large bent angles around 160°, the new homologs with an alkylthio tail exhibit the antiferroelectric smectic APA (SmAPA) banana phase that is transformed on cooling from the calamitic smectic A (SmA) phase. The biaxial polar packing of bent molecules in the SmAPA phase is considered to arise from the hindered rotation around the molecular long axis due to the expansion of the mesophase temperatures to a lower temperature region. This study indicates that the bent molecules, even with a large bent angle, have the potential to form a switchable banana phase with a remarkable decrease in its phase temperature range to around 60 °C.

  2. Histone H3 Lysine Methylation in Cognition and Intellectual Disability Disorders

    Science.gov (United States)

    Parkel, Sven; Lopez-Atalaya, Jose P.; Barco, Angel

    2013-01-01

    Recent research indicates that epigenetic mechanisms and, in particular, the post-translational modification (PTM) of histones may contribute to memory encoding and storage. Among the dozens of possible histone PTMs, the methylation/demethylation of lysines in the N-terminal tail of histone H3 exhibits particularly strong links with cognitive…

  3. A prawn core histone 4: derivation of N- and C-terminal peptides and their antimicrobial properties, molecular characterization and mRNA transcription.

    Science.gov (United States)

    Chaurasia, Mukesh Kumar; Palanisamy, Rajesh; Bhatt, Prasanth; Kumaresan, Venkatesh; Gnanam, Annie J; Pasupuleti, Mukesh; Kasi, Marimuthu; Harikrishnan, Ramaswamy; Arockiaraj, Jesu

    2015-01-01

    This study investigates the complete molecular characterization including bioinformatics characterization, gene expression, synthesis of N and C terminal peptides and their antimicrobial activity of the core histone 4 (H4) from freshwater giant prawn Macrobrachium rosenbergii (Mr). A cDNA encoding MrH4 was identified from the constructed cDNA library of M. rosenbergii during screening and the sequence was obtained using internal sequencing primers. The MrH4 coding region possesses a polypeptide of 103 amino acids with a calculated molecular weight of 11kDa and an isoelectric point of 11.5. The bioinformatics analysis showed that the MrH4 polypeptide contains a H4 signature at (15)GAKRH(19). Multiple sequence alignment of MrH4 showed that the N-terminal (21-42) and C-terminal (87-101) antimicrobial peptide regions and the pentapeptide or H4 signature (15-19) are highly conserved including in humans. The phylogenetic tree formed two separate clades of vertebrate and invertebrate H4, wherein MrH4 was located within the arthropod monophyletic clade of invertebrate H4 groups. Three-dimensional model of MrH4 was established using I-TASSER program and the model was validated using Ramachandran plot analysis. Schiffer-Edmundson helical wheel modeling was used to predict the helix propensity of N (21-42) and C (87-101) terminal derived Mr peptides. The highest gene expression was observed in gills and is induced by viral [white spot syndrome baculovirus (WSBV) and M. rosenbergii nodovirus (MrNV)] and bacterial (Aeromonas hydrophila and Vibrio harveyi) infections. The N and C terminal peptides were synthesized and their antimicrobial and hemolytic properties were examined. Both peptides showed activity against the tested Gram negative and Gram positive bacteria; however, the highest activity was noticed against Gram negative bacteria. Among the two peptides used in this study, C-terminal peptide yielded better results than the N-terminal peptide. Therefore, C terminal

  4. Biochemical Analysis Reveals the Multifactorial Mechanism of Histone H3 Clipping by Chicken Liver Histone H3 Protease

    KAUST Repository

    Chauhan, Sakshi

    2016-09-02

    Proteolytic clipping of histone H3 has been identified in many organisms. Despite several studies, the mechanism of clipping, the substrate specificity, and the significance of this poorly understood epigenetic mechanism are not clear. We have previously reported histone H3 specific proteolytic clipping and a protein inhibitor in chicken liver. However, the sites of clipping are still not known very well. In this study, we attempt to identify clipping sites in histone H3 and to determine the mechanism of inhibition by stefin B protein, a cysteine protease inhibitor. By employing site-directed mutagenesis and in vitro biochemical assays, we have identified three distinct clipping sites in recombinant human histone H3 and its variants (H3.1, H3.3, and H3t). However, post-translationally modified histones isolated from chicken liver and Saccharomyces cerevisiae wild-type cells showed different clipping patterns. Clipping of histone H3 N-terminal tail at three sites occurs in a sequential manner. We have further observed that clipping sites are regulated by the structure of the N-terminal tail as well as the globular domain of histone H3. We also have identified the QVVAG region of stefin B protein to be very crucial for inhibition of the protease activity. Altogether, our comprehensive biochemical studies have revealed three distinct clipping sites in histone H3 and their regulation by the structure of histone H3, histone modifications marks, and stefin B.

  5. Histone and Ribosomal RNA Repetitive Gene Clusters of the Boll Weevil are Linked in a Tandem Array

    Science.gov (United States)

    Histones are the major protein component of chromatin structure. The histone family is made up of a quintet of proteins, four core histones (H2A, H2B, H3 & H4) and the linker histones (H1). Spacers are found between the coding regions. Among insects this quintet of genes is usually clustered and ...

  6. Open and closed: the roles of linker histones in plants and animals.

    Science.gov (United States)

    Over, Ryan S; Michaels, Scott D

    2014-03-01

    Histones package DNA in all eukaryotes and play key roles in regulating gene expression. Approximately 150 base pairs of DNA wraps around an octamer of core histones to form the nucleosome, the basic unit of chromatin. Linker histones compact chromatin further by binding to and neutralizing the charge of the DNA between nucleosomes. It is well established that chromatin packing is regulated by a complex pattern of posttranslational modifications (PTMs) to core histones, but linker histone function is less well understood. In this review, we describe the current understanding of the many roles that linker histones play in cellular processes, including gene regulation, cell division, and development, while putting the linker histone in the context of other nuclear proteins. Although intriguing roles for plant linker histones are beginning to emerge, much of our current understanding comes from work in animal systems. Many unanswered questions remain and additional work is required to fully elucidate the complex processes mediated by linker histones in plants.

  7. Histone deacetylases and their roles in mineralized tissue regeneration

    Directory of Open Access Journals (Sweden)

    Nam Cong-Nhat Huynh

    2017-12-01

    Full Text Available Histone acetylation is an important epigenetic mechanism that controls expression of certain genes. It includes non-sequence-based changes of chromosomal regional structure that can alter the expression of genes. Acetylation of histones is controlled by the activity of two groups of enzymes: the histone acetyltransferases (HATs and histone deacetylases (HDACs. HDACs remove acetyl groups from the histone tail, which alters its charge and thus promotes compaction of DNA in the nucleosome. HDACs render the chromatin structure into a more compact form of heterochromatin, which makes the genes inaccessible for transcription. By altering the transcriptional activity of bone-associated genes, HDACs control both osteogenesis and osteoclastogenesis. This review presents an overview of the function of HDACs in the modulation of bone formation. Special attention is paid to the use of HDAC inhibitors in mineralized tissue regeneration from cells of dental origin.

  8. Covalent Modifications of Histone H3K9 Promote Binding of CHD3

    Directory of Open Access Journals (Sweden)

    Adam H. Tencer

    2017-10-01

    Full Text Available Chromatin remodeling is required for genome function and is facilitated by ATP-dependent complexes, such as nucleosome remodeling and deacetylase (NuRD. Among its core components is the chromodomain helicase DNA binding protein 3 (CHD3 whose functional significance is not well established. Here, we show that CHD3 co-localizes with the other NuRD subunits, including HDAC1, near the H3K9ac-enriched promoters of the NuRD target genes. The tandem PHD fingers of CHD3 bind histone H3 tails and posttranslational modifications that increase hydrophobicity of H3K9—methylation or acetylation (H3K9me3 or H3K9ac—enhance this interaction. Binding of CHD3 PHDs promotes H3K9Cme3-nucleosome unwrapping in vitro and perturbs the pericentric heterochromatin structure in vivo. Methylation or acetylation of H3K9 uniquely alleviates the intra-nucleosomal interaction of histone H3 tails, increasing H3K9 accessibility. Collectively, our data suggest that the targeting of covalently modified H3K9 by CHD3 might be essential in diverse functions of NuRD.

  9. An advanced coarse-grained nucleosome core particle model for computer simulations of nucleosome-nucleosome interactions under varying ionic conditions.

    Directory of Open Access Journals (Sweden)

    Yanping Fan

    Full Text Available In the eukaryotic cell nucleus, DNA exists as chromatin, a compact but dynamic complex with histone proteins. The first level of DNA organization is the linear array of nucleosome core particles (NCPs. The NCP is a well-defined complex of 147 bp DNA with an octamer of histones. Interactions between NCPs are of paramount importance for higher levels of chromatin compaction. The polyelectrolyte nature of the NCP implies that nucleosome-nucleosome interactions must exhibit a great influence from both the ionic environment as well as the positively charged and highly flexible N-terminal histone tails, protruding out from the NCP. The large size of the system precludes a modelling analysis of chromatin at an all-atom level and calls for coarse-grained approximations. Here, a model of the NCP that include the globular histone core and the flexible histone tails described by one particle per each amino acid and taking into account their net charge is proposed. DNA wrapped around the histone core was approximated at the level of two base pairs represented by one bead (bases and sugar plus four beads of charged phosphate groups. Computer simulations, using a Langevin thermostat, in a dielectric continuum with explicit monovalent (K(+, divalent (Mg(2+ or trivalent (Co(NH(3(6 (3+ cations were performed for systems with one or ten NCPs. Increase of the counterion charge results in a switch from repulsive NCP-NCP interaction in the presence of K(+, to partial aggregation with Mg(2+ and to strong mutual attraction of all 10 NCPs in the presence of CoHex(3+. The new model reproduced experimental results and the structure of the NCP-NCP contacts is in agreement with available data. Cation screening, ion-ion correlations and tail bridging contribute to the NCP-NCP attraction and the new NCP model accounts for these interactions.

  10. Histone variants and lipid metabolism

    NARCIS (Netherlands)

    Borghesan, Michela; Mazzoccoli, Gianluigi; Sheedfar, Fareeba; Oben, Jude; Pazienza, Valerio; Vinciguerra, Manlio

    2014-01-01

    Within nucleosomes, canonical histones package the genome, but they can be opportunely replaced with histone variants. The incorporation of histone variants into the nucleosome is a chief cellular strategy to regulate transcription and cellular metabolism. In pathological terms, cellular steatosis

  11. Interactions of Nickel(II) with histones: interactions of Nickel(II) with CH3CO-Thr-Glu-Ser-His-His-Lys-NH2, a peptide modeling the potential metal binding site in the "C-Tail" region of histone H2A.

    Science.gov (United States)

    Bal, W; Lukszo, J; Bialkowski, K; Kasprzak, K S

    1998-09-01

    A combined pH-metric and spectroscopic (UV/vis, CD, NMR) study of the Ni(II) binding to CH3CO-Thr-Glu-Ser-His-His-Lys-NH2 (AcTESHHKam), a blocked hexapeptide modeling a part of the C-terminal sequence of the major variant of histone H2A (residues 120-125), revealed the formation of a pseudo-octahedral NiHL complex in weakly acidic and neutral solutions. Ni(II) is bound to the peptide through imidazole nitrogens on both of its histidine residues and the carboxylate of the side chain of glutamic acid. At higher pH, a series of square-planar complexes are formed. This process is accompanied by hydrolytic degradation of the peptide. At pH 7.4, the peptide hydrolyzes in a Ni(II)-assisted fashion, yielding the square-planar Ni(II) complex of SHHKam as the sole product detected by CD, MALDI-TOF MS, and HPLC. Quantitative analysis of complex stabilities indicates that the -TESHHK- motif is a very likely binding site for carcinogenic Ni(II) ions in the cell nucleus. The Ni(II)-assisted hydrolysis of the C-terminal chain of histone H2A may provide a novel mechanism of genotoxicity combining the damage to the nucleosome with the generation of further toxic Ni(II) species.

  12. Rapid divergence of histones in Hydrozoa (Cnidaria) and evolution of a novel histone involved in DNA damage response in hydra.

    Science.gov (United States)

    Reddy, Puli Chandramouli; Ubhe, Suyog; Sirwani, Neha; Lohokare, Rasika; Galande, Sanjeev

    2017-08-01

    Histones are fundamental components of chromatin in all eukaryotes. Hydra, an emerging model system belonging to the basal metazoan phylum Cnidaria, provides an ideal platform to understand the evolution of core histone components at the base of eumetazoan phyla. Hydra exhibits peculiar properties such as tremendous regenerative capacity, lack of organismal senescence and rarity of malignancy. In light of the role of histone modifications and histone variants in these processes it is important to understand the nature of histones themselves and their variants in hydra. Here, we report identification of the complete repertoire of histone-coding genes in the Hydra magnipapillata genome. Hydra histones were classified based on their copy numbers, gene structure and other characteristic features. Genomic organization of canonical histone genes revealed the presence of H2A-H2B and H3-H4 paired clusters in high frequency and also a cluster with all core histones along with H1. Phylogenetic analysis of identified members of H2A and H2B histones suggested rapid expansion of these groups in Hydrozoa resulting in the appearance of unique subtypes. Amino acid sequence level comparisons of H2A and H2B forms with bilaterian counterparts suggest the possibility of a highly mobile nature of nucleosomes in hydra. Absolute quantitation of transcripts confirmed the high copy number of histones and supported the canonical nature of H2A. Furthermore, functional characterization of H2A.X.1 and a unique variant H2A.X.2 in the gastric region suggest their role in the maintenance of genome integrity and differentiation processes. These findings provide insights into the evolution of histones and their variants in hydra. Copyright © 2017 Elsevier GmbH. All rights reserved.

  13. Germline-specific H1 variants: the "sexy" linker histones.

    Science.gov (United States)

    Pérez-Montero, Salvador; Carbonell, Albert; Azorín, Fernando

    2016-03-01

    The eukaryotic genome is packed into chromatin, a nucleoprotein complex mainly formed by the interaction of DNA with the abundant basic histone proteins. The fundamental structural and functional subunit of chromatin is the nucleosome core particle, which is composed by 146 bp of DNA wrapped around an octameric protein complex formed by two copies of each core histone H2A, H2B, H3, and H4. In addition, although not an intrinsic component of the nucleosome core particle, linker histone H1 directly interacts with it in a monomeric form. Histone H1 binds nucleosomes near the exit/entry sites of linker DNA, determines nucleosome repeat length and stabilizes higher-order organization of nucleosomes into the ∼30 nm chromatin fiber. In comparison to core histones, histone H1 is less well conserved through evolution. Furthermore, histone H1 composition in metazoans is generally complex with most species containing multiple variants that play redundant as well as specific functions. In this regard, a characteristic feature is the presence of specific H1 variants that replace somatic H1s in the germline and during early embryogenesis. In this review, we summarize our current knowledge about their structural and functional properties.

  14. Novel chemokine-like activities of histones in tumor metastasis.

    Science.gov (United States)

    Chen, Ruochan; Xie, Yangchun; Zhong, Xiao; Fu, Yongmin; Huang, Yan; Zhen, Yixiang; Pan, Pinhua; Wang, Haichao; Bartlett, David L; Billiar, Timothy R; Lotze, Michael T; Zeh, Herbert J; Fan, Xue-Gong; Tang, Daolin; Kang, Rui

    2016-09-20

    Histones are intracellular nucleosomal components and extracellular damage-associated molecular pattern molecules that modulate chromatin remodeling, as well as the immune response. However, their extracellular roles in cell migration and invasion remain undefined. Here, we demonstrate that histones are novel regulators of tumor metastasis with chemokine-like activities. Indeed, exogenous histones promote both hepatocellular carcinoma (HCC) cell migration and invasion through toll-like receptor (TLR)4, but not TLR2 or the receptor for advanced glycosylation end product. TLR4-mediated activation of nuclear factor-κB (NF-κB) by extracellular signal-regulated kinase (ERK) is required for histone-induced chemokine (e.g., C-C motif ligand 9/10) production. Pharmacological and genetic inhibition of TLR4-ERK-NF-κB signaling impairs histone-induced chemokine production and HCC cell migration. Additionally, TLR4 depletion (by using TLR4-/- mice and TLR4-shRNA) or inhibition of histone release/activity (by administration of heparin and H3 neutralizing antibody) attenuates lung metastasis of HCC cells injected via the tail vein of mice. Thus, histones promote tumor metastasis of HCC cells through the TLR4-NF-κB pathway and represent novel targets for treating patients with HCC.

  15. Analytical Results for 35 Mine-Waste Tailings Cores and Six Bed-Sediment Samples, and An Estimate of the Volume of Contaminated Material at Buckeye Meadow on Upper Basin Creek, Northern Jefferson County, Montana

    Science.gov (United States)

    Fey, David L.; Church, Stan E.; Finney, Christopher J.

    1999-01-01

    Metal-mining related wastes in the Boulder River basin study area in northern Jefferson County, Montana have been implicated in their detrimental effects on water quality with regard to acid-generation and toxic-metal solubilization. Flotation-mill tailings in the meadow below the Buckeye mine, hereafter referred to as the Buckeye mill-tailings site, have been identified as significant contributors to water quality degradation of Basin Creek, Montana. Basin Creek is one of three tributaries to the Boulder River in the study area; bed sediments and waters draining from the Buckeye mine have also been implicated. Geochemical analysis of 35 tailings cores and six bed-sediment samples was undertaken to determine the concentrations of Ag, As, Cd, Cu, Pb,and Zn present in these materials. These elements are environmentally significant, in that they can be toxic to fish and/or the invertebrate organisms that constitute their food. A suite of one-inch cores of dispersed flotation-mill tailings and underlying premining material was taken from a large, flat area north of Basin Creek near the site of the Buckeye mine. Thirty-five core samples were taken and divided into 204 subsamples. The samples were analyzed by ICP-AES (inductively coupled plasma-atomic emission spectroscopy) using a mixed-acid digestion. Results of the core analyses show that the elements listed above are present at moderate to very high concentrations (arsenic to 63,000 ppm, silver to 290 ppm, cadmium to 370 ppm, copper to 4,800 ppm, lead to 93,000 ppm, and zinc to 23,000 ppm). Volume calculations indicate that an estimated 8,400 metric tons of contaminated material are present at the site. Six bed-sediment samples were also subjected to the mixed-acid total digestion, and a warm (50°C) 2M HCl-1% H2O2 leach and analyzed by ICP-AES. Results indicate that bed sediments of Basin Creek are only slightly impacted by past mining above the Buckeye-Enterprise complex, moderately impacted at the upper (eastern

  16. Radiation damage to histones

    International Nuclear Information System (INIS)

    Mee, L.K.; Adelstein, S.J.

    1985-01-01

    The damage to histones irradiated in isolation is being elaborated to aid the identification of the crosslinking sites in radiation-induced DNA-histone adducts. Histones are being examined by amino acid analysis to determine the destruction of residues and by polyacrylamide gel electrophoresis to delineate changes in conformation. For the slightly lysine-rich histone, H2A, a specific attack on selective residues has been established, the aromatic residues, tyrosine and phenylalanine, and the heterocyclic residue, histidine, being significantly destroyed. In addition, a significant increase in aspartic acid was found; this may represent a radiation product from scission of the ring in the histidine residues. The similarity of the effects on residues in nitrous oxide-saturated and nitrogen-saturated solutions suggests that OH . and e/sub aq//sup -/ are equally efficient and selective in their attack. On gel electrophoresis degradation of the histone H2A was found to be greatest for irradiations in nitrous oxide-saturated solutions, suggesting CH . is the most effective radical for producing changes in conformation; O/sub 2//sup -/ was essentially ineffective. Other histones are being examined for changes in amino acid composition, conformation, and for the formation of radiation products

  17. Global histone analysis by mass spectrometry reveals a high content of acetylated lysine residues in the malaria parasite Plasmodium falciparum

    DEFF Research Database (Denmark)

    Trelle, Morten Beck; Salcedo-Amaya, Adriana M; Cohen, Adrian

    2009-01-01

    Post-translational modifications (PTMs) of histone tails play a key role in epigenetic regulation of gene expression in a range of organisms from yeast to human, however, little is known about histone proteins from the parasite that causes malaria in humans, Plasmodium falciparum. We characterize...... comprehensive map of histone modifications in Plasmodium falciparum and highlight the utility of tandem MS for detailed analysis of peptides containing multiple PTMs....

  18. Middle-down hybrid chromatography/tandem mass spectrometry workflow for characterization of combinatorial post-translational modifications in histones

    DEFF Research Database (Denmark)

    Sidoli, Simone; Schwämmle, Veit; Ruminowicz, Chrystian

    2014-01-01

    chromatography (WCX-HILIC) interfaced directly to high mass accuracy ESI MS/MS using electron transfer dissociation (ETD). This enabled automated and efficient separation and sequencing of hypermodified histone N-terminal tails for unambiguous localization of combinatorial PTMs. We present Histone Coder and Iso...

  19. Middle-down hybrid chromatography/tandem mass spectrometry workflow for characterization of combinatorial post-translational modifications in histones.

    Science.gov (United States)

    Sidoli, Simone; Schwämmle, Veit; Ruminowicz, Chrystian; Hansen, Thomas A; Wu, Xudong; Helin, Kristian; Jensen, Ole N

    2014-10-01

    We present an integrated middle-down proteomics platform for sensitive mapping and quantification of coexisting PTMs in large polypeptides (5-7 kDa). We combined an RP trap column with subsequent weak cation exchange-hydrophilic interaction LC interfaced directly to high mass accuracy ESI MS/MS using electron transfer dissociation. This enabled automated and efficient separation and sequencing of hypermodified histone N-terminal tails for unambiguous localization of combinatorial PTMs. We present Histone Coder and IsoScale software to extract, filter, and analyze MS/MS data, including quantification of cofragmenting isobaric polypeptide species. We characterized histone tails derived from murine embryonic stem cells knockout in suppressor of zeste12 (Suz12(-/-) ) and quantified 256 combinatorial histone marks in histones H3, H4, and H2A. Furthermore, a total of 713 different combinatorial histone marks were identified in purified histone H3. We measured a seven-fold reduction of H3K27me2/me3 (where me2 and me3 are dimethylation and trimethylation, respectively) in Suz12(-) (/) (-) cells and detected significant changes of the relative abundance of 16 other single PTMs of histone H3 and other combinatorial marks. We conclude that the inactivation of Suz12 is associated with changes in the abundance of not only H3K27 methylation but also multiple other PTMs in histone H3 tails. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Developmentally Regulated Post-translational Modification of Nucleoplasmin Controls Histone Sequestration and Deposition

    Directory of Open Access Journals (Sweden)

    Takashi Onikubo

    2015-03-01

    Full Text Available Nucleoplasmin (Npm is an abundant histone chaperone in vertebrate oocytes and embryos. During embryogenesis, regulation of Npm histone binding is critical for its function in storing and releasing maternal histones to establish and maintain the zygotic epigenome. Here, we demonstrate that Xenopus laevis Npm post-translational modifications (PTMs specific to the oocyte and egg promote either histone deposition or sequestration, respectively. Mass spectrometry and Npm phosphomimetic mutations used in chromatin assembly assays identified hyperphosphorylation on the N-terminal tail as a critical regulator for sequestration. C-terminal tail phosphorylation and PRMT5-catalyzed arginine methylation enhance nucleosome assembly by promoting histone interaction with the second acidic tract of Npm. Electron microscopy reconstructions of Npm and TTLL4 activity toward the C-terminal tail demonstrate that oocyte- and egg-specific PTMs cause Npm conformational changes. Our results reveal that PTMs regulate Npm chaperoning activity by modulating Npm conformation and Npm-histone interaction, leading to histone sequestration in the egg.

  1. Trichostatin-A induces differential changes in histone protein dynamics and expression in HeLa cells

    International Nuclear Information System (INIS)

    Rao, Jyothsna; Bhattacharya, Dipanjan; Banerjee, Bidisha; Sarin, Apurva; Shivashankar, G.V.

    2007-01-01

    Trichostatin-A (TSA), a histone deacetylase (HDAC) inhibitor, results in enhanced acetylation of core histones thereby disrupting chromatin organization within living cells. We report on changes in chromatin organization and the resultant alteration in nuclear architecture following treatment with TSA using fluorescence imaging. TSA triggers an expected increase in the euchromatin fraction which is accompanied by a significant increase in nuclear volume and alterations in chromatin compaction mapped using fluorescence anisotropy imaging. We observe differential changes in the mobility of core and linker histones as measured by fluorescence recovery after photo-bleaching (FRAP) and fluorescence correlation spectroscopy (FCS) methods. Further TSA induces a differential increase in linker histone transcription and increased phosphorylation of linker histone proteins accompanying an expected increase in core histone acetylation patterns. Thus subtle feedback responses triggered by changes in chromatin configurations impinge selectively on linker histone mobility and its expression. These observations have implications for understanding the role of HDAC in the dynamic maintenance of chromatin organization

  2. Somatic mutations of the histone H3K27 demethylase, UTX, in human cancer

    Science.gov (United States)

    van Haaften, Gijs; Dalgliesh, Gillian L; Davies, Helen; Chen, Lina; Bignell, Graham; Greenman, Chris; Edkins, Sarah; Hardy, Claire; O’Meara, Sarah; Teague, Jon; Butler, Adam; Hinton, Jonathan; Latimer, Calli; Andrews, Jenny; Barthorpe, Syd; Beare, Dave; Buck, Gemma; Campbell, Peter J; Cole, Jennifer; Dunmore, Rebecca; Forbes, Simon; Jia, Mingming; Jones, David; Kok, Chai Yin; Leroy, Catherine; Lin, Meng-Lay; McBride, David J; Maddison, Mark; Maquire, Simon; McLay, Kirsten; Menzies, Andrew; Mironenko, Tatiana; Lee, Mulderrig; Mudie, Laura; Pleasance, Erin; Shepherd, Rebecca; Smith, Raffaella; Stebbings, Lucy; Stephens, Philip; Tang, Gurpreet; Tarpey, Patrick S; Turner, Rachel; Turrell, Kelly; Varian, Jennifer; West, Sofie; Widaa, Sara; Wray, Paul; Collins, V Peter; Ichimura, Koichi; Law, Simon; Wong, John; Yuen, Siu Tsan; Leung, Suet Yi; Tonon, Giovanni; DePinho, Ronald A; Tai, Yu-Tzu; Anderson, Kenneth C; Kahnoski, Richard J.; Massie, Aaron; Khoo, Sok Kean; Teh, Bin Tean; Stratton, Michael R; Futreal, P Andrew

    2010-01-01

    Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase, UTX, pointing to histone H3 lysine methylation deregulation in multiple tumour types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene. PMID:19330029

  3. Arginine-rich histones have strong antiviral activity for influenza A viruses.

    Science.gov (United States)

    Hoeksema, Marloes; Tripathi, Shweta; White, Mitchell; Qi, Li; Taubenberger, Jeffery; van Eijk, Martin; Haagsman, Henk; Hartshorn, Kevan L

    2015-10-01

    While histones are best known for DNA binding and transcription-regulating properties, they also have antimicrobial activity against a broad range of potentially pathogenic organisms. Histones are abundant in neutrophil extracellular traps, where they play an important role in NET-mediated antimicrobial killing. Here, we show anti-influenza activity of histones against both seasonal H3N2 and H1N1, but not pandemic H1N1. The arginine rich histones, H3 and H4, had greater neutralizing and viral aggregating activity than the lysine rich histones, H2A and H2B. Of all core histones, histone H4 is most potent in neutralizing IAV, and incubation with IAV with histone H4 results in a decrease in uptake and viral replication by epithelial cells when measured by qRT-PCR. The antiviral activity of histone H4 is mediated principally by direct effects on viral particles. Histone H4 binds to IAV as assessed by ELISA and co-sedimentation of H4 with IAV. H4 also induces aggregation, as assessed by confocal microscopy and light transmission assays. Despite strong antiviral activity against the seasonal IAV strains, H4 was inactive against pandemic H1N1. These findings indicate a possible role for histones in the innate immune response against IAV. © The Author(s) 2015.

  4. Post-Translational Modifications of Histones in Human Sperm.

    Science.gov (United States)

    Krejčí, Jana; Stixová, Lenka; Pagáčová, Eva; Legartová, Soňa; Kozubek, Stanislav; Lochmanová, Gabriela; Zdráhal, Zbyněk; Sehnalová, Petra; Dabravolski, Siarhei; Hejátko, Jan; Bártová, Eva

    2015-10-01

    We examined the levels and distribution of post-translationally modified histones and protamines in human sperm. Using western blot immunoassay, immunofluorescence, mass spectrometry (MS), and FLIM-FRET approaches, we analyzed the status of histone modifications and the protamine P2. Among individual samples, we observed variability in the levels of H3K9me1, H3K9me2, H3K27me3, H3K36me3, and H3K79me1, but the level of acetylated (ac) histones H4 was relatively stable in the sperm head fractions, as demonstrated by western blot analysis. Sperm heads with lower levels of P2 exhibited lower levels of H3K9ac, H3K9me1, H3K27me3, H3K36me3, and H3K79me1. A very strong correlation was observed between the levels of P2 and H3K9me2. FLIM-FRET analysis additionally revealed that acetylated histones H4 are not only parts of sperm chromatin but also appear in a non-integrated form. Intriguingly, H4ac and H3K27me3 were detected in sperm tail fractions via western blot analysis. An appearance of specific histone H3 and H4 acetylation and H3 methylation in sperm tail fractions was also confirmed by both LC-MS/MS and MALDI-TOF MS analysis. Taken together, these data indicate that particular post-translational modifications of histones are uniquely distributed in human sperm, and this distribution varies among individuals and among the sperm of a single individual. © 2015 Wiley Periodicals, Inc.

  5. Rapid purification of recombinant histones.

    Science.gov (United States)

    Klinker, Henrike; Haas, Caroline; Harrer, Nadine; Becker, Peter B; Mueller-Planitz, Felix

    2014-01-01

    The development of methods to assemble nucleosomes from recombinant histones decades ago has transformed chromatin research. Nevertheless, nucleosome reconstitution remains time consuming to this day, not least because the four individual histones must be purified first. Here, we present a streamlined purification protocol of recombinant histones from bacteria. We termed this method "rapid histone purification" (RHP) as it circumvents isolation of inclusion bodies and thereby cuts out the most time-consuming step of traditional purification protocols. Instead of inclusion body isolation, whole cell extracts are prepared under strongly denaturing conditions that directly solubilize inclusion bodies. By ion exchange chromatography, the histones are purified from the extracts. The protocol has been successfully applied to all four canonical Drosophila and human histones. RHP histones and histones that were purified from isolated inclusion bodies had similar purities. The different purification strategies also did not impact the quality of octamers reconstituted from these histones. We expect that the RHP protocol can be readily applied to the purification of canonical histones from other species as well as the numerous histone variants.

  6. Histone methylations in heart development, congenital and adult heart diseases.

    Science.gov (United States)

    Zhang, Qing-Jun; Liu, Zhi-Ping

    2015-01-01

    Heart development comprises myocyte specification, differentiation and cardiac morphogenesis. These processes are regulated by a group of core cardiac transcription factors in a coordinated temporal and spatial manner. Histone methylation is an emerging epigenetic mechanism for regulating gene transcription. Interplay among cardiac transcription factors and histone lysine modifiers plays important role in heart development. Aberrant expression and mutation of the histone lysine modifiers during development and in adult life can cause either embryonic lethality or congenital heart diseases, and influences the response of adult hearts to pathological stresses. In this review, we describe current body of literature on the role of several common histone methylations and their modifying enzymes in heart development, congenital and adult heart diseases.

  7. The Histone Demethylase Jhdm1a Regulates Hepatic Gluconeogenesis

    Science.gov (United States)

    Zou, Tie; Yao, Annie Y.; Cooper, Marcus P.; Boyartchuk, Victor; Wang, Yong-Xu

    2012-01-01

    Hepatic gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to fasting hyperglycemia. To date, the impacts of chromatin modifying enzymes and chromatin landscape on gluconeogenesis are poorly understood. Through catalyzing the removal of methyl groups from specific lysine residues in the histone tail, histone demethylases modulate chromatin structure and, hence, gene expression. Here we perform an RNA interference screen against the known histone demethylases and identify a histone H3 lysine 36 (H3K36) demethylase, Jhdm1a, as a key negative regulator of gluconeogenic gene expression. In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level. Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Mechanistically, we find that Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPα. This is achieved, at least in part, by its USF1-dependent association with the C/EBPα promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPα locus. Our work provides compelling evidence that links histone demethylation to transcriptional regulation of gluconeogenesis and has important implications for the treatment of diabetes. PMID:22719268

  8. The histone demethylase Jhdm1a regulates hepatic gluconeogenesis.

    Directory of Open Access Journals (Sweden)

    Dongning Pan

    Full Text Available Hepatic gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to fasting hyperglycemia. To date, the impacts of chromatin modifying enzymes and chromatin landscape on gluconeogenesis are poorly understood. Through catalyzing the removal of methyl groups from specific lysine residues in the histone tail, histone demethylases modulate chromatin structure and, hence, gene expression. Here we perform an RNA interference screen against the known histone demethylases and identify a histone H3 lysine 36 (H3K36 demethylase, Jhdm1a, as a key negative regulator of gluconeogenic gene expression. In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level. Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Mechanistically, we find that Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPα. This is achieved, at least in part, by its USF1-dependent association with the C/EBPα promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPα locus. Our work provides compelling evidence that links histone demethylation to transcriptional regulation of gluconeogenesis and has important implications for the treatment of diabetes.

  9. Eviction of linker histone H1 by NAP-family histone chaperones enhances activated transcription.

    Science.gov (United States)

    Zhang, Qian; Giebler, Holli A; Isaacson, Marisa K; Nyborg, Jennifer K

    2015-01-01

    In the Metazoan nucleus, core histones assemble the genomic DNA to form nucleosome arrays, which are further compacted into dense chromatin structures by the linker histone H1. The extraordinary density of chromatin creates an obstacle for accessing the genetic information. Regulation of chromatin dynamics is therefore critical to cellular homeostasis, and histone chaperones serve as prominent players in these processes. In the current study, we examined the role of specific histone chaperones in negotiating the inherently repressive chromatin structure during transcriptional activation. Using a model promoter, we demonstrate that the human nucleosome assembly protein family members hNap1 and SET/Taf1β stimulate transcription in vitro during pre-initiation complex formation, prior to elongation. This stimulatory effect is dependent upon the presence of activators, p300, and Acetyl-CoA. We show that transcription from our chromatin template is strongly repressed by H1, and that both histone chaperones enhance RNA synthesis by overcoming H1-induced repression. Importantly, both hNap1 and SET/Taf1β directly bind H1, and function to enhance transcription by evicting the linker histone from chromatin reconstituted with H1. In vivo studies demonstrate that SET/Taf1β, but not hNap1, strongly stimulates activated transcription from the chromosomally-integrated model promoter, consistent with the observation that SET/Taf1β is nuclear, whereas hNap1 is primarily cytoplasmic. Together, these observations indicate that SET/Taf1β may serve as a critical regulator of H1 dynamics and gene activation in vivo. These studies uncover a novel function for SET that mechanistically couples transcriptional derepression with H1 dynamics. Furthermore, they underscore the significance of chaperone-dependent H1 displacement as an essential early step in the transition of a promoter from a dense chromatin state into one that is permissive to transcription factor binding and robust

  10. Biophysical characterization of the association of histones with single-stranded DNA.

    Science.gov (United States)

    Wang, Ying; van Merwyk, Luis; Tönsing, Katja; Walhorn, Volker; Anselmetti, Dario; Fernàndez-Busquets, Xavier

    2017-11-01

    Despite the profound current knowledge of the architecture and dynamics of nucleosomes, little is known about the structures generated by the interaction of histones with single-stranded DNA (ssDNA), which is widely present during replication and transcription. Non-denaturing gel electrophoresis, transmission electron microscopy, atomic force microscopy, magnetic tweezers. Histones have a high affinity for ssDNA in 0.15M NaCl ionic strength, with an apparent binding constant similar to that calculated for their association with double-stranded DNA (dsDNA). The length of DNA (number of nucleotides in ssDNA or base pairs in dsDNA) associated with a fixed core histone mass is the same for both ssDNA and dsDNA. Although histone-ssDNA complexes show a high tendency to aggregate, nucleosome-like structures are formed at physiological salt concentrations. Core histones are able to protect ssDNA from digestion by micrococcal nuclease, and a shortening of ssDNA occurs upon its interaction with histones. The purified (+) strand of a cloned DNA fragment of nucleosomal origin has a higher affinity for histones than the purified complementary (-) strand. At physiological ionic strength histones have high affinity for ssDNA, possibly associating with it into nucleosome-like structures. In the cell nucleus histones may spontaneously interact with ssDNA to facilitate their participation in the replication and transcription of chromatin. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. HiHiMap: single-cell quantitation of histones and histone posttranslational modifications across the cell cycle by high-throughput imaging.

    Science.gov (United States)

    Zane, Linda; Chapus, Fleur; Pegoraro, Gianluca; Misteli, Tom

    2017-08-15

    We describe Hi gh-throughput Hi stone Map ping (HiHiMap), a high-throughput imaging method to measure histones and histone posttranslational modifications (PTMs) in single cells. HiHiMap uses imaging-based quantification of DNA and cyclin A to stage individual cells in the cell cycle to determine the levels of histones or histone PTMs in each stage of the cell cycle. As proof of principle, we apply HiHiMap to measure the level of 21 core histones, histone variants, and PTMs in primary, immortalized, and transformed cells. We identify several histone modifications associated with oncogenic transformation. HiHiMap allows the rapid, high-throughput study of histones and histone PTMs across the cell cycle and the study of subpopulations of cells. © 2017 Zane et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  12. Intracellular distribution of histone mRNAs in human fibroblasts studied by in situ hybridization

    International Nuclear Information System (INIS)

    Lawrence, J.B.; Singer, R.H.; Villnave, C.A.; Stein, J.L.; Stein, G.S.

    1988-01-01

    We have used in situ hybridization to study the intracellular distribution of mRNAs for cell cycle-dependent core and H1 histone proteins in human WI-38 fibroblasts. Because histones are abundant nuclear proteins and histone mRNA expression is tightly coupled to DNA synthesis, it was of interest to determine whether histone mRNAs are localized near the nucleus. Cells were hybridized with tritiated DNA probes specific for either histone H1, histone H4, actin, or poly(A)+ mRNA and were processed for autoradiography. In exponentially growing cultures, the fraction of histone mRNA-positive cells correlated well with the fraction of cells in S phase and was eliminated by hydroxyurea inhibition of DNA synthesis. Within individual cells the label for histone mRNA was widely distributed throughout the cytoplasm and did not appear to be more heavily concentrated near the nucleus. However, histone mRNA appeared to exhibit patchy, nonhomogeneous localization, and a quantitative evaluation confirmed that grain distributions were not as uniform as they were after hybridizations to poly(A)+ mRNA. Actin mRNA in WI-38 cells was also widely distributed throughout the cytoplasm but differed from histone mRNA in that label for actin mRNA was frequently most dense at the outermost region of narrow cell extensions. The localization of actin mRNA was less pronounced but qualitatively very similar to that previously described for chicken embryonic myoblasts and fibroblasts. We conclude that localization of histones in WI-38 cells is not facilitated by localization of histone protein synthesis near the nucleus and that there are subtle but discrete and potentially functional differences in the distributions of histone, actin, and poly(A)+ mRNAs

  13. Structural and Histone Binding Ability Characterizations of Human PWWP Domains

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Hong; Zeng, Hong; Lam, Robert; Tempel, Wolfram; Amaya, Maria F.; Xu, Chao; Dombrovski, Ludmila; Qiu, Wei; Wang, Yanming; Min, Jinrong (Toronto); (Penn)

    2013-09-25

    The PWWP domain was first identified as a structural motif of 100-130 amino acids in the WHSC1 protein and predicted to be a protein-protein interaction domain. It belongs to the Tudor domain 'Royal Family', which consists of Tudor, chromodomain, MBT and PWWP domains. While Tudor, chromodomain and MBT domains have long been known to bind methylated histones, PWWP was shown to exhibit histone binding ability only until recently. The PWWP domain has been shown to be a DNA binding domain, but sequence analysis and previous structural studies show that the PWWP domain exhibits significant similarity to other 'Royal Family' members, implying that the PWWP domain has the potential to bind histones. In order to further explore the function of the PWWP domain, we used the protein family approach to determine the crystal structures of the PWWP domains from seven different human proteins. Our fluorescence polarization binding studies show that PWWP domains have weak histone binding ability, which is also confirmed by our NMR titration experiments. Furthermore, we determined the crystal structures of the BRPF1 PWWP domain in complex with H3K36me3, and HDGF2 PWWP domain in complex with H3K79me3 and H4K20me3. PWWP proteins constitute a new family of methyl lysine histone binders. The PWWP domain consists of three motifs: a canonical {beta}-barrel core, an insertion motif between the second and third {beta}-strands and a C-terminal {alpha}-helix bundle. Both the canonical {beta}-barrel core and the insertion motif are directly involved in histone binding. The PWWP domain has been previously shown to be a DNA binding domain. Therefore, the PWWP domain exhibits dual functions: binding both DNA and methyllysine histones.

  14. Histone methyltransferases in cancer

    DEFF Research Database (Denmark)

    Albert, Mareike; Helin, Kristian

    2009-01-01

    Cancer is perceived as a heterogeneous group of diseases that is characterized by aberrant patterns of gene expression. In the last decade, an increasing amount of data has pointed to a key role for epigenetic alterations in human cancer. In this review, we focus on a subclass of epigenetic...... regulators, namely histone methyltransferases (HMTs). Several HMTs have been linked to different types of cancer; however, in most cases we only have limited knowledge regarding the molecular mechanisms by which the HMTs contribute to disease development. We summarize the current knowledge regarding some...

  15. Histone turnover within nonproliferating cells

    International Nuclear Information System (INIS)

    Commerford, S.L.; Carsten, A.L.; Cronkite, E.P.

    1982-01-01

    The turnover of DNA and histones in the livers and brains of mice has been determined. These mice had been exposed to constant levels of tritiated water from conception until they were 8 months old. At this point, exposure to tritium was discontinued, and the tritium remaining in DNA and histones was measured at various intervals afterward. The half-lives calculated for these components (with 95% confidence limits given in parentheses) were 117 (85 to 188) days for liver histone, 318 (241 to 466) days for liver DNA, 159 (129 to 208) days for brain histone and 593 (376 to 1406) days for brain DNA. The difference between histone and DNA turnover is statistically significant for both tissues and indicates that histone turnover within tissues cannot be solely accounted for by cell turnover within the tissue but also must include histone turnover within living cells. The half-life of histone within cells is estimated to be 117 (88 to 178) days in liver and 223 (187 to 277) days in brain

  16. A fluorescence resonance energy transfer-based method for histone methyltransferases

    DEFF Research Database (Denmark)

    Devkota, Kanchan; Lohse, Brian; Nyby Jakobsen, Camilla

    2015-01-01

    A simple dye–quencher fluorescence resonance energy transfer (FRET)-based assay for methyltransferases was developed and used to determine kinetic parameters and inhibitory activity at EHMT1 and EHMT2. Peptides mimicking the truncated histone H3 tail were functionalized in each end with a dye...

  17. Tail gut cyst.

    Science.gov (United States)

    Rao, G Mallikarjuna; Haricharan, P; Ramanujacharyulu, S; Reddy, K Lakshmi

    2002-01-01

    The tail gut is a blind extension of the hindgut into the tail fold just distal to the cloacal membrane. Remnants of this structure may form tail gut cyst. We report a 14-year-old girl with tail gut cyst that presented as acute abdomen. The patient recovered after cyst excision.

  18. Novel E3 ubiquitin ligases that regulate histone protein levels in the budding yeast Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Rakesh Kumar Singh

    Full Text Available Core histone proteins are essential for packaging the genomic DNA into chromatin in all eukaryotes. Since multiple genes encode these histone proteins, there is potential for generating more histones than what is required for chromatin assembly. The positively charged histones have a very high affinity for negatively charged molecules such as DNA, and any excess of histone proteins results in deleterious effects on genomic stability and cell viability. Hence, histone levels are known to be tightly regulated via transcriptional, posttranscriptional and posttranslational mechanisms. We have previously elucidated the posttranslational regulation of histone protein levels by the ubiquitin-proteasome pathway involving the E2 ubiquitin conjugating enzymes Ubc4/5 and the HECT (Homologous to E6-AP C-Terminus domain containing E3 ligase Tom1 in the budding yeast. Here we report the identification of four additional E3 ligases containing the RING (Really Interesting New Gene finger domains that are involved in the ubiquitylation and subsequent degradation of excess histones in yeast. These E3 ligases are Pep5, Snt2 as well as two previously uncharacterized Open Reading Frames (ORFs YKR017C and YDR266C that we have named Hel1 and Hel2 (for Histone E3 Ligases respectively. Mutants lacking these E3 ligases are sensitive to histone overexpression as they fail to degrade excess histones and accumulate high levels of endogenous histones on histone chaperones. Co-immunoprecipitation assays showed that these E3 ligases interact with the major E2 enzyme Ubc4 that is involved in the degradation related ubiquitylation of histones. Using mutagenesis we further demonstrate that the RING domains of Hel1, Hel2 and Snt2 are required for histone regulation. Lastly, mutants corresponding to Hel1, Hel2 and Pep5 are sensitive to replication inhibitors. Overall, our results highlight the importance of posttranslational histone regulatory mechanisms that employ multiple E3

  19. High-resolution structure of the native histone octamer

    International Nuclear Information System (INIS)

    Wood, Christopher M.; Nicholson, James M.; Lambert, Stanley J.; Chantalat, Laurent; Reynolds, Colin D.; Baldwin, John P.

    2005-01-01

    The high-resolution (1.90 Å) model of the native histone octamer allows structural comparisons to be made with the nucleosome-core particle, along with an identification of a likely core-histone binding site. Crystals of native histone octamers (H2A–H2B)–(H4–H3)–(H3′–H4′)–(H2B′–H2A′) from chick erythrocytes in 2 M KCl, 1.35 M potassium phosphate pH 6.9 diffract X-rays to 1.90 Å resolution, yielding a structure with an R work value of 18.7% and an R free of 22.2%. The crystal space group is P6 5 , the asymmetric unit of which contains one complete octamer. This high-resolution model of the histone-core octamer allows further insight into intermolecular interactions, including water molecules, that dock the histone dimers to the tetramer in the nucleosome-core particle and have relevance to nucleosome remodelling. The three key areas analysed are the H2A′–H3–H4 molecular cluster (also H2A–H3′–H4′), the H4–H2B′ interaction (also H4′–H2B) and the H2A′–H4 β-sheet interaction (also H2A–H4′). The latter of these three regions is important to nucleosome remodelling by RNA polymerase II, as it is shown to be a likely core-histone binding site, and its disruption creates an instability in the nucleosome-core particle. A majority of the water molecules in the high-resolution octamer have positions that correlate to similar positions in the high-resolution nucleosome-core particle structure, suggesting that the high-resolution octamer model can be used for comparative studies with the high-resolution nucleosome-core particle

  20. Galaxies with long tails

    International Nuclear Information System (INIS)

    Schweizer, F.

    1978-01-01

    Two types of galaxies with long tails are described. The first occurs in pairs, each individual one having a long tail and the second occurs on its own with two tails. NGC 7252 shows several characteristics which one would expect of a merger: a pair of tidal tails despite the splendid isolation, a single nucleus, tail motions in opposite directions relative to the nucleus, and chaotic motions of a strangely looped main body. (C.F.)

  1. A histone H3K9M mutation traps histone methyltransferase Clr4 to prevent heterochromatin spreading

    Energy Technology Data Exchange (ETDEWEB)

    Shan, Chun-Min; Wang, Jiyong; Xu, Ke; Chen, Huijie; Yue, Jia-Xing; Andrews, Stuart; Moresco, James J.; Yates, John R.; Nagy, Peter L.; Tong, Liang; Jia, Songtao

    2016-09-20

    Histone lysine-to-methionine (K-to-M) mutations are associated with multiple cancers, and they function in a dominant fashion to block the methylation of corresponding lysines on wild type histones. However, their mechanisms of function are controversial. Here we show that in fission yeast, introducing the K9M mutation into one of the three histone H3 genes dominantly blocks H3K9 methylation on wild type H3 across the genome. In addition, H3K9M enhances the interaction of histone H3 tail with the H3K9 methyltransferase Clr4 in a SAM (S-adenosyl-methionine)-dependent manner, and Clr4 is trapped at nucleation sites to prevent its spreading and the formation of large heterochromatin domains. We further determined the crystal structure of an H3K9M peptide in complex with human H3K9 methyltransferase G9a and SAM, which reveales that the methionine side chain had enhanced van der Waals interactions with G9a. Therefore, our results provide a detailed mechanism by which H3K9M regulates H3K9 methylation.

  2. Histone peptide AKRHRK enhances H2O2-induced DNA damage and alters its site specificity

    International Nuclear Information System (INIS)

    Midorikawa, Kaoru; Murata, Mariko; Kawanishi, Shosuke

    2005-01-01

    Histone proteins are involved in compaction of DNA and the protection of cells from oxygen toxicity. However, several studies have demonstrated that the metal-binding histone reacts with H 2 O 2 , leading to oxidative damage to a nucleobase. We investigated whether histone can accelerate oxidative DNA damage, using a minimal model for the N-terminal tail of histone H4, CH 3 CO-AKRHRK-CONH 2 , which has a metal-binding site. This histone peptide enhanced DNA damage induced by H 2 O 2 and Cu(II), especially at cytosine residues, and induced additional DNA cleavage at the 5'-guanine of GGG sequences. The peptide also enhanced the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine and ESR spin-trapping signal from H 2 O 2 and Cu(II). Cyclic redox reactions involving histone-bound Cu(II) and H 2 O 2 , may give rise to multiple production of radicals leading to multiple hits in DNA. It is noteworthy that the histone H4 peptide with specific sequence AKRHRK can cause DNA damage rather than protection under metal-overloaded condition

  3. Histone deacetylase inhibition as an alternative strategy against invasive aspergillosis

    Directory of Open Access Journals (Sweden)

    Frederic eLamoth

    2015-02-01

    Full Text Available Invasive aspergillosis (IA is a life-threatening infection due to Aspergillus fumigatus and other Aspergillus spp. Drugs targeting the fungal cell membrane (triazoles, amphotericin B or cell wall (echinocandins are currently the sole therapeutic options against IA. Their limited efficacy and the emergence of resistance warrant the identification of new antifungal targets. Histone deacetylases (HDACs are enzymes responsible of the deacetylation of lysine residues of core histones, thus controlling chromatin remodeling and transcriptional activation. HDACs also control the acetylation and activation status of multiple non-histone proteins, including the heat shock protein 90 (Hsp90, an essential molecular chaperone for fungal virulence and antifungal resistance. This review provides an overview of the different HDACs in Aspergillus spp. as well as their respective contribution to total HDAC activity, fungal growth, stress responses, and virulence. The potential of HDAC inhibitors, currently under development for cancer therapy, as novel alternative antifungal agents against IA is discussed.

  4. Identification of novel post-translational modifications in linker histones from chicken erythrocytes.

    Science.gov (United States)

    Sarg, Bettina; Lopez, Rita; Lindner, Herbert; Ponte, Inma; Suau, Pedro; Roque, Alicia

    2015-01-15

    Chicken erythrocyte nuclei were digested with micrococcal nuclease and fractionated by centrifugation in low-salt buffer into soluble and insoluble fractions. Post-translational modifications of the purified linker histones of both fractions were analyzed by LC-ESI-MS/MS. All six histone H1 subtypes (H1.01, H1.02, H1.03, H1.10, H1.1L and H1.1R) and histone H5 were identified. Mass spectrometry analysis enabled the identification of a wide range of PTMs, including N(α)-terminal acetylation, acetylation, formylation, phosphorylation and oxidation. A total of nine new modifications in chicken linker histones were mapped, most of them located in the N-terminal and globular domains. Relative quantification of the modified peptides showed that linker histone PTMs were differentially distributed among both chromatin fractions, suggesting their relevance in the regulation of chromatin structure. The analysis of our results combined with previously reported data for chicken and some mammalian species showed that most of the modified positions were conserved throughout evolution, highlighting their importance in specific linker histone functions and epigenetics. Post-translational modifications of linker histones could have a role in the regulation of gene expression through the modulation of chromatin higher-order structure and chromatin remodeling. Finding new PTMs in linker histones is the first step to elucidate their role in the histone code. In this manuscript we report nine new post-translational modifications of the linker histones from chicken erythrocytes, one in H5 and eight in the H1 subtypes. Chromatin fractionated by centrifugation in low-salt buffer resulted in two fractions with different contents and compositions of linker histones and enriched in specific core histone PTMs. Of particular interest is the fact that linker histone PTMs were differentially distributed in both chromatin fractions, suggesting specific functions. Future studies are needed to

  5. The histone codes for meiosis.

    Science.gov (United States)

    Wang, Lina; Xu, Zhiliang; Khawar, Muhammad Babar; Liu, Chao; Li, Wei

    2017-09-01

    Meiosis is a specialized process that produces haploid gametes from diploid cells by a single round of DNA replication followed by two successive cell divisions. It contains many special events, such as programmed DNA double-strand break (DSB) formation, homologous recombination, crossover formation and resolution. These events are associated with dynamically regulated chromosomal structures, the dynamic transcriptional regulation and chromatin remodeling are mainly modulated by histone modifications, termed 'histone codes'. The purpose of this review is to summarize the histone codes that are required for meiosis during spermatogenesis and oogenesis, involving meiosis resumption, meiotic asymmetric division and other cellular processes. We not only systematically review the functional roles of histone codes in meiosis but also discuss future trends and perspectives in this field. © 2017 Society for Reproduction and Fertility.

  6. Implication of Posttranslational Histone Modifications in Nucleotide Excision Repair

    Directory of Open Access Journals (Sweden)

    Shisheng Li

    2012-09-01

    Full Text Available Histones are highly alkaline proteins that package and order the DNA into chromatin in eukaryotic cells. Nucleotide excision repair (NER is a conserved multistep reaction that removes a wide range of generally bulky and/or helix-distorting DNA lesions. Although the core biochemical mechanism of NER is relatively well known, how cells detect and repair lesions in diverse chromatin environments is still under intensive research. As with all DNA-related processes, the NER machinery must deal with the presence of organized chromatin and the physical obstacles it presents. A huge catalogue of posttranslational histone modifications has been documented. Although a comprehensive understanding of most of these modifications is still lacking, they are believed to be important regulatory elements for many biological processes, including DNA replication and repair, transcription and cell cycle control. Some of these modifications, including acetylation, methylation, phosphorylation and ubiquitination on the four core histones (H2A, H2B, H3 and H4 or the histone H2A variant H2AX, have been found to be implicated in different stages of the NER process. This review will summarize our recent understanding in this area.

  7. Stage-specific histone modification profiles reveal global transitions in the Xenopus embryonic epigenome.

    Directory of Open Access Journals (Sweden)

    Tobias D Schneider

    Full Text Available Vertebrate embryos are derived from a transitory pool of pluripotent cells. By the process of embryonic induction, these precursor cells are assigned to specific fates and differentiation programs. Histone post-translational modifications are thought to play a key role in the establishment and maintenance of stable gene expression patterns underlying these processes. While on gene level histone modifications are known to change during differentiation, very little is known about the quantitative fluctuations in bulk histone modifications during development. To investigate this issue we analysed histones isolated from four different developmental stages of Xenopus laevis by mass spectrometry. In toto, we quantified 59 modification states on core histones H3 and H4 from blastula to tadpole stages. During this developmental period, we observed in general an increase in the unmodified states, and a shift from histone modifications associated with transcriptional activity to transcriptionally repressive histone marks. We also compared these naturally occurring patterns with the histone modifications of murine ES cells, detecting large differences in the methylation patterns of histone H3 lysines 27 and 36 between pluripotent ES cells and pluripotent cells from Xenopus blastulae. By combining all detected modification transitions we could cluster their patterns according to their embryonic origin, defining specific histone modification profiles (HMPs for each developmental stage. To our knowledge, this data set represents the first compendium of covalent histone modifications and their quantitative flux during normogenesis in a vertebrate model organism. The HMPs indicate a stepwise maturation of the embryonic epigenome, which may be causal to the progressing restriction of cellular potency during development.

  8. The multi-domain protein Np95 connects DNA methylation and histone modification

    Science.gov (United States)

    Rottach, Andrea; Frauer, Carina; Pichler, Garwin; Bonapace, Ian Marc; Spada, Fabio; Leonhardt, Heinrich

    2010-01-01

    DNA methylation and histone modifications play a central role in the epigenetic regulation of gene expression and cell differentiation. Recently, Np95 (also known as UHRF1 or ICBP90) has been found to interact with Dnmt1 and to bind hemimethylated DNA, indicating together with genetic studies a central role in the maintenance of DNA methylation. Using in vitro binding assays we observed a weak preference of Np95 and its SRA (SET- and Ring-associated) domain for hemimethylated CpG sites. However, the binding kinetics of Np95 in living cells was not affected by the complete loss of genomic methylation. Investigating further links with heterochromatin, we could show that Np95 preferentially binds histone H3 N-terminal tails with trimethylated (H3K9me3) but not acetylated lysine 9 via a tandem Tudor domain. This domain contains three highly conserved aromatic amino acids that form an aromatic cage similar to the one binding H3K9me3 in the chromodomain of HP1ß. Mutations targeting the aromatic cage of the Np95 tandem Tudor domain (Y188A and Y191A) abolished specific H3 histone tail binding. These multiple interactions of the multi-domain protein Np95 with hemimethylated DNA and repressive histone marks as well as with DNA and histone methyltransferases integrate the two major epigenetic silencing pathways. PMID:20026581

  9. The multi-domain protein Np95 connects DNA methylation and histone modification.

    Science.gov (United States)

    Rottach, Andrea; Frauer, Carina; Pichler, Garwin; Bonapace, Ian Marc; Spada, Fabio; Leonhardt, Heinrich

    2010-04-01

    DNA methylation and histone modifications play a central role in the epigenetic regulation of gene expression and cell differentiation. Recently, Np95 (also known as UHRF1 or ICBP90) has been found to interact with Dnmt1 and to bind hemimethylated DNA, indicating together with genetic studies a central role in the maintenance of DNA methylation. Using in vitro binding assays we observed a weak preference of Np95 and its SRA (SET- and Ring-associated) domain for hemimethylated CpG sites. However, the binding kinetics of Np95 in living cells was not affected by the complete loss of genomic methylation. Investigating further links with heterochromatin, we could show that Np95 preferentially binds histone H3 N-terminal tails with trimethylated (H3K9me3) but not acetylated lysine 9 via a tandem Tudor domain. This domain contains three highly conserved aromatic amino acids that form an aromatic cage similar to the one binding H3K9me3 in the chromodomain of HP1ss. Mutations targeting the aromatic cage of the Np95 tandem Tudor domain (Y188A and Y191A) abolished specific H3 histone tail binding. These multiple interactions of the multi-domain protein Np95 with hemimethylated DNA and repressive histone marks as well as with DNA and histone methyltransferases integrate the two major epigenetic silencing pathways.

  10. Preferential Phosphorylation on Old Histones during Early Mitosis in Human Cells*

    Science.gov (United States)

    Lin, Shu; Yuan, Zuo-Fei; Han, Yumiao; Marchione, Dylan M.; Garcia, Benjamin A.

    2016-01-01

    How histone post-translational modifications (PTMs) are inherited through the cell cycle remains poorly understood. Canonical histones are made in the S phase of the cell cycle. Combining mass spectrometry-based technologies and stable isotope labeling by amino acids in cell culture, we question the distribution of multiple histone PTMs on old versus new histones in synchronized human cells. We show that histone PTMs can be grouped into three categories according to their distributions. Most lysine mono-methylation and acetylation PTMs are either symmetrically distributed on old and new histones or are enriched on new histones. In contrast, most di- and tri-methylation PTMs are enriched on old histones, suggesting that the inheritance of different PTMs is regulated distinctly. Intriguingly, old and new histones are distinct in their phosphorylation status during early mitosis in the following three human cell types: HeLa, 293T, and human foreskin fibroblast cells. The mitotic hallmark H3S10ph is predominantly associated with old H3 at early mitosis and becomes symmetric with the progression of mitosis. This same distribution was observed with other mitotic phosphorylation marks, including H3T3/T6ph, H3.1/2S28ph, and H1.4S26ph but not S28/S31ph on the H3 variant H3.3. Although H3S10ph often associates with the neighboring Lys-9 di- or tri-methylations, they are not required for the asymmetric distribution of Ser-10 phosphorylation on the same H3 tail. Inhibition of the kinase Aurora B does not change the distribution despite significant reduction of H3S10ph levels. However, K9me2 abundance on the new H3 is significantly reduced after Aurora B inhibition, suggesting a cross-talk between H3S10ph and H3K9me2. PMID:27226594

  11. Uranium Mill Tailings Management

    International Nuclear Information System (INIS)

    Nelson, J.D.

    1982-01-01

    This book presents the papers given at the Fifth Symposium on Uranium Mill Tailings Management. Advances made with regard to uranium mill tailings management, environmental effects, regulations, and reclamation are reviewed. Topics considered include tailings management and design (e.g., the Uranium Mill Tailings Remedial Action Project, environmental standards for uranium mill tailings disposal), surface stabilization (e.g., the long-term stability of tailings, long-term rock durability), radiological aspects (e.g. the radioactive composition of airborne particulates), contaminant migration (e.g., chemical transport beneath a uranium mill tailings pile, the interaction of acidic leachate with soils), radon control and covers (e.g., radon emanation characteristics, designing surface covers for inactive uranium mill tailings), and seepage and liners (e.g., hydrologic observations, liner requirements)

  12. Cell cycle-dependent O-GlcNAc modification of tobacco histones and their interaction with the tobacco lectin.

    Science.gov (United States)

    Delporte, Annelies; De Zaeytijd, Jeroen; De Storme, Nico; Azmi, Abdelkrim; Geelen, Danny; Smagghe, Guy; Guisez, Yves; Van Damme, Els J M

    2014-10-01

    The Nicotiana tabacum agglutinin or Nictaba is a nucleocytoplasmic lectin that is expressed in tobacco after the plants have been exposed to jasmonate treatment or insect herbivory. Nictaba specifically recognizes GlcNAc residues. Recently, it was shown that Nictaba is interacting in vitro with the core histone proteins from calf thymus. Assuming that plant histones - similar to their animal counterparts - undergo O-GlcNAcylation, this interaction presumably occurs through binding of the lectin to the O-GlcNAc modification present on the histones. Hereupon, the question was raised whether this modification also occurs in plants and if it is cell cycle dependent. To this end, histones were purified from tobacco BY-2 suspension cells and the presence of O-GlcNAc modifications was checked. Concomitantly, O-GlcNAcylation of histone proteins was studied. Our data show that similar to animal histones plant histones are modified by O-GlcNAc in a cell cycle-dependent fashion. In addition, the interaction between Nictaba and tobacco histones was confirmed using lectin chromatography and far Western blot analysis. Collectively these findings suggest that Nictaba can act as a modulator of gene transcription through its interaction with core histones. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  13. The organization structure and regulatory elements of Chlamydomonas histone genes reveal features linking plant and animal genes.

    Science.gov (United States)

    Fabry, S; Müller, K; Lindauer, A; Park, P B; Cornelius, T; Schmitt, R

    1995-09-01

    The genome of the green alga Chlamydomonas reinhardtii contains approximately 15 gene clusters of the nucleosomal (or core) histone H2A, H2B, H3 and H4 genes and at least one histone H1 gene. Seven non-allelic histone gene loci were isolated from a genomic library, physically mapped, and the nucleotide sequences of three isotypes of each core histone gene species and one linked H1 gene determined. The core histone genes are organized in clusters of H2A-H2B and H3-H4 pairs, in which each gene pair shows outwardly divergent transcription from a short (< 300 bp) intercistronic region. These intercistronic regions contain typically conserved promoter elements, namely a TATA-box and the three motifs TGGCCAG-G(G/C)-CGAG, CGTTGACC and CGGTTG. Different from the genes of higher plants, but like those of animals and the related alga Volvox, the 3' untranslated regions contain no poly A signal, but a palindromic sequence (3' palindrome) essential for mRNA processing is present. One single H1 gene was found in close linkage to a H2A-H2B pair. The H1 upstream region contains the octameric promoter element GGTTGACC (also found upstream of the core histone genes) and two specific sequence motifs that are shared only with the Volvox H1 promoters. This suggests differential transcription of the H1 and the core histone genes. The H1 gene is interrupted by two introns. Unlike Volvox H3 genes, the three sequenced H3 isoforms are intron-free. Primer-directed PCR of genomic DNA demonstrated, however, that at least 8 of the about 15 H3 genes do contain one intron at a conserved position. In synchronized C. reinhardtii cells, H4 mRNA levels (representative of all core histone mRNAs) peak during cell division, suggesting strict replication-dependent gene control. The derived peptide sequences place C. reinhardtii core histones closer to plants than to animals, except that the H2A histones are more animal-like. The peptide sequence of histone H1 is closely related to the V. carteri VH1-II

  14. Histone HIST1H1C/H1.2 regulates autophagy in the development of diabetic retinopathy.

    Science.gov (United States)

    Wang, Wenjun; Wang, Qing; Wan, Danyang; Sun, Yue; Wang, Lin; Chen, Hong; Liu, Chengyu; Petersen, Robert B; Li, Jianshuang; Xue, Weili; Zheng, Ling; Huang, Kun

    2017-05-04

    Autophagy plays critical and complex roles in many human diseases, including diabetes and its complications. However, the role of autophagy in the development of diabetic retinopathy remains uncertain. Core histone modifications have been reported involved in the development of diabetic retinopathy, but little is known about the histone variants. Here, we observed increased autophagy and histone HIST1H1C/H1.2, an important variant of the linker histone H1, in the retinas of type 1 diabetic rodents. Overexpression of histone HIST1H1C upregulates SIRT1 and HDAC1 to maintain the deacetylation status of H4K16, leads to upregulation of ATG proteins, then promotes autophagy in cultured retinal cell line. Histone HIST1H1C overexpression also promotes inflammation and cell toxicity in vitro. Knockdown of histone HIST1H1C reduces both the basal and stresses (including high glucose)-induced autophagy, and inhibits high glucose induced inflammation and cell toxicity. Importantly, AAV-mediated histone HIST1H1C overexpression in the retinas leads to increased autophagy, inflammation, glial activation and neuron loss, similar to the pathological changes identified in the early stage of diabetic retinopathy. Furthermore, knockdown of histone Hist1h1c by siRNA in the retinas of diabetic mice significantly attenuated the diabetes-induced autophagy, inflammation, glial activation and neuron loss. These results indicate that histone HIST1H1C may offer a novel therapeutic target for preventing diabetic retinopathy.

  15. Histone phosphorylation during radiation-induced mitotic delay in synchronous plasmodia of Physarum polycephalum

    International Nuclear Information System (INIS)

    Brewer, E.N.; Oleinick, N.L.

    1980-01-01

    Using the nearly perfect synchrony of the mitotic stages in Physarum plasmodia, and making use of 32 P as a tracer, studies were made to define the time course of histone phosphorylation during the late G2 and prophase and the alterations in that time course accompanying radiation-induced mitotic delay. Histone H1 was phosphorylated throughout the last 2-3 hours of the mitotic cycle coincident with the early stages of chromosome condensation. H1 phosphorylation appeared to be reduced in irradiated plasmodia. It is postulated that a longer time period, i.e. the mitotic delay, may be required to obtain the same eventual level of H1-phosphate. In normal cultures, nucleosome core histones were phosphorylated late in G2 and prophase, the peak corresponding closely with the γ-transition point. In irradiated plasmodia, phosphorylation of the core histones had an extended time course similar to H1. (U.K.)

  16. Heavy tails of OLS

    DEFF Research Database (Denmark)

    Mikosch, Thomas Valentin; de Vries, Casper

    2013-01-01

    Suppose the tails of the noise distribution in a regression exhibit power law behavior. Then the distribution of the OLS regression estimator inherits this tail behavior. This is relevant for regressions involving financial data. We derive explicit finite sample expressions for the tail probabili...

  17. Tandem affinity purification of histones, coupled to mass spectrometry, identifies associated proteins and new sites of post-translational modification in Saccharomyces cerevisiae.

    Science.gov (United States)

    Valero, M Luz; Sendra, Ramon; Pamblanco, Mercè

    2016-03-16

    Histones and their post-translational modifications contribute to regulating fundamental biological processes in all eukaryotic cells. We have applied a conventional tandem affinity purification strategy to histones H3 and H4 of the yeast Saccharomyces cerevisiae. Mass spectrometry analysis of the co-purified proteins revealed multiple associated proteins, including core histones, which indicates that tagged histones may be incorporated to the nucleosome particle. Among the many other co-isolated proteins there are histone chaperones, elements of chromatin remodeling, of nucleosome assembly/disassembly, and of histone modification complexes. The histone chaperone Rtt106p, two members of chromatin assembly FACT complex and Psh1p, an ubiquitin ligase, were the most abundant proteins obtained with both H3-TAP and H4-TAP, regardless of the cell extraction medium stringency. Our mass spectrometry analyses have also revealed numerous novel post-translational modifications, including 30 new chemical modifications in histones, mainly by ubiquitination. We have discovered not only new sites of ubiquitination but that, besides lysine, also serine and threonine residues are targets of ubiquitination on yeast histones. Our results show the standard tandem affinity purification procedure is suitable for application to yeast histones, in order to isolate and characterize histone-binding proteins and post-translational modifications, avoiding the bias caused by histone purification from a chromatin-enriched fraction. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Biochemical systems approaches for the analysis of histone modification readout.

    Science.gov (United States)

    Soldi, Monica; Bremang, Michael; Bonaldi, Tiziana

    2014-08-01

    Chromatin is the macromolecular nucleoprotein complex that governs the organization of genetic material in the nucleus of eukaryotic cells. In chromatin, DNA is packed with histone proteins into nucleosomes. Core histones are prototypes of hyper-modified proteins, being decorated by a large number of site-specific reversible and irreversible post-translational modifications (PTMs), which contribute to the maintenance and modulation of chromatin plasticity, gene activation, and a variety of other biological processes and disease states. The observations of the variety, frequency and co-occurrence of histone modifications in distinct patterns at specific genomic loci have led to the idea that hPTMs can create a molecular barcode, read by effector proteins that translate it into a specific transcriptional state, or process, on the underlying DNA. However, despite the fact that this histone-code hypothesis was proposed more than 10 years ago, the molecular details of its working mechanisms are only partially characterized. In particular, two questions deserve specific investigation: how the different modifications associate and synergize into patterns and how these PTM configurations are read and translated by multi-protein complexes into a specific functional outcome on the genome. Mass spectrometry (MS) has emerged as a versatile tool to investigate chromatin biology, useful for both identifying and validating hPTMs, and to dissect the molecular determinants of histone modification readout systems. We review here the MS techniques and the proteomics methods that have been developed to address these fundamental questions in epigenetics research, emphasizing approaches based on the proteomic dissection of distinct native chromatin regions, with a critical evaluation of their present challenges and future potential. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Histone modifications: Cycling with chromosomal replication

    DEFF Research Database (Denmark)

    Thon, Genevieve

    2008-01-01

    Histone modifications tend to be lost during chromosome duplication. Several recent studies suggest that the RNA interference pathway becomes active during the weakened transcriptional repression occurring at centromeres in S phase, resulting in the re-establishment of histone modifications...

  20. Histone Lysine Methylation and Neurodevelopmental Disorders

    Directory of Open Access Journals (Sweden)

    Jeong-Hoon Kim

    2017-06-01

    Full Text Available Methylation of several lysine residues of histones is a crucial mechanism for relatively long-term regulation of genomic activity. Recent molecular biological studies have demonstrated that the function of histone methylation is more diverse and complex than previously thought. Moreover, studies using newly available genomics techniques, such as exome sequencing, have identified an increasing number of histone lysine methylation-related genes as intellectual disability-associated genes, which highlights the importance of accurate control of histone methylation during neurogenesis. However, given the functional diversity and complexity of histone methylation within the cell, the study of the molecular basis of histone methylation-related neurodevelopmental disorders is currently still in its infancy. Here, we review the latest studies that revealed the pathological implications of alterations in histone methylation status in the context of various neurodevelopmental disorders and propose possible therapeutic application of epigenetic compounds regulating histone methylation status for the treatment of these diseases.

  1. Histone chaperone networks shaping chromatin function

    DEFF Research Database (Denmark)

    Hammond, Colin; Strømme, Caroline Bianchi; Huang, Hongda

    2017-01-01

    and fate, which affects all chromosomal processes, including gene expression, chromosome segregation and genome replication and repair. Here, we review the distinct structural and functional properties of the expanding network of histone chaperones. We emphasize how chaperones cooperate in the histone...... chaperone network and via co-chaperone complexes to match histone supply with demand, thereby promoting proper nucleosome assembly and maintaining epigenetic information by recycling modified histones evicted from chromatin....

  2. APPLICATION OF POSTFLOTATION TAILINGS IN HYDROENGINEERING STRUCTURES

    Directory of Open Access Journals (Sweden)

    Katarzyna Stefaniak

    2017-01-01

    Full Text Available Economic development stimulated by the increased demand for production of consumer goods and the growing human population result in increasing amounts of various wastes, including tailings. The mining industry in Poland, comprising also mining of non-ferrous metal ores, is a strategic branch of the national economy and at the same time a leading waste producer. Tailings management is a significant problem both in Poland and worldwide. Frequently considerable amounts of wastes are accumulated in mine spoil tips, in areas not always suitable for their deposition, thus leading to the degradation of the surrounding environment. At the huge volume of produced wastes their rational and economically viable management is becoming crucial. On the other hand, depletion of natural aggregate deposits is an important incentive to search for substitutes, which would be suitable for the development of road infrastructure or which could be used in earth structure engineering to construct hydroengineering objects. Since no profitable recovery technologies are available at present, tailings generated by copper mining are deposited in tailings storage facilities. The largest and at the same time the only currently operating facility in Poland is the Żelazny Most Mining Tailings Storage Facility, belonging to KGHM Polska Miedź S.A. The paper presents criteria for material quality and density imposed on the material embedded in the static core of the tailings pond dam. For this purpose studies were conducted to confirm applicability of sorted tailings as a material for the construction of earth structures.

  3. Characterization and monitoring of transverse beam tails

    International Nuclear Information System (INIS)

    Seeman, J.T.; Decker, F.J.; Hsu, I.; Young, C.

    1991-05-01

    Low emittance electron beams accelerated to high energy in a linac experience transverse effects (wakefield, filamentation, optics) which produce non-Gaussian projected transverse beam distributions. Characterizations of the beam shapes are difficult because the shapes are asymmetric and change with betatron phase. In this note several methods to describe beam distributions are discussed including an accelerator physics model of these tails. The uses of these characterizations in monitoring the beam emittances in the SLC are described in this paper. First, two dimensional distributions from profile monitor screens are reviewed showing correlated tails. Second, a fitting technique for non-Gaussian one dimensional distributions is used to extract the core from the tail areas. Finally, a model for tail propagation in the linac is given. 3 refs., 6 figs

  4. Consolidation of tailings

    International Nuclear Information System (INIS)

    Nelson, J.D.; Wardwell, R.E.; Abt, S.R.; Staub, W.P.

    1983-09-01

    The integrity of cover systems placed on tailings impoundments will be affected by the potential for differential settlement of the tailings surface. Settlement of the sand fraction will occur relatively rapidly. The slimes will take longer time for consolidation and will produce greater settlement. This report reviews the phenomenon of consolidation for saturated and unsaturated tailings. The effect of load application by cover placement and the extent to which dewatering of tailings will cause consolidation are considered. In addition, the feasibility of inducing consolidation by alternative means and the potential applicability of these methods to tailings impoundments reclamation are discussed. Differential settlement of the tailings will cause tensile strain to be developed in covers. This strain could be large enough to cause cracking within a relatively brittle compacted clay. Dewatering of tailings by drainage can cause settlement even greater than that by placement of a cover material. Dewatering of the tailings would also increase the stability of the tailings surface, thereby enhancing reclamation operations. Consequently, in view of the enhanced surface stability and the fact that a portion of the differential settlement can be accomplished prior to cover placement, dewatering of tailings impoundments during operations may have benefical effects

  5. Uranium tailings bibliography

    International Nuclear Information System (INIS)

    Holoway, C.F.; Goldsmith, W.A.; Eldridge, V.M.

    1975-12-01

    A bibliography containing 1,212 references is presented with its focus on the general problem of reducing human exposure to the radionuclides contained in the tailings from the milling of uranium ore. The references are divided into seven broad categories: uranium tailings pile (problems and perspectives), standards and philosophy, etiology of radiation effects, internal dosimetry and metabolism, environmental transport, background sources of tailings radionuclides, and large-area decontamination

  6. CSR-1 RNAi pathway positively regulates histone expression in C. elegans.

    Science.gov (United States)

    Avgousti, Daphne C; Palani, Santhosh; Sherman, Yekaterina; Grishok, Alla

    2012-10-03

    Endogenous small interfering RNAs (endo-siRNAs) have been discovered in many organisms, including mammals. In C. elegans, depletion of germline-enriched endo-siRNAs found in complex with the CSR-1 Argonaute protein causes sterility and defects in chromosome segregation in early embryos. We discovered that knockdown of either csr-1, the RNA-dependent RNA polymerase (RdRP) ego-1, or the dicer-related helicase drh-3, leads to defects in histone mRNA processing, resulting in severe depletion of core histone proteins. The maturation of replication-dependent histone mRNAs, unlike that of other mRNAs, requires processing of their 3'UTRs through an endonucleolytic cleavage guided by the U7 snRNA, which is lacking in C. elegans. We found that CSR-1-bound antisense endo-siRNAs match histone mRNAs and mRNA precursors. Consistently, we demonstrate that CSR-1 directly binds to histone mRNA in an ego-1-dependent manner using biotinylated 2'-O-methyl RNA oligonucleotides. Moreover, we demonstrate that increasing the dosage of histone genes rescues the lethality associated with depletion of CSR-1 and EGO-1. These results support a positive and direct effect of RNAi on histone gene expression.

  7. [Proteolytic activity of IgG-antibodies of mice, immunized by calf thymus histones].

    Science.gov (United States)

    Kit, Iu Ia; Korniĭ, N; Kril', I Ĭ; Mahorivs'ka, I B; Tkachenko, V; Bilyĭ, R O; Stoĭka, R S

    2014-01-01

    The main goal of the study was to determine the ability of histones to induce production of the proteolytically active IgG-antibodies in BALB/c mice. In order to perform this study 8 mice were immunized with the fraction of total calf thymus histones. IgGs were isolated from the serum of the immunized and not immunized animals by means of precipitation with 33% ammonium sulfate, followed by affinity chromatography on protein G-Sepharose column. Histones, myelin basic protein (MBP), lysozyme, BSA, ovalbumin, macroglobulin, casein and cytochrome c served as substrates for determining the proteolytic activity. It was found that IgGs from the blood serum of immunized mice are capable of hydrolyzing histone H1, core histone and MBP. On the contrary, the proteolytic activity of IgGs from the blood serum of not immunized mice was not detected. The absence of proteolytical enzymes in the fraction of IgGs was proven by HPLC chromatography. High levels of proteolytic activity toward histones have been also detected in affinity purified IgGs from blood serum of patients with rheumatoid arthritis, but not in healthy donors. These data indicate that eukaryotic histones may induce production of protabzymes in mammals. The possible origin of these protabzymes and their potential biological role in mammalians is discussed.

  8. Uranium tailings sampling manual

    International Nuclear Information System (INIS)

    Feenstra, S.; Reades, D.W.; Cherry, J.A.; Chambers, D.B.; Case, G.G.; Ibbotson, B.G.

    1985-01-01

    The purpose of this manual is to describe the requisite sampling procedures for the application of uniform high-quality standards to detailed geotechnical, hydrogeological, geochemical and air quality measurements at Canadian uranium tailings disposal sites. The selection and implementation of applicable sampling procedures for such measurements at uranium tailings disposal sites are complicated by two primary factors. Firstly, the physical and chemical nature of uranium mine tailings and effluent is considerably different from natural soil materials and natural waters. Consequently, many conventional methods for the collection and analysis of natural soils and waters are not directly applicable to tailings. Secondly, there is a wide range in the physical and chemical nature of uranium tailings. The composition of the ore, the milling process, the nature of tailings depositon, and effluent treatment vary considerably and are highly site-specific. Therefore, the definition and implementation of sampling programs for uranium tailings disposal sites require considerable evaluation, and often innovation, to ensure that appropriate sampling and analysis methods are used which provide the flexibility to take into account site-specific considerations. The following chapters describe the objective and scope of a sampling program, preliminary data collection, and the procedures for sampling of tailings solids, surface water and seepage, tailings pore-water, and wind-blown dust and radon

  9. Uranium mill tailings management

    International Nuclear Information System (INIS)

    1982-01-01

    Facilities for the disposal of uranium mill tailings will invariably be subjected to geomorphological and climatological influences in the long-term. Proceedings of a workshop discuss how the principles of geomorphology can be applied to the siting, design, construction, decommissioning and rehabilitation of disposal facilities in order to provide for long-term containment and stability of tailings. The characteristics of tailings and their behaviour after disposal influence the potential impacts which might occur in the long-term. Proceedings of another workshop examine the technologies for uranium ore processing and tailings conditioning with a view to identifying improvements that could be made in such characteristics

  10. Engineering assessment of inactive uranium mill tailings

    International Nuclear Information System (INIS)

    1981-07-01

    The Grand Junction site has been reevaluated in order to revise the October 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Grand Junction, Colorado. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 1.9 million tons of tailings at the Grand Junction site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation are also factors. The eight alternative actions presented herein range from millsite and off-site decontamination with the addition of 3 m of stabilization cover material (Option I), to removal of the tailings to remote disposal sites and decontamination of the tailings site (Options II through VIII). Cost estimates for the eight options range from about $10,200,000 for stabilization in-place to about $39,500,000 for disposal in the DeBeque area, at a distance of about 35 mi, using transportation by rail. If transportation to DeBeque were by truck, the cost estimated to be about $41,900,000. Three principal alternatives for the reprocessing of the Grand Junction tailings were examined: (a) heap leaching; (b) treatment at an existing mill; and (c) reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be about $200/lb by heap leach and $150/lb by conventional plant processes. The spot market price for uranium was $25/lb early in 1981. Therefore, reprocessing the tailings for uranium recovery appears not to be economically attractive

  11. Engineering assessment of inactive uranium mill tailings

    Energy Technology Data Exchange (ETDEWEB)

    1981-07-01

    The Grand Junction site has been reevaluated in order to revise the October 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Grand Junction, Colorado. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 1.9 million tons of tailings at the Grand Junction site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation are also factors. The eight alternative actions presented herein range from millsite and off-site decontamination with the addition of 3 m of stabilization cover material (Option I), to removal of the tailings to remote disposal sites and decontamination of the tailings site (Options II through VIII). Cost estimates for the eight options range from about $10,200,000 for stabilization in-place to about $39,500,000 for disposal in the DeBeque area, at a distance of about 35 mi, using transportation by rail. If transportation to DeBeque were by truck, the cost estimated to be about $41,900,000. Three principal alternatives for the reprocessing of the Grand Junction tailings were examined: (a) heap leaching; (b) treatment at an existing mill; and (c) reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be about $200/lb by heap leach and $150/lb by conventional plant processes. The spot market price for uranium was $25/lb early in 1981. Therefore, reprocessing the tailings for uranium recovery appears not to be economically attractive.

  12. Biochemical profiling of histone binding selectivity of the yeast bromodomain family.

    Directory of Open Access Journals (Sweden)

    Qiang Zhang

    2010-01-01

    Full Text Available It has been shown that molecular interactions between site-specific chemical modifications such as acetylation and methylation on DNA-packing histones and conserved structural modules present in transcriptional proteins are closely associated with chromatin structural changes and gene activation. Unlike methyl-lysine that can interact with different protein modules including chromodomains, Tudor and MBT domains, as well as PHD fingers, acetyl-lysine (Kac is known thus far to be recognized only by bromodomains. While histone lysine acetylation plays a crucial role in regulation of chromatin-mediated gene transcription, a high degree of sequence variation of the acetyl-lysine binding site in the bromodomains has limited our understanding of histone binding selectivity of the bromodomain family. Here, we report a systematic family-wide analysis of 14 yeast bromodomains binding to 32 lysine-acetylated peptides derived from known major acetylation sites in four core histones that are conserved in eukaryotes.The histone binding selectivity of purified recombinant yeast bromodomains was assessed by using the native core histones in an overlay assay, as well as N-terminally biotinylated lysine-acetylated histone peptides spotted on streptavidin-coated nitrocellulose membrane in a dot blot assay. NMR binding analysis further validated the interactions between histones and selected bromodomain. Structural models of all yeast bromodomains were built using comparative modeling to provide insights into the molecular basis of their histone binding selectivity.Our study reveals that while not all members of the bromodomain family are privileged to interact with acetylated-lysine, identifiable sequence features from those that bind histone emerge. These include an asparagine residue at the C-terminus of the third helix in the 4-helix bundle, negatively charged residues around the ZA loop, and preponderance of aromatic amino acid residues in the binding pocket

  13. Identification and Interrogation of Combinatorial Histone Modifications

    Directory of Open Access Journals (Sweden)

    Kelly R Karch

    2013-12-01

    Full Text Available Histone proteins are dynamically modified to mediate a variety of cellular processes including gene transcription, DNA damage repair, and apoptosis. Regulation of these processes occurs through the recruitment of non-histone proteins to chromatin by specific combinations of histone post-translational modifications (PTMs. Mass spectrometry has emerged as an essential tool to discover and quantify histone PTMs both within and between samples in an unbiased manner. Developments in mass spectrometry that allow for characterization of large histone peptides or intact protein has made it possible to determine which modifications occur simultaneously on a single histone polypeptide. A variety of techniques from biochemistry, biophysics, and chemical biology have been employed to determine the biological relevance of discovered combinatorial codes. This review first describes advancements in the field of mass spectrometry that have facilitated histone PTM analysis and then covers notable approaches to probe the biological relevance of these modifications in their nucleosomal context.

  14. Ornithine decarboxylase antizyme induces hypomethylation of genome DNA and histone H3 lysine 9 dimethylation (H3K9me2 in human oral cancer cell line.

    Directory of Open Access Journals (Sweden)

    Daisuke Yamamoto

    2010-09-01

    Full Text Available Methylation of CpG islands of genome DNA and lysine residues of histone H3 and H4 tails regulates gene transcription. Inhibition of polyamine synthesis by ornithine decarboxylase antizyme-1 (OAZ in human oral cancer cell line resulted in accumulation of decarboxylated S-adenosylmethionine (dcSAM, which acts as a competitive inhibitor of methylation reactions. We anticipated that accumulation of dcSAM impaired methylation reactions and resulted in hypomethylation of genome DNA and histone tails.Global methylation state of genome DNA and lysine residues of histone H3 and H4 tails were assayed by Methylation by Isoschizomers (MIAMI method and western blotting, respectively, in the presence or absence of OAZ expression. Ectopic expression of OAZ mediated hypomethylation of CpG islands of genome DNA and histone H3 lysine 9 dimethylation (H3K9me2. Protein level of DNA methyltransferase 3B (DNMT3B and histone H3K9me specific methyltransferase G9a were down-regulated in OAZ transfectant.OAZ induced hypomethylation of CpG islands of global genome DNA and H3K9me2 by down-regulating DNMT3B and G9a protein level. Hypomethylation of CpG islands of genome DNA and histone H3K9me2 is a potent mechanism of induction of the genes related to tumor suppression and DNA double strand break repair.

  15. Top-down and Middle-down Protein Analysis Reveals that Intact and Clipped Human Histones Differ in Post-translational Modification Patterns

    DEFF Research Database (Denmark)

    Tvardovskiy, Andrey; Wrzesinski, Krzysztof; Sidoli, Simone

    2015-01-01

    Post-translational modifications (PTMs) of histone proteins play a fundamental role in regulation of DNA-templated processes. There is also growing evidence that proteolytic cleavage of histone N-terminal tails, known as histone clipping, influences nucleosome dynamics and functional properties...... hepatocytes and the hepatocellular carcinoma cell line HepG2/C3A when grown in spheroid (3D) culture, but not in a flat (2D) culture. Using tandem mass spectrometry we localized four different clipping sites in H3 and one clipping site in H2B. We show that in spheroid culture clipped H3 proteoforms are mainly...

  16. Tales of island tails

    NARCIS (Netherlands)

    Groot, de Alma V.; Oost, Albert P.; Veeneklaas, Roos M.; Lammerts, Evert Jan; Duin, van Willem E.; Wesenbeeck, van Bregje K.

    2016-01-01

    The Frisian islands (Southern North Sea) have extensive island tails, i.e. the entire downdrift side of an island consisting of salt marshes, dunes, beaches and beach plains, and green beaches. Currently, large parts of these tails are ageing and losing dynamics, partly due to human influence.

  17. Bar-tailed

    NARCIS (Netherlands)

    Duijns, S.; Hidayati, N.A.; Piersma, T.

    2013-01-01

    Capsule Across the European wintering range Bar-tailed Godwits Limosa lapponica lapponica selected polychaete worms and especially Ragworms Hediste diversicolor, with differences between areas due to variations in prey availability.Aims To determine the diet of Bar-tailed Godwits across their

  18. The Sodium Tail of the Moon

    Science.gov (United States)

    Matta, M.; Smith, S.; Baumgardner, J.; Wilson, J.; Martinis, C.; Mendillo, M.

    2009-01-01

    During the few days centered about new Moon, the lunar surface is optically hidden from Earth-based observers. However, the Moon still offers an observable: an extended sodium tail. The lunar sodium tail is the escaping "hot" component of a coma-like exosphere of sodium generated by photon-stimulated desorption, solar wind sputtering and meteoroid impact. Neutral sodium atoms escaping lunar gravity experience solar radiation pressure that drives them into the anti-solar direction forming a comet-like tail. During new Moon time, the geometry of the Sun, Moon and Earth is such that the anti-sunward sodium flux is perturbed by the terrestrial gravitational field resulting in its focusing into a dense core that extends beyond the Earth. An all-sky camera situated at the El Leoncito Observatory (CASLEO) in Argentina has been successfully imaging this tail through a sodium filter at each lunation since April 2006. This paper reports on the results of the brightness of the lunar sodium tail spanning 31 lunations between April 2006 and September 2008. Brightness variability trends are compared with both sporadic and shower meteor activity, solar wind proton energy flux and solar near ultra violet (NUV) patterns for possible correlations. Results suggest minimal variability in the brightness of the observed lunar sodium tail, generally uncorrelated with any single source, yet consistent with a multi-year period of minimal solar activity and non-intense meteoric fluxes.

  19. Citrullination regulates pluripotency and histone H1 binding to chromatin

    DEFF Research Database (Denmark)

    Christophorou, Maria A; Castelo-Branco, Gonçalo; Halley-Stott, Richard P

    2014-01-01

    citrullination of core histones has been linked to transcriptional regulation and the DNA damage response. PADI4 (also called PAD4 or PADV), the only PADI with a nuclear localization signal, was previously shown to act in myeloid cells where it mediates profound chromatin decondensation during the innate immune...... and activating their expression. Its inhibition lowers the percentage of pluripotent cells in the early mouse embryo and significantly reduces reprogramming efficiency. Using an unbiased proteomic approach we identify linker histone H1 variants, which are involved in the generation of compact chromatin, as novel...... PADI4 substrates. Citrullination of a single arginine residue within the DNA-binding site of H1 results in its displacement from chromatin and global chromatin decondensation. Together, these results uncover a role for citrullination in the regulation of pluripotency and provide new mechanistic...

  20. Histone H4 hyperacetylation and rapid turnover of its acetyl groups in transcriptionally inactive rooster testis spermatids.

    Science.gov (United States)

    Oliva, R; Mezquita, C

    1982-01-01

    In order to study the relationship between acetylation of histones, chromatin structure and gene activity, the distribution and turnover of acetyl groups among nucleosomal core histones and the extent of histone H4 acetylation were examined in rooster testis cell nuclei at different stages of spermatogenesis. Histone H4 was the predominant acetylated histone in mature testes. Hyperacetylation of H4 and rapid turnover of its acetyl groups are not univocally correlated with transcriptional activity since they were detected in both genetically active testicular cells and genetically inactive elongated spermatids. During the transition from nucleohistone to nucleoprotamine in elongated spermatids the chromatin undergoes dramatic structural changes with exposition of binding sites on DNA (1). Hyperacetylation of H4 and rapid turnover of its acetyl groups could be correlated with the particular conformation of chromatin in elongated spermatids and might represent a necessary condition for binding of chromosomal proteins to DNA. Images PMID:7162988

  1. Tailings management at Nabarlek

    International Nuclear Information System (INIS)

    Waggitt, P.

    1989-01-01

    As the entire uranium deposit at Nabarlek was mined in 1979, the mine pit was available as a tailing's repository from the time of commencement of ore processing. In the early years Nabarlek's tailings were deposited subaqueously. In 1985 the tailings deposition method was changed to a sub-aerial, or semi-dry, method. Over the subsequent three years there was evidence that the tailings settled further and squeezed water from lower layers. The water was pumped away and treated for removal of radium before being evaporated in one of the mine's evaporation ponds. When milling was completed in 1988 it was decided to try and increase the rate of water removal and so obtain even greater consolidation of the trailings in a shorter time. This was achieved by loading the tailings with a layer of screened leached sands and waste rock placed on a layer of geotextile filter fabric that had been laid over the whole of the tailings surface in the pit. Once this was completed a modified piling rig was used to insert vertical drains, or wicks, up to 30 metres into the tailings. The drains were placed on a square grid at a spacing of 3.25 metres. Water that was forced out of the tailings by the downward pressure of the sand and rock could flow freely to the surface up these drains. Once at the surface the water was gathered into a sump and pumped away for treatment as before. The drains are working very well at present although it will be some considerable time before the water stops flowing. Already settlement of the tailings is apparent and the settled density of the material is increasing. As far as is known this is the first time that such a system has been employed on mine tailings in a pit in this way

  2. Frost evolution in tailings

    International Nuclear Information System (INIS)

    1991-04-01

    A review was carried out on the physical and thermal mechanisms of permafrost evaluation in soils and uranium tailings. The primary mechanism controlling permafrost evolution is conductive heat transfer with the latent heat of fusion of water being liberated as phase change occurs. Depending on the soil properties and freezing rate, pore water can be expelled from the frost front or pore water can migrate towards the frost front. Solute redistribution may occur as the frost front penetrates into the soil. The rate of frost penetration is a function of the thermal properties of the tailings and the climatic conditions. Computer modelling programmes capable of modelling permafrost evolution were reviewed. The GEOTHERM programme was selected as being the most appropriate for this study. The GEOTHERM programme uses the finite element method of thermal analysis. The ground surface temperature is determined by solving the energy balance equations a the ground surface. The GEOTHERM programme was used to simulate the permafrost evolution in the Key Lake Mine tailings located in north central Saskatchewan. The analyses indicated that the existing frozen zones in the tailing pond will eventually thaw if an average snow depth covers the tailings. Hundreds of years are required to thaw the tailings. If minimal snow cover is present the extent of the frozen zone in the tailings will increase

  3. The Tail of BPM

    Science.gov (United States)

    Kruba, Steve; Meyer, Jim

    Business process management suites (BPMS's) represent one of the fastest growing segments in the software industry as organizations automate their key business processes. As this market matures, it is interesting to compare it to Chris Anderson's 'Long Tail.' Although the 2004 "Long Tail" article in Wired magazine was primarily about the media and entertainment industries, it has since been applied (and perhaps misapplied) to other markets. Analysts describe a "Tail of BPM" market that is, perhaps, several times larger than the traditional BPMS product market. This paper will draw comparisons between the concepts in Anderson's article (and subsequent book) and the BPM solutions market.

  4. Histone Acetylation in Fungal Pathogens of Plants

    Directory of Open Access Journals (Sweden)

    Junhyun Jeon

    2014-03-01

    Full Text Available Acetylation of histone lysine residues occurs in different organisms ranging from yeast to plants and mammals for the regulation of diverse cellular processes. With the identification of enzymes that create or reverse this modification, our understanding on histone acetylation has expanded at an amazing pace during the last two decades. In fungal pathogens of plants, however, the importance of such modification has only just begun to be appreciated in the recent years and there is a dearth of information on how histone acetylation is implicated in fungal pathogenesis. This review covers the current status of research related to histone acetylation in plant pathogenic fungi and considers relevant findings in the interaction between fungal pathogens and host plants. We first describe the families of histone acetyltransferases and deacetylases. Then we provide the cases where histone acetylation was investigated in the context of fungal pathogenesis. Finally, future directions and perspectives in epigenetics of fungal pathogenesis are discussed.

  5. Histone displacement during nucleotide excision repair

    DEFF Research Database (Denmark)

    Dinant, C.; Bartek, J.; Bekker-Jensen, S.

    2012-01-01

    Nucleotide excision repair (NER) is an important DNA repair mechanism required for cellular resistance against UV light and toxic chemicals such as those found in tobacco smoke. In living cells, NER efficiently detects and removes DNA lesions within the large nuclear macromolecular complex called...... of histone variants and histone displacement (including nucleosome sliding). Here we review current knowledge, and speculate about current unknowns, regarding those chromatin remodeling activities that physically displace histones before, during and after NER....

  6. Estimation of Jump Tails

    DEFF Research Database (Denmark)

    Bollerslev, Tim; Todorov, Victor

    We propose a new and flexible non-parametric framework for estimating the jump tails of Itô semimartingale processes. The approach is based on a relatively simple-to-implement set of estimating equations associated with the compensator for the jump measure, or its "intensity", that only utilizes...... the weak assumption of regular variation in the jump tails, along with in-fill asymptotic arguments for uniquely identifying the "large" jumps from the data. The estimation allows for very general dynamic dependencies in the jump tails, and does not restrict the continuous part of the process...... and the temporal variation in the stochastic volatility. On implementing the new estimation procedure with actual high-frequency data for the S&P 500 aggregate market portfolio, we find strong evidence for richer and more complex dynamic dependencies in the jump tails than hitherto entertained in the literature....

  7. Tail posture predicts tail damage among weaned piglets

    NARCIS (Netherlands)

    Zonderland, J.J.; Riel, van J.W.; Bracke, M.B.M.; Kemp, B.; Hartog, den L.A.; Spoolder, H.A.M.

    2009-01-01

    Tail biting in pigs is a widespread behavioural vice with significant animal welfare and economic consequences. All too often, tail biting is not diagnosed nor dealt with until tail damage is present. To effectively reduce the negative effects of tail biting, it must be diagnosed in an early stage.

  8. Human borna disease virus infection impacts host proteome and histone lysine acetylation in human oligodendroglia cells

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Xia [Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016 (China); Department of Neurology, The Fifth People' s Hospital of Shanghai, School of Medicine, Fudan University, Shanghai, 200240 (China); Zhao, Libo [Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016 (China); Department of Neurology, The Third People' s Hospital of Chongqing, 400014 (China); Yang, Yongtao [Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016 (China); Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, 400016 (China); Institute of Neuroscience, Chongqing Medical University, Chongqing, 400016 (China); Bode, Liv [Bornavirus Research Group affiliated to the Free University of Berlin, Berlin (Germany); Huang, Hua [Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016 (China); Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, 400016 (China); Institute of Neuroscience, Chongqing Medical University, Chongqing, 400016 (China); Liu, Chengyu [Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, 400016 (China); Institute of Neuroscience, Chongqing Medical University, Chongqing, 400016 (China); Huang, Rongzhong [Department of Rehabilitative Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010 (China); Zhang, Liang [Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016 (China); Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, 400016 (China); Institute of Neuroscience, Chongqing Medical University, Chongqing, 400016 (China); and others

    2014-09-15

    Background: Borna disease virus (BDV) replicates in the nucleus and establishes persistent infections in mammalian hosts. A human BDV strain was used to address the first time, how BDV infection impacts the proteome and histone lysine acetylation (Kac) of human oligodendroglial (OL) cells, thus allowing a better understanding of infection-driven pathophysiology in vitro. Methods: Proteome and histone lysine acetylation were profiled through stable isotope labeling for cell culture (SILAC)-based quantitative proteomics. The quantifiable proteome was annotated using bioinformatics. Histone acetylation changes were validated by biochemistry assays. Results: Post BDV infection, 4383 quantifiable differential proteins were identified and functionally annotated to metabolism pathways, immune response, DNA replication, DNA repair, and transcriptional regulation. Sixteen of the thirty identified Kac sites in core histones presented altered acetylation levels post infection. Conclusions: BDV infection using a human strain impacted the whole proteome and histone lysine acetylation in OL cells. - Highlights: • A human strain of BDV (BDV Hu-H1) was used to infect human oligodendroglial cells (OL cells). • This study is the first to reveal the host proteomic and histone Kac profiles in BDV-infected OL cells. • BDV infection affected the expression of many transcription factors and several HATs and HDACs.

  9. Human borna disease virus infection impacts host proteome and histone lysine acetylation in human oligodendroglia cells

    International Nuclear Information System (INIS)

    Liu, Xia; Zhao, Libo; Yang, Yongtao; Bode, Liv; Huang, Hua; Liu, Chengyu; Huang, Rongzhong; Zhang, Liang

    2014-01-01

    Background: Borna disease virus (BDV) replicates in the nucleus and establishes persistent infections in mammalian hosts. A human BDV strain was used to address the first time, how BDV infection impacts the proteome and histone lysine acetylation (Kac) of human oligodendroglial (OL) cells, thus allowing a better understanding of infection-driven pathophysiology in vitro. Methods: Proteome and histone lysine acetylation were profiled through stable isotope labeling for cell culture (SILAC)-based quantitative proteomics. The quantifiable proteome was annotated using bioinformatics. Histone acetylation changes were validated by biochemistry assays. Results: Post BDV infection, 4383 quantifiable differential proteins were identified and functionally annotated to metabolism pathways, immune response, DNA replication, DNA repair, and transcriptional regulation. Sixteen of the thirty identified Kac sites in core histones presented altered acetylation levels post infection. Conclusions: BDV infection using a human strain impacted the whole proteome and histone lysine acetylation in OL cells. - Highlights: • A human strain of BDV (BDV Hu-H1) was used to infect human oligodendroglial cells (OL cells). • This study is the first to reveal the host proteomic and histone Kac profiles in BDV-infected OL cells. • BDV infection affected the expression of many transcription factors and several HATs and HDACs

  10. Functional Roles of Acetylated Histone Marks at Mouse Meiotic Recombination Hot Spots

    Science.gov (United States)

    Wu, Zhen; Fallahi, Mohammad; Ouizem, Souad; Liu, Qin; Li, Weimin; Costi, Roberta; Roush, William R.; Bois, Philippe R. J.

    2016-01-01

    ABSTRACT Meiotic recombination initiates following the formation of DNA double-strand breaks (DSBs) by the Spo11 endonuclease early in prophase I, at discrete regions in the genome coined “hot spots.” In mammals, meiotic DSB site selection is directed in part by sequence-specific binding of PRDM9, a polymorphic histone H3 (H3K4Me3) methyltransferase. However, other chromatin features needed for meiotic hot spot specification are largely unknown. Here we show that the recombinogenic cores of active hot spots in mice harbor several histone H3 and H4 acetylation and methylation marks that are typical of open, active chromatin. Further, deposition of these open chromatin-associated histone marks is dynamic and is manifest at spermatogonia and/or pre-leptotene-stage cells, which facilitates PRDM9 binding and access for Spo11 to direct the formation of DSBs, which are initiated at the leptotene stage. Importantly, manipulating histone acetylase and deacetylase activities established that histone acetylation marks are necessary for both hot spot activity and crossover resolution. We conclude that there are functional roles for histone acetylation marks at mammalian meiotic recombination hot spots. PMID:27821479

  11. Markov Tail Chains

    OpenAIRE

    janssen, Anja; Segers, Johan

    2013-01-01

    The extremes of a univariate Markov chain with regularly varying stationary marginal distribution and asymptotically linear behavior are known to exhibit a multiplicative random walk structure called the tail chain. In this paper we extend this fact to Markov chains with multivariate regularly varying marginal distributions in Rd. We analyze both the forward and the backward tail process and show that they mutually determine each other through a kind of adjoint relation. In ...

  12. Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells

    Directory of Open Access Journals (Sweden)

    Yoda Satoshi

    2008-11-01

    Full Text Available Abstract Background Alterations in the processing of the genetic information in carcinogenesis result from stable genetic mutations or epigenetic modifications. It is becoming clear that nucleosomal histones are central to proper gene expression and that aberrant DNA methylation of genes and histone methylation plays important roles in tumor progression. To date, several histone lysine methyltransferases (HKMTs have been identified and histone lysine methylation is now considered to be a critical regulator of transcription. However, still relatively little is known about the role of HKMTs in tumorigenesis. Results We observed differential HKMT expression in a lung cancer model in which normal human bronchial epithelial (NHBE cells expressing telomerase, SV40 large T antigen, and Ras were immortal, formed colonies in soft agar, and expressed specific HKMTs for H3 lysine 9 and 27 residues but not for H3 lysine 4 residue. Modifications in the H3 tails affect the binding of proteins to the histone tails and regulate protein function and the position of lysine methylation marks a gene to be either activated or repressed. In the present study, suppression by siRNA of HKMTs (EZH2, G9A, SETDB1 and SUV39H1 that are over-expressed in immortalized and transformed cells lead to reduced cell proliferation and much less anchorage-independent colony growth. We also found that the suppression of H3-K9, G9A and SUV39H1 induced apoptosis and the suppression of H3-K27, EZH2 caused G1 arrest. Conclusion Our results indicate the potential of these HKMTs in addition to the other targets for epigenetics such as DNMTs and HDACs to be interesting therapeutic targets.

  13. The rapidly evolving centromere-specific histone has stringent functional requirements in Arabidopsis thaliana.

    Science.gov (United States)

    Ravi, Maruthachalam; Kwong, Pak N; Menorca, Ron M G; Valencia, Joel T; Ramahi, Joseph S; Stewart, Jodi L; Tran, Robert K; Sundaresan, Venkatesan; Comai, Luca; Chan, Simon W-L

    2010-10-01

    Centromeres control chromosome inheritance in eukaryotes, yet their DNA structure and primary sequence are hypervariable. Most animals and plants have megabases of tandem repeats at their centromeres, unlike yeast with unique centromere sequences. Centromere function requires the centromere-specific histone CENH3 (CENP-A in human), which replaces histone H3 in centromeric nucleosomes. CENH3 evolves rapidly, particularly in its N-terminal tail domain. A portion of the CENH3 histone-fold domain, the CENP-A targeting domain (CATD), has been previously shown to confer kinetochore localization and centromere function when swapped into human H3. Furthermore, CENP-A in human cells can be functionally replaced by CENH3 from distantly related organisms including Saccharomyces cerevisiae. We have used cenh3-1 (a null mutant in Arabidopsis thaliana) to replace endogenous CENH3 with GFP-tagged variants. A H3.3 tail domain-CENH3 histone-fold domain chimera rescued viability of cenh3-1, but CENH3's lacking a tail domain were nonfunctional. In contrast to human results, H3 containing the A. thaliana CATD cannot complement cenh3-1. GFP-CENH3 from the sister species A. arenosa functionally replaces A. thaliana CENH3. GFP-CENH3 from the close relative Brassica rapa was targeted to centromeres, but did not complement cenh3-1, indicating that kinetochore localization and centromere function can be uncoupled. We conclude that CENH3 function in A. thaliana, an organism with large tandem repeat centromeres, has stringent requirements for functional complementation in mitosis.

  14. Mild performic acid oxidation enhances chromatographic and top down mass spectrometric analyses of histones.

    Science.gov (United States)

    Pesavento, James J; Garcia, Benjamin A; Streeky, James A; Kelleher, Neil L; Mizzen, Craig A

    2007-09-01

    Recent developments in top down mass spectrometry have enabled closely related histone variants and their modified forms to be identified and quantitated with unprecedented precision, facilitating efforts to better understand how histones contribute to the epigenetic regulation of gene transcription and other nuclear processes. It is therefore crucial that intact MS profiles accurately reflect the levels of variants and modified forms present in a given cell type or cell state for the full benefit of such efforts to be realized. Here we show that partial oxidation of Met and Cys residues in histone samples prepared by conventional methods, together with oxidation that can accrue during storage or during chip-based automated nanoflow electrospray ionization, confounds MS analysis by altering the intact MS profile as well as hindering posttranslational modification localization after MS/MS. We also describe an optimized performic acid oxidation procedure that circumvents these problems without catalyzing additional oxidations or altering the levels of posttranslational modifications common in histones. MS and MS/MS of HeLa cell core histones confirmed that Met and Cys were the only residues oxidized and that complete oxidation restored true intact abundance ratios and significantly enhanced MS/MS data quality. This allowed for the unequivocal detection, at the intact molecule level, of novel combinatorially modified forms of H4 that would have been missed otherwise. Oxidation also enhanced the separation of human core histones by reverse phase chromatography and decreased the levels of salt-adducted forms observed in ESI-FTMS. This method represents a simple and easily automated means for enhancing the accuracy and sensitivity of top down analyses of combinatorially modified forms of histones that may also be of benefit for top down or bottom up analyses of other proteins.

  15. Histone H3 is absent from organelle nucleoids in BY-2 cultured tobacco cells.

    Science.gov (United States)

    Takusagawa, Mari; Tamotsu, Satoshi; Sakai, Atsushi

    2013-07-01

    The core histone proteins (H2A, H2B, H3 and H4) are nuclear-localised proteins that play a central role in the formation of nucleosome structure. They have long been considered to be absent from extra-nuclear, DNA-containing organelles; that is plastids and mitochondria. Recently, however, the targeting of core histone H3 to mitochondria, and the presence of nucleosome-like structures in mitochondrial nucleoids, were proposed in cauliflower and tobacco respectively. Thus, we examined whether histone H3 was present in plant organelles and participated in the organisation of nucleoid structure, using highly purified organelles and organelle nucleoids isolated from BY-2 cultured tobacco cells. Immunofluorescence microscopic observations and Western blotting analyses demonstrated that histone H3 was absent from organelles and organelle nucleoids, consistent with the historical hypothesis. Thus, the organisation of organelle nucleoids, including putative nucleosome-like repetitive structures, should be constructed and maintained without participation of histone H3. © 2013 International Federation for Cell Biology.

  16. Characterization of joining sites of a viral histone H4 on host insect chromosomes.

    Directory of Open Access Journals (Sweden)

    Sunil Kumar

    Full Text Available A viral histone H4 (CpBV-H4 is encoded in a polydnavirus, Cotesia plutellae bracovirus (CpBV. It plays a crucial role in parasitism of an endoparasitoid wasp, C. plutellae, against diamondback moth, Plutella xylostella, by altering host gene expression in an epigenetic mode by its N-terminal tail after joining host nucleosomes. Comparative transcriptomic analysis between parasitized and nonparasitized P. xylostella by RNA-Seq indicated that 1,858 genes were altered at more than two folds in expression levels at late parasitic stage, including 877 up-regulated genes and 981 down-regulated genes. Among parasitic factors altering host gene expression, CpBV-H4 alone explained 16.3% of these expressional changes. To characterize the joining sites of CpBV-H4 on host chromosomes, ChIP-Seq (chromatin immunoprecipitation followed by deep sequencing was applied to chromatins extracted from parasitized larvae. It identified specific 538 ChIP targets. Joining sites were rich (60.2% in AT sequence. Almost 40% of ChIP targets included short nucleotide repeat sequences presumably recognizable by transcriptional factors and chromatin remodeling factors. To further validate these CpBV-H4 targets, CpBV-H4 was transiently expressed in nonparasitized host at late larval stage and subjected to ChIP-Seq. Two kinds of ChIP-Seqs shared 51 core joining sites. Common targets were close (within 1 kb to genes regulated at expression levels by CpBV-H4. However, other host genes not close to CpBV-H4 joining sites were also regulated by CpBV-H4. These results indicate that CpBV-H4 joins specific chromatin regions of P. xylostella and controls about one sixth of the total host genes that were regulated by C. plutellae parasitism in an epigenetic mode.

  17. Preferential Phosphorylation on Old Histones during Early Mitosis in Human Cells.

    Science.gov (United States)

    Lin, Shu; Yuan, Zuo-Fei; Han, Yumiao; Marchione, Dylan M; Garcia, Benjamin A

    2016-07-15

    How histone post-translational modifications (PTMs) are inherited through the cell cycle remains poorly understood. Canonical histones are made in the S phase of the cell cycle. Combining mass spectrometry-based technologies and stable isotope labeling by amino acids in cell culture, we question the distribution of multiple histone PTMs on old versus new histones in synchronized human cells. We show that histone PTMs can be grouped into three categories according to their distributions. Most lysine mono-methylation and acetylation PTMs are either symmetrically distributed on old and new histones or are enriched on new histones. In contrast, most di- and tri-methylation PTMs are enriched on old histones, suggesting that the inheritance of different PTMs is regulated distinctly. Intriguingly, old and new histones are distinct in their phosphorylation status during early mitosis in the following three human cell types: HeLa, 293T, and human foreskin fibroblast cells. The mitotic hallmark H3S10ph is predominantly associated with old H3 at early mitosis and becomes symmetric with the progression of mitosis. This same distribution was observed with other mitotic phosphorylation marks, including H3T3/T6ph, H3.1/2S28ph, and H1.4S26ph but not S28/S31ph on the H3 variant H3.3. Although H3S10ph often associates with the neighboring Lys-9 di- or tri-methylations, they are not required for the asymmetric distribution of Ser-10 phosphorylation on the same H3 tail. Inhibition of the kinase Aurora B does not change the distribution despite significant reduction of H3S10ph levels. However, K9me2 abundance on the new H3 is significantly reduced after Aurora B inhibition, suggesting a cross-talk between H3S10ph and H3K9me2. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Extracellular histones induce erythrocyte fragility and anemia.

    Science.gov (United States)

    Kordbacheh, Farzaneh; O'Meara, Connor H; Coupland, Lucy A; Lelliott, Patrick M; Parish, Christopher R

    2017-12-28

    Extracellular histones have been shown to play an important pathogenic role in many diseases, primarily through their cytotoxicity toward nucleated cells and their ability to promote platelet activation with resultant thrombosis and thrombocytopenia. In contrast, little is known about the effect of extracellular histones on erythrocyte function. We demonstrate in this study that histones promote erythrocyte aggregation, sedimentation, and using a novel in vitro shear stress model, we show that histones induce erythrocyte fragility and lysis in a concentration-dependent manner. Furthermore, histones impair erythrocyte deformability based on reduced passage of erythrocytes through an artificial spleen. These in vitro results were mirrored in vivo with the injection of histones inducing anemia within minutes of administration, with a concomitant increase in splenic hemoglobin content. Thrombocytopenia and leukopenia were also observed. These findings suggest that histones binding to erythrocytes may contribute to the elevated erythrocyte sedimentation rates observed in inflammatory conditions. Furthermore, histone-induced increases in red blood cell lysis and splenic clearance may be a significant factor in the unexplained anemias seen in critically ill patients. © 2017 by The American Society of Hematology.

  19. Histone modifications and nuclear architecture: A review

    Czech Academy of Sciences Publication Activity Database

    Bártová, Eva; Kroupová, Jana; Harničarová, Andrea; Galiová-Šustáčková, Gabriela; Kozubek, Stanislav

    2008-01-01

    Roč. 56, č. 8 (2008), s. 711-721 ISSN 0722-186X R&D Projects: GA ČR(CZ) GA204/06/0978; GA MŠk(CZ) LC535 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : histones * histone modifications * nuclear architecture Subject RIV: BO - Biophysics

  20. Uranium mill tailings stabilization

    International Nuclear Information System (INIS)

    Hartley, J.N.; Koehmstedt, P.L.; Esterl, D.J.; Freeman, H.D.

    1980-02-01

    Uranium mill tailings pose a potential radiation health hazard to the public. Therefore, stabilization or disposal of these tailings in a safe and environmentally sound way is needed to minimize radon exhalation and other environmental hazards. One of the most promising concepts for stabilizing U tailings is the use of asphalt emulsion to contain radon and other hazardous materials within uranium tailings. This approach is being investigated at the Pacific Northwest Laboratory. Results of these studies indicate that a radon flux reduction of greater than 99% can be obtained using either a poured-on/sprayed-on seal (3.0 to 7.0 mm thick) or an admixture seal (2.5 to 12.7 cm thick) containing about 18 wt % residual asphalt. A field test was carried out in June 1979 at the Grand Junction tailings pile in order to demonstrate the sealing process. A reduction in radon flux ranging from 4.5 to greater than 99% (76% average) was achieved using a 15.2-cm (6-in.) admix seal with a sprayed-on top coat. A hydrostatic stabilizer was used to apply the admix. Following compaction, a spray coat seal was applied over the admix as the final step in construction of a radon seal. Overburden was applied to provide a protective soil layer over the seal. Included in part of the overburden was a herbicide to prevent root penetration

  1. Liquefaction of uranium tailings

    International Nuclear Information System (INIS)

    1992-02-01

    Numerical methods for assessing the liquefaction potential of soils are reviewed with a view to their application to uranium tailings. The method can be divided into two categories: total stress analysis, where changes in pore pressure are not considered in the soil model, and effective stress analysis, where changes in pore pressure are included in the soil model. Effective stress analysis is more realistic, but few computer programs exist for such analysis in two or three dimensions. A simple linearized, two-dimensional, finite element effective stress analysis which incorporates volumetric compaction due to shear motion is described and implemented. The new program is applied to the assessment of liquefaction potential of tailings in the Quirke Mine tailings area near Elliot Lake, Ontario. The results are compared with those of a total stress analysis. Both analyses indicate liquefaction would occur if a magnitude 6.0 earthquake were to occur near the area. However, the extent of liquefaction predicted by the effective stress analysis is much less than that predicted by the total stress analysis. The results of both methods are sensitive to assumed material properties and to the method used to determine the cyclic shear strength of the tailings. Further analysis, incorporating more in situ and/or laboratory data, is recommended before conclusions can be made concerning the dynamic stability of these tailings

  2. Mine tailings disposal

    International Nuclear Information System (INIS)

    Gonzales, P.A.; Adams, B.J.

    1980-06-01

    The hydrologic evaluation of mine tailings disposal sites after they are abandoned is considered in relation to their potential environmental impact on a long term basis. There is a direct relation between the amounts and types of water leaving a disposal site and the severity of the potential damage to the environment. The evaluation of the relative distribution of the precipitation reaching the ground into evaporation, runoff and infiltration is obtained for a selected site and type of tailings material whose characteristics and physical properties were determined in the soils laboratory. A conceptual model of the hydrologic processes involved and the corresponding mathematical model were developed to simulate the physical system. A computer program was written to solve the set of equations forming the mathematical model, considering the physical properties of the tailings and the rainfall data selected. The results indicate that the relative distribution of the precipitation depends on the surface and upper layer of the tailings and that the position of the groundwater table is governed by the flow through the bottom of the profile considered. The slope of the surface of the mass of tailings was found to be one of the principal factors affecting the relative distribution of precipitation and, therefore, the potential pollution of the environment

  3. Structure and Functions of Linker Histones.

    Science.gov (United States)

    Lyubitelev, A V; Nikitin, D V; Shaytan, A K; Studitsky, V M; Kirpichnikov, M P

    2016-03-01

    Linker histones such as variants H1, H5, and other similar proteins play an important role in regulation of chromatin structure and dynamics. However, interactions of linker histones with DNA and proteins, as well as specific functions of their different variants, are poorly studied. This is because they acquire tertiary structure only when interacting with a nucleosome, and because of limitations of currently available methods. However, deeper investigation of linker histones and their interactions with other proteins will address a number of important questions - from structure of compacted chromatin to regulation of early embryogenesis. In this review, structures of histone H1 variants and its interaction with chromatin DNA are considered. A possible functional significance of different H1 variants, a role of these proteins in maintaining interphase chromatin structure, and interactions of linker histones with other cellular proteins are also discussed.

  4. The histone deacetylase inhibitor Trichostatin A modulates CD4+ T cell responses

    DEFF Research Database (Denmark)

    Moreira, José Manuel Alfonso; Scheipers, Peter; Sørensen, Poul

    2003-01-01

    though several genes modulated by HDAC inhibition have been identified, those genes clearly responsible for the biological effects of these drugs have remained elusive. We investigated the pharmacological effect of the HDACI and potential anti-cancer agent Trichostatin A (TSA) on primary T cells.......Histone deacetylase inhibitors (HDACIs) induce hyperacetylation of core histones modulating chromatin structure and affecting gene expression. These compounds are also able to induce growth arrest, cell differentiation, and apoptotic cell death of tumor cells in vitro as well as in vivo. Even...

  5. Uranium mill tailings

    International Nuclear Information System (INIS)

    McLaren, L.H.

    1982-11-01

    This bibliography contains information on uranium mill tailings included in the Department of Energy's Energy Data Base from January 1981 through October 1982. The abstracts are grouped by subject category as shown in the table of contents. Entries in the subject index also facilitate access by subject, e.g., Mill Tailings/Radiation Hazards. Within each category the arrangement is by report number for reports, followed by nonreports in reverse chronological order. These citations are to research reports, journal articles, books, patents, theses, and conference papers from worldwide sources. Five indexes, each preceded by a brief description, are provided: Corporate Author, Personal Author, Subject, Contract Number, and Report Number. (335 abstracts)

  6. Computer-aided Molecular Design of Compounds Targeting Histone Modifying Enzymes

    Science.gov (United States)

    Andreoli, Federico; Del Rio, Alberto

    2015-01-01

    Growing evidences show that epigenetic mechanisms play crucial roles in the genesis and progression of many physiopathological processes. As a result, research in epigenetic grew at a fast pace in the last decade. In particular, the study of histone post-translational modifications encountered an extraordinary progression and many modifications have been characterized and associated to fundamental biological processes and pathological conditions. Histone modifications are the catalytic result of a large set of enzyme families that operate covalent modifications on specific residues at the histone tails. Taken together, these modifications elicit a complex and concerted processing that greatly contribute to the chromatin remodeling and may drive different pathological conditions, especially cancer. For this reason, several epigenetic targets are currently under validation for drug discovery purposes and different academic and industrial programs have been already launched to produce the first pre-clinical and clinical outcomes. In this scenario, computer-aided molecular design techniques are offering important tools, mainly as a consequence of the increasing structural information available for these targets. In this mini-review we will briefly discuss the most common types of known histone modifications and the corresponding operating enzymes by emphasizing the computer-aided molecular design approaches that can be of use to speed-up the efforts to generate new pharmaceutically relevant compounds. PMID:26082827

  7. Recurrent Gene Duplication Leads to Diverse Repertoires of Centromeric Histones in Drosophila Species.

    Science.gov (United States)

    Kursel, Lisa E; Malik, Harmit S

    2017-06-01

    Despite their essential role in the process of chromosome segregation in most eukaryotes, centromeric histones show remarkable evolutionary lability. Not only have they been lost in multiple insect lineages, but they have also undergone gene duplication in multiple plant lineages. Based on detailed study of a handful of model organisms including Drosophila melanogaster, centromeric histone duplication is considered to be rare in animals. Using a detailed phylogenomic study, we find that Cid, the centromeric histone gene, has undergone at least four independent gene duplications during Drosophila evolution. We find duplicate Cid genes in D. eugracilis (Cid2), in the montium species subgroup (Cid3, Cid4) and in the entire Drosophila subgenus (Cid5). We show that Cid3, Cid4, and Cid5 all localize to centromeres in their respective species. Some Cid duplicates are primarily expressed in the male germline. With rare exceptions, Cid duplicates have been strictly retained after birth, suggesting that they perform nonredundant centromeric functions, independent from the ancestral Cid. Indeed, each duplicate encodes a distinct N-terminal tail, which may provide the basis for distinct protein-protein interactions. Finally, we show some Cid duplicates evolve under positive selection whereas others do not. Taken together, our results support the hypothesis that Drosophila Cid duplicates have subfunctionalized. Thus, these gene duplications provide an unprecedented opportunity to dissect the multiple roles of centromeric histones. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  8. Histone and ribosomal RNA repetitive gene clusters of the boll weevil are linked in a tandem array.

    Science.gov (United States)

    Roehrdanz, R; Heilmann, L; Senechal, P; Sears, S; Evenson, P

    2010-08-01

    Histones are the major protein component of chromatin structure. The histone family is made up of a quintet of proteins, four core histones (H2A, H2B, H3 & H4) and the linker histones (H1). Spacers are found between the coding regions. Among insects this quintet of genes is usually clustered and the clusters are tandemly repeated. Ribosomal DNA contains a cluster of the rRNA sequences 18S, 5.8S and 28S. The rRNA genes are separated by the spacers ITS1, ITS2 and IGS. This cluster is also tandemly repeated. We found that the ribosomal RNA repeat unit of at least two species of Anthonomine weevils, Anthonomus grandis and Anthonomus texanus (Coleoptera: Curculionidae), is interspersed with a block containing the histone gene quintet. The histone genes are situated between the rRNA 18S and 28S genes in what is known as the intergenic spacer region (IGS). The complete reiterated Anthonomus grandis histone-ribosomal sequence is 16,248 bp.

  9. Chromatin condensation in terminally differentiating mouse erythroblasts does not involve special architectural proteins but depends on histone deacetylation

    Energy Technology Data Exchange (ETDEWEB)

    Popova, Evgenya Y.; Krauss, Sharon Wald; Short, Sarah A.; Lee, Gloria; Villalobos, Jonathan; Etzell, Joan; Koury, Mark J.; Ney, Paul A.; Chasis, Joel Anne; Grigoryev, Sergei A.

    2008-08-21

    Terminal erythroid differentiation in vertebrates is characterized by progressive heterochromatin formation, chromatin condensation and, in mammals, culminates in nuclear extrusion. To date, although mechanisms regulating avian erythroid chromatin condensation have been identified, little is known regarding this process during mammalian erythropoiesis. To elucidate the molecular basis for mammalian erythroblast chromatin condensation, we used Friend virus-infected murine spleen erythroblasts that undergo terminal differentiation in vitro. Chromatin isolated from early and late stage erythroblasts had similar levels of linker and core histones, only a slight difference in nucleosome repeats, and no significant accumulation of known developmentally-regulated architectural chromatin proteins. However, histone H3(K9) dimethylation markedly increased while histone H4(K12) acetylation dramatically decreased and became segregated from the histone methylation as chromatin condensed. One histone deacetylase, HDAC5, was significantly upregulated during the terminal stages of Friend virus-infected erythroblast differentiation. Treatment with histone deacetylase inhibitor, trichostatin A, blocked both chromatin condensation and nuclear extrusion. Based on our data, we propose a model for a unique mechanism in which extensive histone deacetylation at pericentromeric heterochromatin mediates heterochromatin condensation in vertebrate erythroblasts that would otherwise be mediated by developmentally-regulated architectural proteins in nucleated blood cells.

  10. MS_HistoneDB, a manually curated resource for proteomic analysis of human and mouse histones.

    Science.gov (United States)

    El Kennani, Sara; Adrait, Annie; Shaytan, Alexey K; Khochbin, Saadi; Bruley, Christophe; Panchenko, Anna R; Landsman, David; Pflieger, Delphine; Govin, Jérôme

    2017-01-01

    Histones and histone variants are essential components of the nuclear chromatin. While mass spectrometry has opened a large window to their characterization and functional studies, their identification from proteomic data remains challenging. Indeed, the current interpretation of mass spectrometry data relies on public databases which are either not exhaustive (Swiss-Prot) or contain many redundant entries (UniProtKB or NCBI). Currently, no protein database is ideally suited for the analysis of histones and the complex array of mammalian histone variants. We propose two proteomics-oriented manually curated databases for mouse and human histone variants. We manually curated >1700 gene, transcript and protein entries to produce a non-redundant list of 83 mouse and 85 human histones. These entries were annotated in accordance with the current nomenclature and unified with the "HistoneDB2.0 with Variants" database. This resource is provided in a format that can be directly read by programs used for mass spectrometry data interpretation. In addition, it was used to interpret mass spectrometry data acquired on histones extracted from mouse testis. Several histone variants, which had so far only been inferred by homology or detected at the RNA level, were detected by mass spectrometry, confirming the existence of their protein form. Mouse and human histone entries were collected from different databases and subsequently curated to produce a non-redundant protein-centric resource, MS_HistoneDB. It is dedicated to the proteomic study of histones in mouse and human and will hopefully facilitate the identification and functional study of histone variants.

  11. Histone deacetylases (HDACs and brain function

    Directory of Open Access Journals (Sweden)

    Claude-Henry Volmar

    2015-01-01

    Full Text Available Modulation of gene expression is a constant and necessary event for mammalian brain function. An important way of regulating gene expression is through the remodeling of chromatin, the complex of DNA, and histone proteins around which DNA wraps. The “histone code hypothesis” places histone post-translational modifications as a significant part of chromatin remodeling to regulate transcriptional activity. Acetylation of histones by histone acetyl transferases and deacetylation by histone deacetylases (HDACs at lysine residues are the most studied histone post-translational modifications in cognition and neuropsychiatric diseases. Here, we review the literature regarding the role of HDACs in brain function. Among the roles of HDACs in the brain, studies show that they participate in glial lineage development, learning and memory, neuropsychiatric diseases, and even rare neurologic diseases. Most HDACs can be targeted with small molecules. However, additional brain-penetrant specific inhibitors with high central nervous system exposure are needed to determine the cause-and-effect relationship between individual HDACs and brain-associated diseases.

  12. Managing 'tail liability'.

    Science.gov (United States)

    Frese, Richard C; Weber, Ryan J

    2013-11-01

    To reduce and control their level of tail liability, hospitals should: Utilize a self-insurance vehicle; Consider combined limits between the hospital and physicians; Communicate any program changes to the actuary, underwriter, and auditor; Continue risk management and safety practices; Ensure credit is given to the organization's own medical malpractice program.

  13. Antibodies to H2a and H2b histones from the sera of HIV-infected patients catalyze site-specific degradation of these histones.

    Science.gov (United States)

    Baranova, Svetlana V; Dmitrienok, Pavel S; Ivanisenko, Nikita V; Buneva, Valentina N; Nevinsky, Georgy A

    2017-06-01

    Histones and their post-translational modifications have key roles in chromatin remodeling and gene transcription. Besides intranuclear functions, histones act as damage-associated molecules when they are released into the extracellular space. Administration of histones to animals leads to systemic inflammatory and toxic responses. Autoantibodies with enzymatic activities (abzymes) are distinctive features of some autoimmune and viral diseases. Electrophoretically homogeneous IgGs containing no canonical enzymes were isolated from the sera of HIV-infected patients by chromatography on several affinity sorbents including anti-histone Sepharose. In contrast to canonical proteases (trypsin, chymotrypsin, proteinase K), IgGs from HIV-infected patients specifically hydrolyzed only histones but not many other tested globular proteins. Using MALDI mass spectrometry the sites of H2a and H2b histone cleavage by anti-histone IgGs were determined for the first time. One cluster of H2a hydrolysis contains two major (↕) and four moderate (↓) cleavage sites: 31-H↓R↓L↓L↓R↕K G↕N-38. One major and two moderate sites of cleavage were revealed in the second cluster: 14-A↕KSRS↓SRA↓G-22. The third cluster corresponding to the H2a C-terminal part contains only five minor (†) sites of cleavage: 82-H†LQLAIRNDEELN†KLLG†RV†T†I-102. It was shown that two major and four moderate sites of cleavage were present in the main cluster of H2b hydrolysis: 46-K↕QvhpD↓TgiS↓SkA↓M↕GiM↓N-63. Two moderate sites of cleavage correspond to a relatively short 6-mer cluster: 12-K↓GskK↓A-17. The third relatively long 9-mer cluster contains one major and two minor sites of H2b cleavage: 80-L↕AHYN†KRS†T-88. In the nucleosome core particle, most of the major and moderate cleavage sites are located at the H2a/H2b interaction interface. Minor cleavage sites of H2a are involved in binding with H3 in the nucleosome core. Two moderate cleavage sites of H2b and one

  14. Molecular mechanisms and potential functions of histone demethylases

    DEFF Research Database (Denmark)

    Kooistra, Susanne Marije; Helin, Kristian

    2012-01-01

    of two families of enzymes that can demethylate histones has changed this notion. The biochemical activities of these histone demethylases towards specific Lys residues on histones, and in some cases non-histone substrates, have highlighted their importance in developmental control, cell-fate decisions...

  15. Chromatin replication and histone dynamics

    DEFF Research Database (Denmark)

    Alabert, Constance; Jasencakova, Zuzana; Groth, Anja

    2017-01-01

    Inheritance of the DNA sequence and its proper organization into chromatin is fundamental for genome stability and function. Therefore, how specific chromatin structures are restored on newly synthesized DNA and transmitted through cell division remains a central question to understand cell fate...... choices and self-renewal. Propagation of genetic information and chromatin-based information in cycling cells entails genome-wide disruption and restoration of chromatin, coupled with faithful replication of DNA. In this chapter, we describe how cells duplicate the genome while maintaining its proper...... organization into chromatin. We reveal how specialized replication-coupled mechanisms rapidly assemble newly synthesized DNA into nucleosomes, while the complete restoration of chromatin organization including histone marks is a continuous process taking place throughout the cell cycle. Because failure...

  16. Histone modifications in response to DNA damage

    International Nuclear Information System (INIS)

    Altaf, Mohammed; Saksouk, Nehme; Cote, Jacques

    2007-01-01

    The packaging of the eukaryotic genome into highly condensed chromatin makes it inaccessible to the factors required for gene transcription, DNA replication, recombination and repair. Eukaryotes have developed intricate mechanisms to overcome this repressive barrier imposed by chromatin. Histone modifying enzymes and ATP-dependent chromatin remodeling complexes play key roles here as they regulate many nuclear processes by altering the chromatin structure. Significantly, these activities are integral to the process of DNA repair where histone modifications act as signals and landing platforms for various repair proteins. This review summarizes the recent developments in our understanding of histone modifications and their role in the maintenance of genome integrity

  17. Histone demethylases in development and disease

    DEFF Research Database (Denmark)

    Pedersen, Marianne Terndrup; Helin, Kristian

    2010-01-01

    Histone modifications serve as regulatory marks that are instrumental for the control of transcription and chromatin architecture. Strict regulation of gene expression patterns is crucial during development and differentiation, where diverse cell types evolve from common predecessors. Since...... the first histone lysine demethylase was discovered in 2004, a number of demethylases have been identified and implicated in the control of gene expression programmes and cell fate decisions. Histone demethylases are now emerging as important players in developmental processes and have been linked to human...

  18. Uranium mill tailings conditioning technology

    International Nuclear Information System (INIS)

    Dreesen, D.R.; Cokal, E.J.; Wangen, L.E.; Williams, J.M.; O'Brien, P.D.; Thode, E.F.

    1982-01-01

    Conditioning of uranium mill tailings involves the physicochemical alteration of tailings to remove or immobilize mobile radionuclides and toxic trace elements before disposal in a repository. The principal immobilization approach under investigation is sintering tailings at high temperatures (1100-1200 deg. C) to radically alter the structure of tailings. This thermal stabilization at 1200 deg. C reduced radon emanation power for tailings sands by factors of 20 to 200 and for tailings fines by factors of 300 to 1100. Substantial reductions in the leachability of most contaminants have been found for thermally conditioned tailings. Obvious mineral transformations occur, including an increase in amorphous material, the conversion of gypsum to anhydrite and its subsequent decomposition, the disappearance of clay minerals, and some decrease in quartz content. A conceptual thermal stabilization process has been developed wherein obsolete coal-fired rotary cement kilns perform the sintering. An economic analysis of this conceptual process has shown that thermal stabilization can be competitive at certain tailings sites with other remedial actions requiring the excavation, transportation, and burial of tailings in a repository. An analysis of the long-term radiological hazard posed by untreated tailings and by tailings conditioned by radionuclide removal has illustrated the necessity of extracting both 226 Ra and 230 Th to achieve long-term hazard reductions. Sulphuric acid extraction of residual mineral values and important radionuclides from tailings has been investigated. Concentrated H 2 SO 4 can extract up to 80% of the 226 Ra, 70% of the Ba, and 90% of the 230 Th from tailings in a single stage extraction. An economic analysis of a sulphuric acid leach process was made to determine whether the value of minerals recovered from tailings would offset the leaching cost. For one relatively mineral-rich tailings pile, the U and V values would more than pay for the

  19. Detection of histone acetylation levels in the dorsal hippocampus reveals early tagging on specific residues of H2B and H4 histones in response to learning.

    Directory of Open Access Journals (Sweden)

    Olivier Bousiges

    Full Text Available The recent literature provides evidence that epigenetic mechanisms such as DNA methylation and histone modification are crucial to gene transcription linked to synaptic plasticity in the mammalian brain--notably in the hippocampus--and memory formation. We measured global histone acetylation levels in the rat hippocampus at an early stage of spatial or fear memory formation. We found that H3, H4 and H2B underwent differential acetylation at specific sites depending on whether rats had been exposed to the context of a task without having to learn or had to learn about a place or fear therein: H3K9K14 acetylation was mostly responsive to any experimental conditions compared to naive animals, whereas H2B N-terminus and H4K12 acetylations were mostly associated with memory for either spatial or fear learning. Altogether, these data suggest that behavior/experience-dependent changes differently regulate specific acetylation modifications of histones in the hippocampus, depending on whether a memory trace is established or not: tagging of H3K9K14 could be associated with perception/processing of testing-related manipulations and context, thereby enhancing chromatin accessibility, while tagging of H2B N-terminus tail and H4K12 could be more closely associated with the formation of memories requiring an engagement of the hippocampus.

  20. Telling tails: selective pressures acting on investment in lizard tails.

    Science.gov (United States)

    Fleming, Patricia A; Valentine, Leonie E; Bateman, Philip W

    2013-01-01

    Caudal autotomy is a common defense mechanism in lizards, where the animal may lose part or all of its tail to escape entrapment. Lizards show an immense variety in the degree of investment in a tail (i.e., length) across species, with tails of some species up to three or four times body length (snout-vent length [SVL]). Additionally, body size and form also vary dramatically, including variation in leg development and robustness and length of the body and tail. Autotomy is therefore likely to have fundamentally different effects on the overall body form and function in different species, which may be reflected directly in the incidence of lost/regenerating tails within populations or, over a longer period, in terms of relative tail length for different species. We recorded data (literature, museum specimens, field data) for relative tail length (n=350 species) and the incidence of lost/regenerating tails (n=246 species). We compared these (taking phylogeny into account) with intrinsic factors that have been proposed to influence selective pressures acting on caudal autotomy, including body form (robustness, body length, leg development, and tail specialization) and ecology (foraging behavior, physical and temporal niches), in an attempt to identify patterns that might reflect adaptive responses to these different factors. More gracile species have relatively longer tails (all 350 spp., P lost/regenerating tails for nocturnal lizards (all 246 spp., P pressure.

  1. Uranium tailings in Canada

    International Nuclear Information System (INIS)

    Boulden, R.S.; Bragg, K.

    1982-01-01

    The last few years have produced significant changes in the way uranium tailings are managed in Canada. This is due both to the development of new technology and to changes in regulatory approach. The interrelationships between these two areas are examined with particular attention paid to the long term and the development of close-out criteria. New technological initiatives are examined including dry placement techniques, pit disposal and deep lake disposal

  2. Histone Lysine Methylation in Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Guang-dong Sun

    2014-01-01

    Full Text Available Diabetic nephropathy (DN belongs to debilitating microvascular complications of diabetes and is the leading cause of end-stage renal diseases worldwide. Furthermore, outcomes from the DCCT/EDIC study showed that DN often persists and progresses despite intensive glucose control in many diabetes patients, possibly as a result of prior episode of hyperglycemia, which is called “metabolic memory.” The underlying mechanisms responsible for the development and progression of DN remain poorly understood. Activation of multiple signaling pathways and key transcription factors can lead to aberrant expression of DN-related pathologic genes in target renal cells. Increasing evidence suggests that epigenetic mechanisms in chromatin such as DNA methylation, histone acetylation, and methylation can influence the pathophysiology of DN and metabolic memory. Exciting researches from cell culture and experimental animals have shown that key histone methylation patterns and the related histone methyltransferases and histone demethylases can play important roles in the regulation of inflammatory and profibrotic genes in renal cells under diabetic conditions. Because histone methylation is dynamic and potentially reversible, it can provide a window of opportunity for the development of much-needed novel therapeutic potential for DN in the future. In this minireview, we discuss recent advances in the field of histone methylation and its roles in the pathogenesis and progression of DN.

  3. Extracellular histones in tissue injury and inflammation.

    Science.gov (United States)

    Allam, Ramanjaneyulu; Kumar, Santhosh V R; Darisipudi, Murthy N; Anders, Hans-Joachim

    2014-05-01

    Neutrophil NETosis is an important element of host defense as it catapults chromatin out of the cell to trap bacteria, which then are killed, e.g., by the chromatin's histone component. Also, during sterile inflammation TNF-alpha and other mediators trigger NETosis, which elicits cytotoxic effects on host cells. The same mechanism should apply to other forms of regulated necrosis including pyroptosis, necroptosis, ferroptosis, and cyclophilin D-mediated regulated necrosis. Beyond these toxic effects, extracellular histones also trigger thrombus formation and innate immunity by activating Toll-like receptors and the NLRP3 inflammasome. Thereby, extracellular histones contribute to the microvascular complications of sepsis, major trauma, small vessel vasculitis as well as acute liver, kidney, brain, and lung injury. Finally, histones prevent the degradation of extracellular DNA, which promotes autoimmunization, anti-nuclear antibody formation, and autoimmunity in susceptible individuals. Here, we review the current evidence on the pathogenic role of extracellular histones in disease and discuss how to target extracellular histones to improve disease outcomes.

  4. Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors.

    Directory of Open Access Journals (Sweden)

    Oliver N F King

    2010-11-01

    Full Text Available Small molecule modulators of epigenetic processes are currently sought as basic probes for biochemical mechanisms, and as starting points for development of therapeutic agents. N(ε-Methylation of lysine residues on histone tails is one of a number of post-translational modifications that together enable transcriptional regulation. Histone lysine demethylases antagonize the action of histone methyltransferases in a site- and methylation state-specific manner. N(ε-Methyllysine demethylases that use 2-oxoglutarate as co-factor are associated with diverse human diseases, including cancer, inflammation and X-linked mental retardation; they are proposed as targets for the therapeutic modulation of transcription. There are few reports on the identification of templates that are amenable to development as potent inhibitors in vivo and large diverse collections have yet to be exploited for the discovery of demethylase inhibitors.High-throughput screening of a ∼236,000-member collection of diverse molecules arrayed as dilution series was used to identify inhibitors of the JMJD2 (KDM4 family of 2-oxoglutarate-dependent histone demethylases. Initial screening hits were prioritized by a combination of cheminformatics, counterscreening using a coupled assay enzyme, and orthogonal confirmatory detection of inhibition by mass spectrometric assays. Follow-up studies were carried out on one of the series identified, 8-hydroxyquinolines, which were shown by crystallographic analyses to inhibit by binding to the active site Fe(II and to modulate demethylation at the H3K9 locus in a cell-based assay.These studies demonstrate that diverse compound screening can yield novel inhibitors of 2OG dependent histone demethylases and provide starting points for the development of potent and selective agents to interrogate epigenetic regulation.

  5. Injurious tail biting in pigs

    DEFF Research Database (Denmark)

    D'Eath, R.B.; Amott, G.; Turner, S. P.

    2014-01-01

    not allow tail docking at all. Against this background, using a novel approach focusing on research where tail injuries were quantified, we review the measures that can be used to control tail biting in pigs without tail docking. Using this strict criterion, there was good evidence that manipulable...... substrates and feeder space affect damaging tail biting. Only epidemiological evidence was available for effects of temperature and season, and the effect of stocking density was unclear. Studies suggest that group size has little effect, and the effects of nutrition, disease and breed require further...... underlying processes of tail biting. A quantitative comparison of the efficacy of different methods of provision of manipulable materials, and a review of current practices in countries and assurance schemes where tail docking is banned, both suggest that daily provision of small quantities of destructible...

  6. Simplified Method for Rapid Purification of Soluble Histones

    Directory of Open Access Journals (Sweden)

    Nives Ivić

    2016-06-01

    Full Text Available Functional and structural studies of histone-chaperone complexes, nucleosome modifications, their interactions with remodelers and regulatory proteins rely on obtaining recombinant histones from bacteria. In the present study, we show that co-expression of Xenopus laevis histone pairs leads to production of soluble H2AH2B heterodimer and (H3H42 heterotetramer. The soluble histone complexes are purified by simple chromatographic techniques. Obtained H2AH2B dimer and H3H4 tetramer are proficient in histone chaperone binding and histone octamer and nucleosome formation. Our optimized protocol enables rapid purification of multiple soluble histone variants with a remarkable high yield and simplifies histone octamer preparation. We expect that this simple approach will contribute to the histone chaperone and chromatin research. This work is licensed under a Creative Commons Attribution 4.0 International License.

  7. Replication stress interferes with histone recycling and predeposition marking of new histones

    DEFF Research Database (Denmark)

    Jasencakova, Zuzana; Scharf, Annette N D; Ask, Katrine

    2010-01-01

    To restore chromatin on new DNA during replication, recycling of histones evicted ahead of the fork is combined with new histone deposition. The Asf1 histone chaperone, which buffers excess histones under stress, is a key player in this process. Yet how histones handled by human Asf1 are modified...... remains unclear. Here we identify marks on histones H3-H4 bound to Asf1 and changes induced upon replication stress. In S phase, distinct cytosolic and nuclear Asf1b complexes show ubiquitous H4K5K12diAc and heterogeneous H3 marks, including K9me1, K14ac, K18ac, and K56ac. Upon acute replication arrest......, the predeposition mark H3K9me1 and modifications typical of chromatin accumulate in Asf1 complexes. In parallel, ssDNA is generated at replication sites, consistent with evicted histones being trapped with Asf1. During recovery, histones stored with Asf1 are rapidly used as replication resumes. This shows...

  8. A brief histone in time: understanding the combinatorial functions of histone PTMs in the nucleosome context.

    Science.gov (United States)

    Ng, Marlee K; Cheung, Peter

    2016-02-01

    It has been over 50 years since Allfrey et al. proposed that histone acetylation regulates RNA synthesis, and the study of histone modifications has progressed at an extraordinary pace for the past two decades. In this review, we provide a perspective on some key events and advances in our understanding of histone modifications. We also highlight reagents and tools from past to present that facilitated progress in this research field. Using histone H3 phosphorylation as an underlying thread, we review the rationale that led to the proposal of the histone code hypothesis, as well as examples that illustrate the concepts of combinatorial histone modifications and cross-talk pathways. We further highlight the importance of investigating these mechanisms in the context of nucleosomes rather than just at the histone level and present current and developing approaches for such studies. Overall, research on histone modifications has yielded great mechanistic insights into the regulation of genomic functions, and extending these studies using nucleosomes will further elucidate the complexity of these pathways in a more physiologically relevant context.

  9. Organ distribution of histones after intravenous infusion of FITC histones or after sepsis.

    Science.gov (United States)

    Fattahi, Fatemeh; Grailer, Jamison J; Jajou, Lawrence; Zetoune, Firas S; Andjelkovic, Anuska V; Ward, Peter A

    2015-03-01

    Histones appear in plasma during infectious or non-infectious sepsis and are associated with multiorgan injury. In the current studies, intravenous infusion of histones resulted in their localization in major organs. In vitro exposure of mouse macrophages to histones caused a buildup of histones on cell membranes followed by localization into cytosol and into the nucleus. After polymicrobial sepsis (cecal ligation and puncture), histones appeared in plasma as well as in a multiorgan pattern, peaking at 8 h followed by decline. In lungs, histones and neutrophils appeared together, with evidence for formation of neutrophil extracellular traps (NETs), which represent an innate immune response to trap and kill bacteria and other infectious agents. In liver, there was intense NET formation, featuring linear patterns containing histones and strands of DNA. When neutrophils were activated in vitro with C5a or phorbol myristate acetate, NET formation ensued. While formation of NETs represents entrapment and killing of infectious agents, the simultaneous release from neutrophils of histones often results in tissue/organ damage.

  10. Organ Distribution of Histones after Intravenous Infusion of FITC-Histones or after Sepsis

    Science.gov (United States)

    Fattahi, Fatemeh; Grailer, Jamison J.; Jajou, Lawrence; Zetoune, Firas S.; Andjelkovic, Anuska V.; Ward, Peter A.

    2015-01-01

    Histones appear in plasma during infectious or non-infectious sepsis and are associated with multiorgan injury. In the current studies, intravenous infusion of histones resulted in their localization in major organs. In vitro exposure of mouse macrophages to histones caused a buildup of histones on cell membranes followed by localization into cytosol and into the nucleus. After polymicrobial sepsis (cecal ligation and puncture, CLP), histones appeared in plasma as well as in a multiorgan pattern, peaking at 8 hr followed by decline. In lungs, histones and neutrophils appeared together, with evidence for formation of neutrophil extracellular traps (NETs), which represent an innate immune response to trap and kill bacteria and other infectious agents. In liver, there was intense NET formation, featuring linear patterns containing histones and strands of DNA. When neutrophils were activated in vitro with C5a or phorbol myristate acetate, NET formation ensued. While formation of NETs represents entrapment and killing of infectious agents, the simultaneous release from neutrophils of histones often results in tissue/organ damage. PMID:25680340

  11. The histones of the endosymbiont alga of Peridinium balticum (Dinophyceae).

    Science.gov (United States)

    Rizzo, P J; Morris, R L; Zweidler, A

    1988-01-01

    The histones of the endosymbiont nucleus of the binucleate dinoflagellate Peridinium balticum were characterized by amino acid analysis and peptide mapping, and compared to calf thymus histones. Using these and various other criteria we have identified two H1-like histones as well as the highly conserved histones H3 and H4. A 13,000 dalton component in sodium dodecyl sulphate (SDS) gels can be separated into two components in Triton-containing gels. We suggest that these histones (HPb1 and HPb2) correspond to the vertebrate histones H2A and H2B, respectively.

  12. Regulation of replication fork progression through histone supply and demand

    DEFF Research Database (Denmark)

    Groth, Anja; Corpet, Armelle; Cook, Adam J L

    2007-01-01

    DNA replication in eukaryotes requires nucleosome disruption ahead of the replication fork and reassembly behind. An unresolved issue concerns how histone dynamics are coordinated with fork progression to maintain chromosomal stability. Here, we characterize a complex in which the human histone c...... progression and histone supply and demand.......1 chaperone function, histone supply, and replicative unwinding of DNA in chromatin. We propose that Asf1, as a histone acceptor and donor, handles parental and new histones at the replication fork via an Asf1-(H3-H4)-MCM2-7 intermediate and thus provides a means to fine-tune replication fork...

  13. Meiosis-Specific Loading of the Centromere-Specific Histone CENH3 in Arabidopsis thaliana

    Science.gov (United States)

    Ravi, Maruthachalam; Shibata, Fukashi; Ramahi, Joseph S.; Nagaki, Kiyotaka; Chen, Changbin; Murata, Minoru; Chan, Simon W. L.

    2011-01-01

    Centromere behavior is specialized in meiosis I, so that sister chromatids of homologous chromosomes are pulled toward the same side of the spindle (through kinetochore mono-orientation) and chromosome number is reduced. Factors required for mono-orientation have been identified in yeast. However, comparatively little is known about how meiotic centromere behavior is specialized in animals and plants that typically have large tandem repeat centromeres. Kinetochores are nucleated by the centromere-specific histone CENH3. Unlike conventional histone H3s, CENH3 is rapidly evolving, particularly in its N-terminal tail domain. Here we describe chimeric variants of CENH3 with alterations in the N-terminal tail that are specifically defective in meiosis. Arabidopsis thaliana cenh3 mutants expressing a GFP-tagged chimeric protein containing the H3 N-terminal tail and the CENH3 C-terminus (termed GFP-tailswap) are sterile because of random meiotic chromosome segregation. These defects result from the specific depletion of GFP-tailswap protein from meiotic kinetochores, which contrasts with its normal localization in mitotic cells. Loss of the GFP-tailswap CENH3 variant in meiosis affects recruitment of the essential kinetochore protein MIS12. Our findings suggest that CENH3 loading dynamics might be regulated differently in mitosis and meiosis. As further support for our hypothesis, we show that GFP-tailswap protein is recruited back to centromeres in a subset of pollen grains in GFP-tailswap once they resume haploid mitosis. Meiotic recruitment of the GFP-tailswap CENH3 variant is not restored by removal of the meiosis-specific cohesin subunit REC8. Our results reveal the existence of a specialized loading pathway for CENH3 during meiosis that is likely to involve the hypervariable N-terminal tail. Meiosis-specific CENH3 dynamics may play a role in modulating meiotic centromere behavior. PMID:21695238

  14. Small molecule inhibitors of histone deacetylases and acetyltransferases as potential therapeutics in oncology

    NARCIS (Netherlands)

    van den Bosch, Thea; Leus, Niek; Timmerman, Tirza; Dekker, Frank J

    2016-01-01

    Uncontrolled cell proliferation and resistance to apoptosis in cancer are, among others, regulated by post-translational modifications of histone proteins. The most investigated type of histone modification is lysine acetylation. Histone acetyltransferases (HATs), acetylate histone lysine residues,

  15. Histones bundle F-actin filaments and affect actin structure.

    Directory of Open Access Journals (Sweden)

    Edna Blotnick

    Full Text Available Histones are small polycationic proteins complexed with DNA located in the cell nucleus. Upon apoptosis they are secreted from the cells and react with extracellular polyanionic compounds. Actin which is a polyanionic protein, is also secreted from necrotic cells and interacts with histones. We showed that both histone mixture (histone type III and the recombinant H2A histone bundles F-actin, increases the viscosity of the F-actin containing solution and polymerizes G-actin. The histone-actin bundles are relatively insensitive to increase of ionic strength, unlike other polycation, histatin, lysozyme, spermine and LL-37 induced F-actin bundles. The histone-actin bundles dissociate completely only in the presence of 300-400 mM NaCl. DNA, which competes with F-actin for histones, disassembles histone induced actin bundles. DNase1, which depolymerizes F- to G-actin, actively unbundles the H2A histone induced but slightly affects the histone mixture induced actin bundles. Cofilin decreases the amount of F-actin sedimented by low speed centrifugation, increases light scattering and viscosity of F-actin-histone mixture containing solutions and forms star like superstructures by copolymerizing G-actin with H2A histone. The results indicate that histones are tightly attached to F-actin by strong electrostatic and hydrophobic forces. Since both histones and F-actin are present in the sputum of patients with cystic fibrosis, therefore, the formation of the stable histone-actin bundles can contribute to the pathology of this disease by increasing the viscosity of the sputum. The actin-histone interaction in the nucleus might affect gene expression.

  16. Histones bundle F-actin filaments and affect actin structure.

    Science.gov (United States)

    Blotnick, Edna; Sol, Asaf; Muhlrad, Andras

    2017-01-01

    Histones are small polycationic proteins complexed with DNA located in the cell nucleus. Upon apoptosis they are secreted from the cells and react with extracellular polyanionic compounds. Actin which is a polyanionic protein, is also secreted from necrotic cells and interacts with histones. We showed that both histone mixture (histone type III) and the recombinant H2A histone bundles F-actin, increases the viscosity of the F-actin containing solution and polymerizes G-actin. The histone-actin bundles are relatively insensitive to increase of ionic strength, unlike other polycation, histatin, lysozyme, spermine and LL-37 induced F-actin bundles. The histone-actin bundles dissociate completely only in the presence of 300-400 mM NaCl. DNA, which competes with F-actin for histones, disassembles histone induced actin bundles. DNase1, which depolymerizes F- to G-actin, actively unbundles the H2A histone induced but slightly affects the histone mixture induced actin bundles. Cofilin decreases the amount of F-actin sedimented by low speed centrifugation, increases light scattering and viscosity of F-actin-histone mixture containing solutions and forms star like superstructures by copolymerizing G-actin with H2A histone. The results indicate that histones are tightly attached to F-actin by strong electrostatic and hydrophobic forces. Since both histones and F-actin are present in the sputum of patients with cystic fibrosis, therefore, the formation of the stable histone-actin bundles can contribute to the pathology of this disease by increasing the viscosity of the sputum. The actin-histone interaction in the nucleus might affect gene expression.

  17. Histones induce rapid and profound thrombocytopenia in mice

    Science.gov (United States)

    Bhandari, Ashish A.

    2011-01-01

    Histones are released from dying cells and contribute to antimicrobial defense during infection. However, extracellular histones are a double-edged sword because they also damage host tissue and may cause death. We studied the interactions of histones with platelets. Histones bound to platelets, induced calcium influx, and recruited plasma adhesion proteins such as fibrinogen to induce platelet aggregation. Hereby fibrinogen cross-linked histone-bearing platelets and triggered microaggregation. Fibrinogen interactions with αIIbβ3 integrins were not required for this process but were necessary for the formation of large platelet aggregates. Infused histones associated with platelets in vivo and caused a profound thrombocytopenia within minutes after administration. Mice lacking platelets or αIIbβ3 integrins were protected from histone-induced death but not from histone-induced tissue damage. Heparin, at high concentrations, prevented histone interactions with platelets and protected mice from histone-induced thrombocytopenia, tissue damage, and death. Heparin and histones are evolutionary maintained. Histones may combine microbicidal with prothrombotic properties to fight invading microbes and maintain hemostasis after injury. Heparin may provide an innate counter mechanism to neutralize histones and diminish collateral tissue damage. PMID:21700775

  18. Settlement of uranium mill tailings

    International Nuclear Information System (INIS)

    Chen, P.K.; Guros, F.B.; Keshian, B.

    1988-01-01

    Two test embankments were constructed on top of an old tailings deposit near Ambrosia Lake, New Mexico to determine settlement characteristics of hydraulically- deposited uranium mill tailings. Before construction of the embankments, properties of in-situ tailings and foundation soils were determined using data from boreholes, piezocone soundings, and laboratory tests. These properties were used to estimate post-construction settlement of a planned disposal embankment to be constructed on the tailings. However, excessive uncertainty existed in the following: field settlement rates of saturated and unsaturated tailings, degree of preconsolidation of the upper 15 feet of tailings, and the ability of an underlying silty sand foundation layer to facilitate drainage. Thus, assurance could not be provided that differential settlements of the radon barrier and erosion protection layers would be within allowable limits should the planned disposal embankment be constructed in a single-stage

  19. Copper tailings in stucco mortars

    Directory of Open Access Journals (Sweden)

    Osvaldo Pavez

    Full Text Available Abstract This investigation addressed the evaluation of the use of copper tailings in the construction industry in order to reduce the impact on the environment. The evaluation was performed by a technical comparison between stucco mortars prepared with crushed conventional sand and with copper tailings sand. The best results were achieved with the stucco mortars containing tailings. The tailings presented a fine particles size distribution curve different from that suggested by the standard. The values of compressive strength, retentivity, and adherence in the stucco mortars prepared with copper tailings were much higher than those obtained with crushed sand. According to the results from this study, it can be concluded that the preparation of stucco mortars using copper tailings replacing conventional sand is a technically feasible alternative for the construction industry, presenting the benefit of mitigating the impact of disposal to the environment.

  20. Uranium tailings reference materials

    International Nuclear Information System (INIS)

    Smith, C.W.; Steger, H.F.; Bowman, W.S.

    1984-01-01

    Samples of uranium tailings from Bancroft and Elliot Lake, Ontario, and from Beaverlodge and Rabbit Lake, Saskatchewan, have been prepared as compositional reference materials at the request of the National Uranium Tailings Research Program. The four samples, UTS-1 to UTS-4, were ground to minus 104 μm, each mixed in one lot and bottled in 200-g units for UTS-1 to UTS-3 and in 100-g units for UTS-4. The materials were tested for homogeneity with respect to uranium by neutron activation analysis and to iron by an acid-decomposition atomic absorption procedure. In a free choice analytical program, 18 laboratories contributed results for one or more of total iron, titanium, aluminum, calcium, barium, uranium, thorium, total sulphur, and sulphate for all four samples, and for nickel and arsenic in UTS-4 only. Based on a statistical analysis of the data, recommended values were assigned to all elements/constituents, except for sulphate in UTS-3 and nickel in UTS-4. The radioactivity of thorium-230, radium-226, lead-210, and polonium-210 in UTS-1 to UTS-4 and of thorium-232, radium-228, and thorium-228 in UTS-1 and UTS-2 was determined in a radioanalytical program composed of eight laboratories. Recommended values for the radioactivities and associated parameters were calculated by a statistical treatment of the results

  1. Bioassay for uranium mill tailings

    International Nuclear Information System (INIS)

    Tschaeche, A.N.

    1986-01-01

    Uranium mill tailings are composed of fine sand that contains, among other things, some uranium (U/sup 238/ primarily), and all of the uranium daughters starting with /sup 230/Th that are left behind after the usable uranium is removed in the milling process. Millions of pounds of tailings are and continue to be generated at uranium mills around the United States. Discrete uranium mill tailings piles exist near the mills. In addition, the tailings materials were used in communities situated near mill sites for such purposes as building materials, foundations for buildings, pipe runs, sand boxes, gardens, etc. The Uranium Mill Tailings Remedial Action Project (UMTRAP) is a U.S. Department of Energy Program designed with the intention of removing or stabilizing the mill tailings piles and the tailings used to communities so that individuals are not exposed above the EPA limits established for such tailings materials. This paper discusses the bioassay programs that are established for workers who remove tailings from the communities in which they are placed

  2. Uranium mill tailings and radon

    International Nuclear Information System (INIS)

    Hanchey, L.A.

    1981-01-01

    The major health hazard from uranium mill tailings is presumed to be respiratory cancer resulting from the inhalation of radon daughter products. A review of studies on inhalation of radon and its daughters indicates that the hazard from the tailings is extremely small. If the assumptions used in the studies are correct, one or two people per year in the US may develop cancer as a result of radon exhaled from all the Uranium Mill Tailings Remedial Action Program sites. The remedial action should reduce the hazard from the tailings by a factor of about 100

  3. Uranium mill tailings and radon

    Energy Technology Data Exchange (ETDEWEB)

    Hanchey, L A

    1981-04-01

    The major health hazard from uranium mill tailings is presumed to be respiratory cancer resulting from the inhalation of radon daughter products. A review of studies on inhalation of radon and its daughters indicates that the hazard from the tailings is extremely small. If the assumptions used in the studies are correct, one or two people per year in the United States may develop cancer as a result of radon exhaled from all the Uranium Mill Tailings Remedial Action program sites. The remedial action should reduce the hazard from the tailings by a factor of about 100.

  4. Uranium mill tailings and radon

    Energy Technology Data Exchange (ETDEWEB)

    Hanchey, L A

    1981-01-01

    The major health hazard from uranium mill tailings is presumed to be respiratory cancer resulting from the inhalation of radon daughter products. A review of studies on inhalation of radon and its daughters indicates that the hazard from the tailings is extremely small. If the assumptions used in the studies are correct, one or two people per year in the US may develop cancer as a result of radon exhaled from all the Uranium Mill Tailings Remedial Action Program sites. The remedial action should reduce the hazard from the tailings by a factor of about 100.

  5. Summary of the engineering assessment of inactive uranium mill tailings

    International Nuclear Information System (INIS)

    1981-07-01

    The Grand Junction site has been reevaluated in order to revise the october 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Grand Junction, Colorado. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 1.9 million tons of tailings at the Grand Junction site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation are also factors. The eight alternative actions presented herein range from millsite and off-site decontamination with the addition of 3 m of stabilization cover material (Option I), to removal of the tailings to remote disposal sites and decontamination of the tailings site (Option II through VIII). Cost estimates for the eight options range from about $10,200,000 for stabilization in-place to about $39,500,000 for disposal in the DeBeque area, at a distance of about 35 mi, using transportation by rail. If transportation to DeBeque were by truck, the cost is estimated to be about $41,900,000. Three prinicpal alternatives for the reprocessing of the Grand Junction tailings were examined: (a) heap leaching; (b) treatment at an existing mill; and (c) reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be about $200/lb by heap leach and $150/lb by conventional plant processes. The spot market price for uranium was $25/lb early in 1981. Therefore, reprocessing the tailings for uranium recovery appears not to be economically attractive

  6. DNA methylation requires a DNMT1 ubiquitin interacting motif (UIM) and histone ubiquitination.

    Science.gov (United States)

    Qin, Weihua; Wolf, Patricia; Liu, Nan; Link, Stephanie; Smets, Martha; La Mastra, Federica; Forné, Ignasi; Pichler, Garwin; Hörl, David; Fellinger, Karin; Spada, Fabio; Bonapace, Ian Marc; Imhof, Axel; Harz, Hartmann; Leonhardt, Heinrich

    2015-08-01

    DNMT1 is recruited by PCNA and UHRF1 to maintain DNA methylation after replication. UHRF1 recognizes hemimethylated DNA substrates via the SRA domain, but also repressive H3K9me3 histone marks with its TTD. With systematic mutagenesis and functional assays, we could show that chromatin binding further involved UHRF1 PHD binding to unmodified H3R2. These complementation assays clearly demonstrated that the ubiquitin ligase activity of the UHRF1 RING domain is required for maintenance DNA methylation. Mass spectrometry of UHRF1-deficient cells revealed H3K18 as a novel ubiquitination target of UHRF1 in mammalian cells. With bioinformatics and mutational analyses, we identified a ubiquitin interacting motif (UIM) in the N-terminal regulatory domain of DNMT1 that binds to ubiquitinated H3 tails and is essential for DNA methylation in vivo. H3 ubiquitination and subsequent DNA methylation required UHRF1 PHD binding to H3R2. These results show the manifold regulatory mechanisms controlling DNMT1 activity that require the reading and writing of epigenetic marks by UHRF1 and illustrate the multifaceted interplay between DNA and histone modifications. The identification and functional characterization of the DNMT1 UIM suggests a novel regulatory principle and we speculate that histone H2AK119 ubiquitination might also lead to UIM-dependent recruitment of DNMT1 and DNA methylation beyond classic maintenance.

  7. Beyond Histones: New Substrate Proteins of Lysine Deacetylases in Arabidopsis Nuclei

    Directory of Open Access Journals (Sweden)

    Magdalena Füßl

    2018-04-01

    Full Text Available The reversible acetylation of lysine residues is catalyzed by the antagonistic action of lysine acetyltransferases and deacetylases, which can be considered as master regulators of their substrate proteins. Lysine deacetylases, historically referred to as histone deacetylases, have profound functions in regulating stress defenses and development in plants. Lysine acetylation of the N-terminal histone tails promotes gene transcription and decondensation of chromatin, rendering the DNA more accessible to the transcription machinery. In plants, the classical lysine deacetylases from the RPD3/HDA1-family have thus far mainly been studied in the context of their deacetylating activities on histones, and their versatility in molecular activities is still largely unexplored. Here we discuss the potential impact of lysine acetylation on the recently identified nuclear substrate proteins of lysine deacetylases from the Arabidopsis RPD3/HDA1-family. Among the deacetylase substrate proteins, many interesting candidates involved in nuclear protein import, transcriptional regulation, and chromatin remodeling have been identified. These candidate proteins represent key starting points for unraveling new molecular functions of the Arabidopsis lysine deacetylases. Site-directed engineering of lysine acetylation sites on these target proteins might even represent a new approach for optimizing plant growth under climate change conditions.

  8. Histone H4 Lysine 20 methylation

    DEFF Research Database (Denmark)

    Jørgensen, Stine; Schotta, Gunnar; Sørensen, Claus Storgaard

    2013-01-01

    of histones have emerged as key regulators of genomic integrity. Intense research during the past few years has revealed histone H4 lysine 20 methylation (H4K20me) as critically important for the biological processes that ensure genome integrity, such as DNA damage repair, DNA replication and chromatin...... compaction. The distinct H4K20 methylation states are mediated by SET8/PR-Set7 that catalyses monomethylation of H4K20, whereas SUV4-20H1 and SUV4-20H2 enzymes mediate further H4K20 methylation to H4K20me2 and H4K20me3. Disruption of these H4K20-specific histone methyltransferases leads to genomic...

  9. Chemical and semisynthesis of modified histones.

    Science.gov (United States)

    Maity, Suman Kumar; Jbara, Muhammad; Brik, Ashraf

    2016-05-01

    Post-translational modifications (PTMs) of histones play critical roles in the epigenetic regulation of eukaryotic genome by directly altering the biophysical properties of chromatin or by recruiting effector proteins. The large number of PTMs and the inherent complexity in their population and signaling processes make it highly challenging to understand epigenetics-related processes. To address these challenges, accesses to homogeneously modified histones are obligatory. Over the last decade, synthetic protein chemists have been devising novel synthetic tools and applying state-of-the-art chemoselective ligation strategies to prepare precious materials useful in answering fundamental questions in this area. In this short review, we cover some of the recent breakthroughs in these directions in particular the synthesis and semi-synthesis of modified histones and their use to unravel the mysteries of epigenetics. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  10. Distribution pattern of histone H3 phosphorylation at serine 10 ...

    Indian Academy of Sciences (India)

    2013-08-06

    Aug 6, 2013 ... tant consequences for chromatin packing due to change in histone load ... Minas Gerais, Brazil), in B. brizantha (cultivar Marandu, ... (2005), who state that the ..... Mitotic microtubule development and histone H3 phosphoryla-.

  11. Histone Methylation and Epigenetic Silencing in Breast Cancer

    National Research Council Canada - National Science Library

    Simon, Jeffrey A; Lange, Carol A

    2008-01-01

    .... EZH2 is a histone methyltransferase which modifies lysine-27 of histone H3 an epigenetic mark which is generally linked to gene silencing and is implicated in tumor suppressor silencing during breast cancer progression...

  12. Nickel compounds induce histone ubiquitination by inhibiting histone deubiquitinating enzyme activity

    International Nuclear Information System (INIS)

    Ke Qingdong; Ellen, Thomas P.; Costa, Max

    2008-01-01

    Nickel (Ni) compounds are known carcinogens but underlying mechanisms are not clear. Epigenetic changes are likely to play an important role in nickel ion carcinogenesis. Previous studies have shown epigenetic effects of nickel ions, including the loss of histone acetylation and a pronounced increase in dimethylated H3K9 in nickel-exposed cells. In this study, we demonstrated that both water-soluble and insoluble nickel compounds induce histone ubiquitination (uH2A and uH2B) in a variety of cell lines. Investigations of the mechanism by which nickel increases histone ubiquitination in cells reveal that nickel does not affect cellular levels of the substrates of this modification, i.e., ubiquitin, histones, and other non-histone ubiquitinated proteins. In vitro ubiquitination and deubiquitination assays have been developed to further investigate possible effects of nickel on enzymes responsible for histone ubiquitination. Results from the in vitro assays demonstrate that the presence of nickel did not affect the levels of ubiquitinated histones in the ubiquitinating assay. Instead, the addition of nickel significantly prevents loss of uH2A and uH2B in the deubiquitinating assay, suggesting that nickel-induced histone ubiquitination is the result of inhibition of (a) putative deubiquitinating enzyme(s). Additional supporting evidence comes from the comparison of the response to nickel ions with a known deubiquitinating enzyme inhibitor, iodoacetamide (IAA). This study is the first to demonstrate such effects of nickel ions on histone ubiquitination. It also sheds light on the possible mechanisms involved in altering the steady state of this modification. The study provides further evidence that supports the notion that nickel ions alter epigenetic homeostasis in cells, which may lead to altered programs of gene expression and carcinogenesis

  13. TAIL ASYMPTOTICS OF LIGHT-TAILED WEIBULL-LIKE SUMS

    DEFF Research Database (Denmark)

    Asmussen, Soren; Hashorva, Enkelejd; Laub, Patrick J.

    2017-01-01

    We consider sums of n i.i.d. random variables with tails close to exp{-x(beta)} for some beta > 1. Asymptotics developed by Rootzen (1987) and Balkema, Kluppelberg, and Resnick (1993) are discussed from the point of view of tails rather than of densities, using a somewhat different angle...

  14. Developing selective histone deacetylases (HDACs) inhibitors through ebselen and analogs.

    Science.gov (United States)

    Wang, Yuren; Wallach, Jason; Duane, Stephanie; Wang, Yuan; Wu, Jianghong; Wang, Jeffrey; Adejare, Adeboye; Ma, Haiching

    2017-01-01

    Histone deacetylases (HDACs) are key regulators of gene expression in cells and have been investigated as important therapeutic targets for cancer and other diseases. Different subtypes of HDACs appear to play disparate roles in the cells and are associated with specific diseases. Therefore, substantial effort has been made to develop subtype-selective HDAC inhibitors. In an effort to discover existing scaffolds with HDAC inhibitory activity, we screened a drug library approved by the US Food and Drug Administration and a National Institutes of Health Clinical Collection compound library in HDAC enzymatic assays. Ebselen, a clinical safe compound, was identified as a weak inhibitor of several HDACs, including HDAC1, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, and HDAC9 with half maximal inhibitory concentrations approximately single digit of µM. Two ebselen analogs, ebselen oxide and ebsulfur (a diselenide analog of ebselen), also inhibited these HDACs, however with improved potencies on HDAC8. Benzisothiazol, the core structure of ebsulfur, specifically inhibited HDAC6 at a single digit of µM but had no inhibition on other HDACs. Further efforts on structure-activity relationship based on the core structure of ebsulfur led to the discovery of a novel class of potent and selective HDAC6 inhibitors with RBC-2008 as the lead compound with single-digit nM potency. This class of histone deacetylase inhibitor features a novel pharmacophore with an ebsulfur scaffold selectively targeting HDAC6. Consistent with its inhibition on HDAC6, RBC-2008 significantly increased the acetylation levels of α-tubulin in PC-3 cells. Furthermore, treatment with these compounds led to cell death of multiple tumor cell lines in a dose-dependent manner. These results demonstrated that ebselen and ebsulfur analogs are inhibitors of HDACs, supporting further preclinical development of this class of compounds for potential therapeutic applications.

  15. Plant Responses to Abiotic Stress Regulated by Histone Deacetylases

    Directory of Open Access Journals (Sweden)

    Ming Luo

    2017-12-01

    Full Text Available In eukaryotic cells, histone acetylation and deacetylation play an important role in the regulation of gene expression. Histone acetylation levels are modulated by histone acetyltransferases and histone deacetylases (HDACs. Recent studies indicate that HDACs play essential roles in the regulation of gene expression in plant response to environmental stress. In this review, we discussed the recent advance regarding the plant HDACs and their functions in the regulation of abiotic stress responses. The role of HDACs in autophagy was also discussed.

  16. Histones as mediators of host defense, inflammation and thrombosis

    OpenAIRE

    Hoeksema, Marloes; van Eijk, Martin; Haagsman, Henk P; Hartshorn, Kevan L

    2016-01-01

    Histones are known for their ability to bind to and regulate expression of DNA. However, histones are also present in cytoplasm and extracellular fluids where they serve host defense functions and promote inflammatory responses. Histones are a major component of neutrophil extracellular traps that contribute to bacterial killing but also to inflammatory injury. Histones can act as antimicrobial peptides and directly kill bacteria, fungi, parasites and viruses, in vitro and in a variety of ani...

  17. Biological significance of lysine mono-, di- and trimethylation on histone and non-histone proteins

    International Nuclear Information System (INIS)

    Perez-Burgos, L.

    2006-01-01

    Histones are the proteins that compact DNA into the repeating unit of chromatin known as the nucleosome. The N-termini of histones are subject to a series of post-translational modifications, one of which is methylation. This modification is termed 'epigenetic' because it extends the information encoded in the genome. Lysines can be mono-, di- or tri-methylated at different positions on histones H1, H3 and H4. In order to study the biological role of histone lysine methylation, antibodies were generated against mono-, di- and trimethylated H3-K9 and H3-27. Indeed, different chromatin domains in the mouse nucleus are enriched in distinct forms of histone lysine methylation, such as pericentric heterochromatin and the inactive X chromosome. Interestingly, heterochromatin in Arabidopsis thaliana is enriched in the mono- and di-, but not the trimethylated form of H3-K9. Furthermore, there exists a hierarchy of epigenetic modifications in which H3-K9 trimethylation is found to be upstream of DNA methylation on mouse major satellites. Histone lysine methylation is also involved in gene regulation upon development. One example is the chicken 61538;-globin locus, a region of facultative chromatin that undergoes a loss of di- and trimethylated H3-K27 in mature red blood cells, concomitant with expression of the 61538;-globin genes. SET-domain proteins are enzymes that methylate histones, but some of them are also able to methylate non-histone substrates. In particular, p53 is methylated by Set9 on lysine 372, G9a and Glp-1 on lysine 373 and by Smyd2 on lysine 370. Smyd2 transcript levels are greatly increased upon irradiation and dimethylated p53-370 specifically binds to 53BP1, a protein involved in recognizing DNA double-stranded breaks upon ionizing radiation. These results argue for a novel role of p53-K370 methylation in the biology of DNA damage. In summary, lysine methylation is a post-translational modification that can occur both on histone and non-histone proteins

  18. Structural insights into the regulation and the recognition of histone marks by the SET domain of NSD1

    International Nuclear Information System (INIS)

    Morishita, Masayo; Di Luccio, Eric

    2011-01-01

    Highlights: → NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1 are histone methyltransferases linked to numerous cancers. → Little is known about the NSD pathways and HMTase inhibitors are sorely needed in the epigenetic therapy of cancers. → We investigate the regulation and the recognition of histone marks by the SET domain of NSD1. → A unique and key mechanism is driven by a loop at the interface of the SET and postSET region. → Implications for developing specific and selective HMTase inhibitors are presented. -- Abstract: The development of epigenetic therapies fuels cancer hope. DNA-methylation inhibitors, histone-deacetylase and histone-methyltransferase (HMTase) inhibitors are being developed as the utilization of epigenetic targets is emerging as an effective and valuable approach to chemotherapy as well as chemoprevention of cancer. The nuclear receptor binding SET domain (NSD) protein is a family of three HMTases, NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1 that are critical in maintaining the chromatin integrity. A growing number of studies have reported alterations or amplifications of NSD1, NSD2, or NSD3 in numerous carcinogenic events. Reducing NSDs activity through specific lysine-HMTase inhibitors appears promising to help suppressing cancer growth. However, little is known about the NSD pathways and our understanding of the histone lysine-HMTase mechanism is partial. To shed some light on both the recognition and the regulation of epigenetic marks by the SET domain of the NSD family, we investigate the structural mechanisms of the docking of the histone-H4 tail on the SET domain of NSD1. Our finding exposes a key regulatory and recognition mechanism driven by the flexibility of a loop at the interface of the SET and postSET region. Finally, we prospect the special value of this regulatory region for developing specific and selective NSD inhibitors for the epigenetic therapy of cancers.

  19. Specific phosphorylation of histone demethylase KDM3A determines target gene expression in response to heat shock.

    Directory of Open Access Journals (Sweden)

    Mo-bin Cheng

    2014-12-01

    Full Text Available Histone lysine (K residues, which are modified by methyl- and acetyl-transferases, diversely regulate RNA synthesis. Unlike the ubiquitously activating effect of histone K acetylation, the effects of histone K methylation vary with the number of methyl groups added and with the position of these groups in the histone tails. Histone K demethylases (KDMs counteract the activity of methyl-transferases and remove methyl group(s from specific K residues in histones. KDM3A (also known as JHDM2A or JMJD1A is an H3K9me2/1 demethylase. KDM3A performs diverse functions via the regulation of its associated genes, which are involved in spermatogenesis, metabolism, and cell differentiation. However, the mechanism by which the activity of KDM3A is regulated is largely unknown. Here, we demonstrated that mitogen- and stress-activated protein kinase 1 (MSK1 specifically phosphorylates KDM3A at Ser264 (p-KDM3A, which is enriched in the regulatory regions of gene loci in the human genome. p-KDM3A directly interacts with and is recruited by the transcription factor Stat1 to activate p-KDM3A target genes under heat shock conditions. The demethylation of H3K9me2 at the Stat1 binding site specifically depends on the co-expression of p-KDM3A in the heat-shocked cells. In contrast to heat shock, IFN-γ treatment does not phosphorylate KDM3A via MSK1, thereby abrogating its downstream effects. To our knowledge, this is the first evidence that a KDM can be modified via phosphorylation to determine its specific binding to target genes in response to thermal stress.

  20. Effects of weather and tailings properties on tailings drying times

    Energy Technology Data Exchange (ETDEWEB)

    Gantzer, C.; Fasking, T.; Costello, M.; Greenwood, J. [Barr Engineering, Calgary, AB (Canada)

    2010-07-01

    This PowerPoint presentation presented the results of a study conducted to determine the effects of weather and tailings properties on tailings drying times. Weather conditions have a significant impact the potential evaporation (PE) and actual evaporation (AE) of oil sands tailings. A 2-stage drying of slurry at a constant PE was conducted to determine the shrinkage limit of untreated mature fine tailings (MFT). An evaporation and seepage model was used to determine maximum first-stage drying rates. Measurements were also taken in a wind tunnel. Potential evaporation rates were calculated and evaporative water losses from the MFT were determined. Estimated drying times were presented. Results of the approach were compared with field measurements conducted in a previous study. Results of the study showed that evaporative water loss rates for May through August were limited by the properties of the tailings. Water loss rates were limited by weather for other months in the year-long study. tabs., figs.

  1. Trichostatin A induced histone acetylation causes decondensation of interphase chromatin.

    NARCIS (Netherlands)

    T.A. Knoch (Tobias); M. Wachsmuth (Malte); M. Frank-Stöhr (Monika); M. Stöhr (Michael); C.P. Bacher (Christian); K. Rippe (Karsten)

    2004-01-01

    textabstractThe effect of trichostatin A (TSA)-induced histone acetylation on the interphase chromatin structure was visualized in vivo with a HeLa cell line stably expressing histone H2A, which was fused to enhanced yellow fluorescent protein. The globally increased histone acetylation caused a

  2. Biochemical studies on histones of the central nervous system. 2

    International Nuclear Information System (INIS)

    Schmitt, M.; Matthies, H.

    1979-01-01

    There are no qualitative differences in the electrophoretic patterns of histones from neurones and glia. A 25% increased acetylation rate is found in neutronal histones as compared to glial histones after incubation of chopped brain in a [ 14 C]-acetate containing medium. This result probably reflects different condensation states of the chromatins of both cell types, as demonstrated by electron microscopy. (author)

  3. Histones as mediators of host defense, inflammation and thrombosis

    NARCIS (Netherlands)

    Hoeksema, Marloes; Eijk, Martin van; Haagsman, Henk P; Hartshorn, Kevan L

    2016-01-01

    Histones are known for their ability to bind to and regulate expression of DNA. However, histones are also present in cytoplasm and extracellular fluids where they serve host defense functions and promote inflammatory responses. Histones are a major component of neutrophil extracellular traps that

  4. The histone chaperone ASF1 is essential for sexual development in the filamentous fungus Sordaria macrospora.

    Science.gov (United States)

    Gesing, Stefan; Schindler, Daniel; Fränzel, Benjamin; Wolters, Dirk; Nowrousian, Minou

    2012-05-01

    Ascomycetes develop four major types of fruiting bodies that share a common ancestor, and a set of common core genes most likely controls this process. One way to identify such genes is to search for conserved expression patterns. We analysed microarray data of Fusarium graminearum and Sordaria macrospora, identifying 78 genes with similar expression patterns during fruiting body development. One of these genes was asf1 (anti-silencing function 1), encoding a predicted histone chaperone. asf1 expression is also upregulated during development in the distantly related ascomycete Pyronema confluens. To test whether asf1 plays a role in fungal development, we generated an S. macrospora asf1 deletion mutant. The mutant is sterile and can be complemented to fertility by transformation with the wild-type asf1 and its P. confluens homologue. An ASF1-EGFP fusion protein localizes to the nucleus. By tandem-affinity purification/mass spectrometry as well as yeast two-hybrid analysis, we identified histones H3 and H4 as ASF1 interaction partners. Several developmental genes are dependent on asf1 for correct transcriptional expression. Deletion of the histone chaperone genes rtt106 and cac2 did not cause any developmental phenotypes. These data indicate that asf1 of S. macrospora encodes a conserved histone chaperone that is required for fruiting body development. © 2012 Blackwell Publishing Ltd.

  5. Turbulence-driven anisotropic electron tail generation during magnetic reconnection

    Science.gov (United States)

    DuBois, A. M.; Scherer, A.; Almagri, A. F.; Anderson, J. K.; Pandya, M. D.; Sarff, J. S.

    2018-05-01

    Magnetic reconnection (MR) plays an important role in particle transport, energization, and acceleration in space, astrophysical, and laboratory plasmas. In the Madison Symmetric Torus reversed field pinch, discrete MR events release large amounts of energy from the equilibrium magnetic field, a fraction of which is transferred to electrons and ions. Previous experiments revealed an anisotropic electron tail that favors the perpendicular direction and is symmetric in the parallel. New profile measurements of x-ray emission show that the tail distribution is localized near the magnetic axis, consistent modeling of the bremsstrahlung emission. The tail appears first near the magnetic axis and then spreads radially, and the dynamics in the anisotropy and diffusion are discussed. The data presented imply that the electron tail formation likely results from a turbulent wave-particle interaction and provides evidence that high energy electrons are escaping the core-localized region through pitch angle scattering into the parallel direction, followed by stochastic parallel transport to the plasma edge. New measurements also show a strong correlation between high energy x-ray measurements and tearing mode dynamics, suggesting that the coupling between core and edge tearing modes is essential for energetic electron tail formation.

  6. Runaway tails in magnetized plasmas

    Science.gov (United States)

    Moghaddam-Taaheri, E.; Vlahos, L.; Rowland, H. L.; Papadopoulos, K.

    1985-01-01

    The evolution of a runaway tail driven by a dc electric field in a magnetized plasma is analyzed. Depending on the strength of the electric field and the ratio of plasma to gyrofrequency, there are three different regimes in the evolution of the tail. The tail can be (1) stable with electrons accelerated to large parallel velocities, (2) unstable to Cerenkov resonance because of the depletion of the bulk and the formation of a positive slope, (3) unstable to the anomalous Doppler resonance instability driven by the large velocity anisotropy in the tail. Once an instability is triggered (Cerenkov or anomalous Doppler resonance) the tail relaxes into an isotropic distribution. The role of a convection type loss term is also discussed.

  7. Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study

    Directory of Open Access Journals (Sweden)

    Cabrera Gustavo

    2005-07-01

    Full Text Available Abstract Background The development of cancer has been associated with epigenetic alterations such as aberrant histone deacetylase (HDAC activity. It was recently reported that valproic acid is an effective inhibitor of histone deacetylases and as such induces tumor cell differentiation, apoptosis, or growth arrest. Methods Twelve newly diagnosed patients with cervical cancer were treated with magnesium valproate after a baseline tumor biopsy and blood sampling at the following dose levels (four patients each: 20 mg/kg; 30 mg/kg, or 40 mg/kg for 5 days via oral route. At day 6, tumor and blood sampling were repeated and the study protocol ended. Tumor acetylation of H3 and H4 histones and HDAC activity were evaluated by Western blot and colorimetric HDAC assay respectively. Blood levels of valproic acid were determined at day 6 once the steady-state was reached. Toxicity of treatment was evaluated at the end of study period. Results All patients completed the study medication. Mean daily dose for all patients was 1,890 mg. Corresponding means for the doses 20-, 30-, and 40-mg/kg were 1245, 2000, and 2425 mg, respectively. Depressed level of consciousness grade 2 was registered in nine patients. Ten patients were evaluated for H3 and H4 acetylation and HDAC activity. After treatment, we observed hyperacetylation of H3 and H4 in the tumors of nine and seven patients, respectively, whereas six patients demonstrated hyperacetylation of both histones. Serum levels of valproic acid ranged from 73.6–170.49 μg/mL. Tumor deacetylase activity decreased in eight patients (80%, whereas two had either no change or a mild increase. There was a statistically significant difference between pre and post-treatment values of HDAC activity (mean, 0.36 vs. 0.21, two-tailed t test p Conclusion Magnesium valproate at a dose between 20 and 40 mg/kg inhibits deacetylase activity and hyperacetylates histones in tumor tissues.

  8. Drosophila Kismet regulates histone H3 lysine 27 methylation and early elongation by RNA polymerase II.

    Directory of Open Access Journals (Sweden)

    Shrividhya Srinivasan

    2008-10-01

    Full Text Available Polycomb and trithorax group proteins regulate cellular pluripotency and differentiation by maintaining hereditable states of transcription. Many Polycomb and trithorax group proteins have been implicated in the covalent modification or remodeling of chromatin, but how they interact with each other and the general transcription machinery to regulate transcription is not well understood. The trithorax group protein Kismet-L (KIS-L is a member of the CHD subfamily of chromatin-remodeling factors that plays a global role in transcription by RNA polymerase II (Pol II. Mutations in CHD7, the human counterpart of kis, are associated with CHARGE syndrome, a developmental disorder affecting multiple tissues and organs. To clarify how KIS-L activates gene expression and counteracts Polycomb group silencing, we characterized defects resulting from the loss of KIS-L function in Drosophila. These studies revealed that KIS-L acts downstream of P-TEFb recruitment to stimulate elongation by Pol II. The presence of two chromodomains in KIS-L suggested that its recruitment or function might be regulated by the methylation of histone H3 lysine 4 by the trithorax group proteins ASH1 and TRX. Although we observed significant overlap between the distributions of KIS-L, ASH1, and TRX on polytene chromosomes, KIS-L did not bind methylated histone tails in vitro, and loss of TRX or ASH1 function did not alter the association of KIS-L with chromatin. By contrast, loss of kis function led to a dramatic reduction in the levels of TRX and ASH1 associated with chromatin and was accompanied by increased histone H3 lysine 27 methylation-a modification required for Polycomb group repression. A similar increase in H3 lysine 27 methylation was observed in ash1 and trx mutant larvae. Our findings suggest that KIS-L promotes early elongation and counteracts Polycomb group repression by recruiting the ASH1 and TRX histone methyltransferases to chromatin.

  9. An NF-Y-dependent switch of positive and negative histone methyl marks on CCAAT promoters.

    Directory of Open Access Journals (Sweden)

    Giacomo Donati

    Full Text Available BACKGROUND: Histone tails have a plethora of different post-translational modifications, which are located differently in "open" and "closed" parts of genomes. H3K4me3/H3K79me2 and H4K20me3 are among the histone marks associated with the early establishment of active and inactive chromatin, respectively. One of the most widespread promoter elements is the CCAAT box, bound by the NF-Y trimer. Two of NF-Y subunits have an H2A-H2B-like structure. PRINCIPAL FINDINGS: We established the causal relationship between NF-Y binding and positioning of methyl marks, by ChIP analysis of mouse and human cells infected with a dominant negative NF-YA: a parallel decrease in NF-Y binding, H3K4me3, H3K79me2 and transcription was observed in promoters that are dependent upon NF-Y. On the contrary, changes in the levels of H3K9-14ac were more subtle. Components of the H3K4 methylating MLL complex are not recruited in the absence of NF-Y. As for repressed promoters, NF-Y removal leads to a decrease in the H4K20me3 mark and deposition of H3K4me3. CONCLUSIONS: Two relevant findings are reported: (i NF-Y gains access to its genomic locations independently from the presence of methyl histone marks, either positive or negative; (ii NF-Y binding has profound positive or negative consequences on the deposition of histone methyl marks. Therefore NF-Y is a fundamental switch at the heart of decision between gene activation and repression in CCAAT regulated genes.

  10. dKDM2 couples histone H2A ubiquitylation to histone H3 demethylation during Polycomb group silencing

    NARCIS (Netherlands)

    A. Lagarou (Anna); A.B. Mohd Sarip; Y.M. Moshkin (Yuri); G.E. Chalkley (Gillian); K. Bezstarosti (Karel); J.A.A. Demmers (Jeroen); C.P. Verrijzer (Peter)

    2008-01-01

    textabstractTranscription regulation involves enzyme-mediated changes in chromatin structure. Here, we describe a novel mode of histone crosstalk during gene silencing, in which histone H2A monoubiquitylation is coupled to the removal of histone H3 Lys 36 dimethylation (H3K36me2). This pathway was

  11. Histone Modification Is Involved in Okadaic Acid (OA Induced DNA Damage Response and G2-M Transition Arrest in Maize.

    Directory of Open Access Journals (Sweden)

    Hao Zhang

    Full Text Available Histone modifications are involved in regulation of chromatin structure. To investigate the relationship between chromatin modification and cell cycle regulation during plant cell proliferation, Okadaic acid (OA, a specific inhibitor of serine/threonine protein phosphatase, was applied in this study. The results showed that OA caused the cell cycle arrest at preprophase, leading to seedling growth inhibition. Western blotting assay revealed that the spatial distribution of phosphorylation of Ser10 histone H3 tails (H3S10ph signals was altered under OA treatment. Reactive oxygen species (ROS was found to be at higher levels and TdT-mediated dUTP nick end labeling (TUNEL assay displayed DNA breaks happened at the chromatin after treatment with OA, companied with an increase in the acetylation of histone H4 at lysine 5 (H4K5ac level. From these observations, we speculated that the alteration of the spatial distribution of H3S10ph and the level of H4K5ac was involved in the procedure that OA induced DNA breaks and G2-M arrested by the accumulation of ROS, and that the histone H3S10ph and H4K5ac might facilitate DNA repair by their association with the chromatin decondensation.

  12. Labelling of histone H5 and its interaction with DNA. 1. Histone H5 labelling with fluorescein isothiocyanate.

    Science.gov (United States)

    Favazza, M; Lerho, M; Houssier, C

    1990-06-01

    Histone H5 has been labelled with fluorescein isothiocyanate (FITC) with particular attention to the reaction conditions (pH, reaction time and input FITC/H5 molar ratio) and to the complete elimination of non-covalently bound dye. We preferred to use reaction conditions which yielded non-specific uniform labelling rather than specific alpha-NH2 terminal labelling, in order to obtain higher sensitivity in further studies dealing with the detection of perturbation at the binding sites of H5 on DNA. FITC-labelled H5 was further characterized by absorption and circular dichroism spectroscopy, and the fluorescein probe titrated in the 4-8 pH range. The structural integrity of H5 was found to be preserved after labelling. The positive electrostatic potential of the environment in which the FITC probe is embedded in the arginine/lysine-rich tails of H5 is believed to be responsible for the drop of pK of 1 unit found for H5-FITC as compared to free FITC. For the globular part of H5, the pK of covalently-bound FITC was only slightly lowered; this is a consequence of the much lower content in positively-charged amino-acid side chains in this region.

  13. Overview of the Classical Histone Deacetylase Enzymes and Histone Deacetylase Inhibitors

    OpenAIRE

    Ververis, Katherine; Karagiannis, Tom C.

    2012-01-01

    The important role of histone deacetylase enzymes in regulating gene expression, cellular proliferation, and survival has made them attractive targets for the development of histone deacetylase inhibitors as anticancer drugs. Suberoylanilide hydroxamic acid (Vorinostat, Zolinza), a structural analogue of the prototypical Trichostatin A, was approved by the US Food and Drug Administration for the treatment of advanced cutaneous T-cell lymphoma in 2006. This was followed by approval of the cycl...

  14. Nitric Oxide Modulates Histone Acetylation at Stress Genes by Inhibition of Histone Deacetylases1[OPEN

    Science.gov (United States)

    Mengel, Alexander; Ageeva, Alexandra; Durner, Jörg

    2017-01-01

    Histone acetylation, which is an important mechanism to regulate gene expression, is controlled by the opposing action of histone acetyltransferases and histone deacetylases (HDACs). In animals, several HDACs are subjected to regulation by nitric oxide (NO); in plants, however, it is unknown whether NO affects histone acetylation. We found that treatment with the physiological NO donor S-nitrosoglutathione (GSNO) increased the abundance of several histone acetylation marks in Arabidopsis (Arabidopsis thaliana), which was strongly diminished in the presence of the NO scavenger 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide. This increase was likely triggered by NO-dependent inhibition of HDAC activity, since GSNO and S-nitroso-N-acetyl-dl-penicillamine significantly and reversibly reduced total HDAC activity in vitro (in nuclear extracts) and in vivo (in protoplasts). Next, genome-wide H3K9/14ac profiles in Arabidopsis seedlings were generated by chromatin immunoprecipitation sequencing, and changes induced by GSNO, GSNO/2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide or trichostatin A (an HDAC inhibitor) were quantified, thereby identifying genes that display putative NO-regulated histone acetylation. Functional classification of these genes revealed that many of them are involved in the plant defense response and the abiotic stress response. Furthermore, salicylic acid, which is the major plant defense hormone against biotrophic pathogens, inhibited HDAC activity and increased histone acetylation by inducing endogenous NO production. These data suggest that NO affects histone acetylation by targeting and inhibiting HDAC complexes, resulting in the hyperacetylation of specific genes. This mechanism might operate in the plant stress response by facilitating the stress-induced transcription of genes. PMID:27980017

  15. Nitric Oxide Modulates Histone Acetylation at Stress Genes by Inhibition of Histone Deacetylases.

    Science.gov (United States)

    Mengel, Alexander; Ageeva, Alexandra; Georgii, Elisabeth; Bernhardt, Jörg; Wu, Keqiang; Durner, Jörg; Lindermayr, Christian

    2017-02-01

    Histone acetylation, which is an important mechanism to regulate gene expression, is controlled by the opposing action of histone acetyltransferases and histone deacetylases (HDACs). In animals, several HDACs are subjected to regulation by nitric oxide (NO); in plants, however, it is unknown whether NO affects histone acetylation. We found that treatment with the physiological NO donor S-nitrosoglutathione (GSNO) increased the abundance of several histone acetylation marks in Arabidopsis (Arabidopsis thaliana), which was strongly diminished in the presence of the NO scavenger 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide. This increase was likely triggered by NO-dependent inhibition of HDAC activity, since GSNO and S-nitroso-N-acetyl-dl-penicillamine significantly and reversibly reduced total HDAC activity in vitro (in nuclear extracts) and in vivo (in protoplasts). Next, genome-wide H3K9/14ac profiles in Arabidopsis seedlings were generated by chromatin immunoprecipitation sequencing, and changes induced by GSNO, GSNO/2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide or trichostatin A (an HDAC inhibitor) were quantified, thereby identifying genes that display putative NO-regulated histone acetylation. Functional classification of these genes revealed that many of them are involved in the plant defense response and the abiotic stress response. Furthermore, salicylic acid, which is the major plant defense hormone against biotrophic pathogens, inhibited HDAC activity and increased histone acetylation by inducing endogenous NO production. These data suggest that NO affects histone acetylation by targeting and inhibiting HDAC complexes, resulting in the hyperacetylation of specific genes. This mechanism might operate in the plant stress response by facilitating the stress-induced transcription of genes. © 2017 American Society of Plant Biologists. All Rights Reserved.

  16. Histone deacetylases in memory and cognition.

    Science.gov (United States)

    Penney, Jay; Tsai, Li-Huei

    2014-12-09

    Over the past 30 years, lysine acetylation of histone and nonhistone proteins has become established as a key modulator of gene expression regulating numerous aspects of cell biology. Neuronal growth and plasticity are no exception; roles for lysine acetylation and deacetylation in brain function and dysfunction continue to be uncovered. Transcriptional programs coupling synaptic activity to changes in gene expression are critical to the plasticity mechanisms underlying higher brain functions. These transcriptional programs can be modulated by changes in histone acetylation, and in many cases, transcription factors and histone-modifying enzymes are recruited together to plasticity-associated genes. Lysine acetylation, catalyzed by lysine acetyltransferases (KATs), generally promotes cognitive performance, whereas the opposing process, catalyzed by histone lysine deacetylases (HDACs), appears to negatively regulate cognition in multiple brain regions. Consistently, mutation or deregulation of different KATs or HDACs contributes to neurological dysfunction and neurodegeneration. HDAC inhibitors have shown promise as a treatment to combat the cognitive decline associated with aging and neurodegenerative disease, as well as to ameliorate the symptoms of depression and posttraumatic stress disorder, among others. In this review, we discuss the evidence for the roles of HDACs in cognitive function as well as in neurological disorders and disease. In particular, we focus on HDAC2, which plays a central role in coupling lysine acetylation to synaptic plasticity and mediates many of the effects of HDAC inhibition in cognition and disease. Copyright © 2014, American Association for the Advancement of Science.

  17. The emerging functions of histone demethylases

    DEFF Research Database (Denmark)

    Agger, Karl; Christensen, Jesper; Cloos, Paul Ac

    2008-01-01

    characteristic features evolve from the same ancestor, despite identical genomic material. The characterization of several enzymes catalyzing histone lysine methylation have supported this concept by showing the requirement of these enzymes for normal development and their involvement in diseases such as cancer...

  18. Histone acetylation regulates the time of replication origin firing.

    Science.gov (United States)

    Vogelauer, Maria; Rubbi, Liudmilla; Lucas, Isabelle; Brewer, Bonita J; Grunstein, Michael

    2002-11-01

    The temporal firing of replication origins throughout S phase in yeast depends on unknown determinants within the adjacent chromosomal environment. We demonstrate here that the state of histone acetylation of surrounding chromatin is an important regulator of temporal firing. Deletion of RPD3 histone deacetylase causes earlier origin firing and concurrent binding of the replication factor Cdc45p to origins. In addition, increased acetylation of histones in the vicinity of the late origin ARS1412 by recruitment of the histone acetyltransferase Gcn5p causes ARS1412 alone to fire earlier. These data indicate that histone acetylation is a direct determinant of the timing of origin firing.

  19. Phosphorylation of rat thymus histones, its control and the effects thereon of γ-irradiation

    International Nuclear Information System (INIS)

    Fonagy, A.; Ord, M.G.; Stocken, L.A.

    1977-01-01

    The phosphate content of rat thymus histones was determined. As expected for a replicating tissue, histones 1 and 2B were more phosphorylated and had higher 32 P uptakes than did histones from resting liver nuclei; the other histones all showed 32 P uptake, but the phosphate content and uptake of histone 2A was about half that for liver histone 2A. When thymus nuclei were incubated in a slightly hypo-osmotic medium, non-histone proteins and phosphorylated histones were released into solution; this was enhanced if ATP was present in the medium. [γ- 32 P]ATP was incorporated into non-histone proteins, including Pl, and into the ADP-ribosylated form of histone 1; negligible 32 P was incorporated into the other, bound, histones. Histones 1 and 2B added to the incubation medium were extensively, and histones 2A and 4 slightly, phosphorylated. Histones released by increasing the ionic strength of the medium were phosphorylated. Added lysozyme and cytochrome c were neither bound nor phosphorylated, but added non-histone protein Pl was phosphorylated, causing other histones to be released from the nuclei, especially histones 2A and 3. The released histones were phosphorylated. γ-irradiation decreased 32 P uptake into the non-ADP-ribosylated histones 1 and 4; phosphorylation of histone 1 in vitro was unaffected. The importance of non-histone proteins, ATP availability and nuclear protein kinases to the control of histone phosphorylation in vivo is discussed. (author)

  20. Role of extracellular histones in the cardiomyopathy of sepsis.

    Science.gov (United States)

    Kalbitz, Miriam; Grailer, Jamison J; Fattahi, Fatemeh; Jajou, Lawrence; Herron, Todd J; Campbell, Katherine F; Zetoune, Firas S; Bosmann, Markus; Sarma, J Vidya; Huber-Lang, Markus; Gebhard, Florian; Loaiza, Randall; Valdivia, Hector H; Jalife, José; Russell, Mark W; Ward, Peter A

    2015-05-01

    The purpose of this study was to define the relationship in polymicrobial sepsis (in adult male C57BL/6 mice) between heart dysfunction and the appearance in plasma of extracellular histones. Procedures included induction of sepsis by cecal ligation and puncture and measurement of heart function using echocardiogram/Doppler parameters. We assessed the ability of histones to cause disequilibrium in the redox status and intracellular [Ca(2+)]i levels in cardiomyocytes (CMs) (from mice and rats). We also studied the ability of histones to disturb both functional and electrical responses of hearts perfused with histones. Main findings revealed that extracellular histones appearing in septic plasma required C5a receptors, polymorphonuclear leukocytes (PMNs), and the Nacht-, LRR-, and PYD-domains-containing protein 3 (NLRP3) inflammasome. In vitro exposure of CMs to histones caused loss of homeostasis of the redox system and in [Ca(2+)]i, as well as defects in mitochondrial function. Perfusion of hearts with histones caused electrical and functional dysfunction. Finally, in vivo neutralization of histones in septic mice markedly reduced the parameters of heart dysfunction. Histones caused dysfunction in hearts during polymicrobial sepsis. These events could be attenuated by histone neutralization, suggesting that histones may be targets in the setting of sepsis to reduce cardiac dysfunction. © FASEB.

  1. Histones as mediators of host defense, inflammation and thrombosis.

    Science.gov (United States)

    Hoeksema, Marloes; van Eijk, Martin; Haagsman, Henk P; Hartshorn, Kevan L

    2016-01-01

    Histones are known for their ability to bind to and regulate expression of DNA. However, histones are also present in cytoplasm and extracellular fluids where they serve host defense functions and promote inflammatory responses. Histones are a major component of neutrophil extracellular traps that contribute to bacterial killing but also to inflammatory injury. Histones can act as antimicrobial peptides and directly kill bacteria, fungi, parasites and viruses, in vitro and in a variety of animal hosts. In addition, histones can trigger inflammatory responses in some cases acting through Toll-like receptors or inflammasome pathways. Extracellular histones mediate organ injury (lung, liver), sepsis physiology, thrombocytopenia and thrombin generation and some proteins can bind histones and reduce these potentially harmful effects.

  2. Mercury's Dynamic Magnetic Tail

    Science.gov (United States)

    Slavin, James A.

    2010-01-01

    The Mariner 10 and MESSENGER flybys of Mercury have revealed a magnetosphere that is likely the most responsive to upstream interplanetary conditions of any in the solar system. The source of the great dynamic variability observed during these brief passages is due to Mercury's proximity to the Sun and the inverse proportionality between reconnection rate and solar wind Alfven Mach number. However, this planet's lack of an ionosphere and its small physical dimensions also contribute to Mercury's very brief Dungey cycle, approx. 2 min, which governs the time scale for internal plasma circulation. Current observations and understanding of the structure and dynamics of Mercury's magnetotail are summarized and discussed. Special emphasis will be placed upon such questions as: 1) How much access does the solar wind have to this small magnetosphere as a function of upstream conditions? 2) What roles do heavy planetary ions play? 3) Do Earth-like substorms take place at Mercury? 4) How does Mercury's tail respond to extreme solar wind events such coronal mass ejections? Prospects for progress due to advances in the global magnetohydrodynamic and hybrid simulation modeling and the measurements to be taken by MESSENGER after it enters Mercury orbit on March 18, 2011 will be discussed.

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

    DEFF Research Database (Denmark)

    Schwämmle, Veit; Sidoli, Simone; Ruminowicz, Chrystian

    2016-01-01

    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....... 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 H3K37...

  4. Dynamic changes of histone H3 marks during Caenorhabditis elegans lifecycle revealed by middle-down proteomics

    DEFF Research Database (Denmark)

    Sidoli, Simone; Vandamme, Julien; Elisabetta Salcini, Anna

    2016-01-01

    We applied a middle-down proteomics strategy for large scale protein analysis during in vivo development of Caenorhabditis elegans. We characterized post-translational modifications (PTMs) on histone H3 N-terminal tails at eight time points during the C. elegans lifecycle, including embryo, larval......-occurring PTMs. We measured temporally distinct combinatorial PTM profiles during C. elegans development. We show that the doubly modified form H3K23me3K27me3, which is rare or non-existent in mammals, is the most abundant PTM in all stages of C. elegans lifecycle. The abundance of H3K23me3 increased during...... that is transmitted during dauer formation. Collectively, our data describe the dynamics of histone H3 combinatorial code during C. elegans lifecycle and demonstrate the feasibility of using middle-down proteomics to study in vivo development of multicellular organisms. This article is protected by copyright. All...

  5. Structural basis for inhibition of the histone chaperone activity of SET/TAF-Iβ by cytochrome c.

    Science.gov (United States)

    González-Arzola, Katiuska; Díaz-Moreno, Irene; Cano-González, Ana; Díaz-Quintana, Antonio; Velázquez-Campoy, Adrián; Moreno-Beltrán, Blas; López-Rivas, Abelardo; De la Rosa, Miguel A

    2015-08-11

    Chromatin is pivotal for regulation of the DNA damage process insofar as it influences access to DNA and serves as a DNA repair docking site. Recent works identify histone chaperones as key regulators of damaged chromatin's transcriptional activity. However, understanding how chaperones are modulated during DNA damage response is still challenging. This study reveals that the histone chaperone SET/TAF-Iβ interacts with cytochrome c following DNA damage. Specifically, cytochrome c is shown to be translocated into cell nuclei upon induction of DNA damage, but not upon stimulation of the death receptor or stress-induced pathways. Cytochrome c was found to competitively hinder binding of SET/TAF-Iβ to core histones, thereby locking its histone-binding domains and inhibiting its nucleosome assembly activity. In addition, we have used NMR spectroscopy, calorimetry, mutagenesis, and molecular docking to provide an insight into the structural features of the formation of the complex between cytochrome c and SET/TAF-Iβ. Overall, these findings establish a framework for understanding the molecular basis of cytochrome c-mediated blocking of SET/TAF-Iβ, which subsequently may facilitate the development of new drugs to silence the oncogenic effect of SET/TAF-Iβ's histone chaperone activity.

  6. Prediction of RNA Polymerase II recruitment, elongation and stalling from histone modification data

    DEFF Research Database (Denmark)

    Chen, Yun; Jørgensen, Mette; Kolde, Raivo

    2011-01-01

    of RNAPII stalling. CONCLUSIONS: In this study we introduce a general framework to accurately predict the level of RNAPII recruitment, elongation, stalling and mRNA expression from chromatin signals. The versatility of the method also makes it ideally suited to investigate other genomic data....... strategies are needed to progress from descriptive annotation of data to quantitative, predictive models. RESULTS: Here, we describe a computational framework which with high accuracy can predict the locations of core promoters, the amount of recruited RNAPII at the promoter, the amount of elongating RNAPII...... of these four marks are found to be necessary for recruitment of RNAPII but not sufficient for the elongation. We also show that the spatial distributions of histone marks are almost as predictive as the signal strength and that a set of histone marks immediately downstream of the TSS is highly predictive...

  7. Theseus Tail Being Unloaded

    Science.gov (United States)

    1996-01-01

    The tail of the Theseus prototype research aircraft is seen here being unloaded at NASA's Dryden Flight Research Center, Edwards, California, in May of 1996. The Theseus aircraft, built and operated by Aurora Flight Sciences Corporation, Manassas, Virginia, was a unique aircraft flown at NASA's Dryden Flight Research Center, Edwards, California, under a cooperative agreement between NASA and Aurora. Dryden hosted the Theseus program, providing hangar space and range safety for flight testing. Aurora Flight Sciences was responsible for the actual flight testing, vehicle flight safety, and operation of the aircraft. The Theseus remotely piloted aircraft flew its maiden flight on May 24, 1996, at Dryden. During its sixth flight on November 12, 1996, Theseus experienced an in-flight structural failure that resulted in the loss of the aircraft. As of the beginning of the year 2000, Aurora had not rebuilt the aircraft. Theseus was built for NASA under an innovative, $4.9 million fixed-price contract by Aurora Flight Sciences Corporation and its partners, West Virginia University, Morgantown, West Virginia, and Fairmont State College, Fairmont, West Virginia. The twin-engine, unpiloted vehicle had a 140-foot wingspan, and was constructed largely of composite materials. Powered by two 80-horsepower, turbocharged piston engines that drove twin 9-foot-diameter propellers, Theseus was designed to fly autonomously at high altitudes, with takeoff and landing under the active control of a ground-based pilot in a ground control station 'cockpit.' With the potential ability to carry 700 pounds of science instruments to altitudes above 60,000 feet for durations of greater than 24 hours, Theseus was intended to support research in areas such as stratospheric ozone depletion and the atmospheric effects of future high-speed civil transport aircraft engines. Instruments carried aboard Theseus also would be able to validate satellite-based global environmental change measurements

  8. Rehabilitation of uranium tailings impoundments

    International Nuclear Information System (INIS)

    Crawley, A.H.

    1983-01-01

    Under Australian environmental controls relating to the management of uranium tailings, it is no longer acceptable practice to search for a rehabilitation strategy at the end of production when the generation of tailings has ceased. The uranium projects currently in production and those being proposed are tightly regulated by the authorities. The waste management plans must consider site specific factors and must include selection of appropriate disposal sites and design for long term containment. The final encapsulation in engineered facilities must take into account the probable routes to the environment of the tailings. Rehabilitation shoud be undertaken by the mining and milling operators to standards approved by appropriate authorities. Appropriate administrative arrangements are required, by way of technical committees and financial bonds to ensure that agreed standards of rehabilitation may be achieved. Past and present experience with the rehabilitation of uranium tailings impoundments in Australia is discussed

  9. Sub-aerial tailings deposition

    International Nuclear Information System (INIS)

    Knight, R.B.; Haile, J.P.

    1984-01-01

    The sub-aerial technique involves the systematic deposition of tailings in thin layers and allowing each layer to settle, drain and partially air dry prior to covering with a further layer. Underdrainage produces densities in excess of those achieved by sub-aqueous deposition and any air-drying serves to preconsolidate each layer with a resulting further increase in density. The low permeability of the tailings surface resulting from this deposition technique results in high runoff coefficients and, by decanting the runoff component of direct precipitation, a net evaporation condition can be achieved even in high rainfall areas. An underdrainage system prevents the build-up of excess pore-pressures within the tailings mass and at decommissioning the tailings are fully consolidated and drained thereby eliminating the possibility of any long term seepage. This paper presents a general description of these design concepts, and details of two projects where the concepts have been applied

  10. Sirenomelia apus with vestigial tail.

    Science.gov (United States)

    Parikh, Tushar B; Nanavati, Ruchi N; Udani, Rekha H

    2005-04-01

    Sirenomelia is an exceptionally rare congenital malformation characterized by complete or near complete fusion of lower limbs. A newborn with clinical features of sirenomelia including fused lower limbs in medial position, absent fibula, anal atresia, complete absence of urogenital system (bilateral renal agenesis, absent ureters, urinary bladder, absent internal and external genitalia), a single umbilical artery and a vestigial tail is reported. Association of vestigial tail with sirenomelia is not described in the literature.

  11. The Role of Extracellular Histones in Influenza Virus Pathogenesis.

    Science.gov (United States)

    Ashar, Harshini K; Mueller, Nathan C; Rudd, Jennifer M; Snider, Timothy A; Achanta, Mallika; Prasanthi, Maram; Pulavendran, Sivasami; Thomas, Paul G; Ramachandran, Akhilesh; Malayer, Jerry R; Ritchey, Jerry W; Rajasekhar, Rachakatla; Chow, Vincent T K; Esmon, Charles T; Teluguakula, Narasaraju

    2018-01-01

    Although exaggerated host immune responses have been implicated in influenza-induced lung pathogenesis, the etiologic factors that contribute to these events are not completely understood. We previously demonstrated that neutrophil extracellular traps exacerbate pulmonary injury during influenza pneumonia. Histones are the major protein components of neutrophil extracellular traps and are known to have cytotoxic effects. Here, we examined the role of extracellular histones in lung pathogenesis during influenza. Mice infected with influenza virus displayed high accumulation of extracellular histones, with widespread pulmonary microvascular thrombosis. Occluded pulmonary blood vessels with vascular thrombi often exhibited endothelial necrosis surrounded by hemorrhagic effusions and pulmonary edema. Histones released during influenza induced cytotoxicity and showed strong binding to platelets within thrombi in infected mouse lungs. Nasal wash samples from influenza-infected patients also showed increased accumulation of extracellular histones, suggesting a possible clinical relevance of elevated histones in pulmonary injury. Although histones inhibited influenza growth in vitro, in vivo treatment with histones did not yield antiviral effects and instead exacerbated lung pathology. Blocking with antihistone antibodies caused a marked decrease in lung pathology in lethal influenza-challenged mice and improved protection when administered in combination with the antiviral agent oseltamivir. These findings support the pathogenic effects of extracellular histones in that pulmonary injury during influenza was exacerbated. Targeting histones provides a novel therapeutic approach to influenza pneumonia. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  12. Multichannel thickener of flotation tailings

    Energy Technology Data Exchange (ETDEWEB)

    Kondratenko, A F; Shuliko, A N; Zinchenko, A F

    1983-04-01

    A multichannel thickener of flotation tailings developed by Ukrniiugleobogashchenie is described. Tailings with solid content ranging from 40 to 60 g/l are mixed with flocculation reagents (quantity ratio from 60 to 70 g/l) in a turbulent mixer: waste water with tailings fed to the mixer is divided into three streams, flocculation reagents are batched in stages with each water stream. After turbulent mixing, water, tailings and reagent are fed to the settling chamber. Settling chamber (dimensions 2.4 x 1.5 x 1.0 m) is divided into a number of channels by settling surfaces of 0.35 m/sup 2/ each, inclined at an angle of 55 degrees. Distance between the surfaces is 50 mm. The thickener has a total settling surface of 18.7 m/sup 2/. Water with tailings flows upwards, cleaned water is removed by a separating system and settled tailings move downward and accumulate in the compacting chamber (dimensions 1.5 x 1.5 x 0.9 m). From the compacting chamber thickened slurry with solid content from 90 to 150 g/l is removed by a hydraulic system. During performance testing in some plants preparing coal difficult to wash, thickening efficiency amounted to 100%. The results of performance testing are shown in two tables. Factors which influence thickener productivity are evaluated. (In Russian)

  13. Histone H2AX in DNA repair

    International Nuclear Information System (INIS)

    Lewandowska, H.; Szumiel, I.

    2002-01-01

    The paper reviews the recent reports on the role of the phosphorylated histone H2AX (γ-H2AX). The modification of this histone is an important part of the cellular response to the induction of DNA double strand brakes (DSB) by ionising radiation and other DSB-generating factors. In irradiated cells the modification is carried out mainly by ATM (ataxia-telangiectasia mutated) kinase, the enzyme that starts the alarm signalling upon induction of DSB.γ-H2AX molecules are formed within 1-3 min after irradiation and form foci at the sites of DSB. This seems to be necessary for the recruitment of repair factors that are later present in foci of damaged nuclei. Modification of a constant percentage of H2AX molecules per DSB takes place, corresponding to chromatin domains of megabase of DNA. (author)

  14. Histone deacetylase inhibitors in multiple myeloma

    Directory of Open Access Journals (Sweden)

    Sarah Deleu

    2009-06-01

    Full Text Available Novel drugs such as bortezomib and high dose chemotherapy combined with stem cell transplantation improved the outcome of multiple myeloma patients in the past decade. However, multiple myeloma often remains incurable due to the development of drug resistance governed by the bone marrow micro-environment. Therefore targeting new pathways to overcome this resistance is needed. Histone deacetylase (HDAC inhibitors represent a new class of anti-myeloma agents. Inhibiting HDACs results in histone hyperacetylation and alterations in chromatine structure, which, in turn, cause growth arrest differentiation and/or apoptosis in several tumor cells. Here we summarize the molecular actions of HDACi as a single agent or in combination with other drugs in different in vitro and in vivo myeloma models and in (preclinical trials.

  15. Replicating chromatin: a tale of histones

    DEFF Research Database (Denmark)

    Groth, Anja

    2009-01-01

    Chromatin serves structural and functional roles crucial for genome stability and correct gene expression. This organization must be reproduced on daughter strands during replication to maintain proper overlay of epigenetic fabric onto genetic sequence. Nucleosomes constitute the structural...... framework of chromatin and carry information to specify higher-order organization and gene expression. When replication forks traverse the chromosomes, nucleosomes are transiently disrupted, allowing the replication machinery to gain access to DNA. Histone recycling, together with new deposition, ensures...

  16. Histone Deacetylase Inhibitors as Anticancer Drugs.

    Science.gov (United States)

    Eckschlager, Tomas; Plch, Johana; Stiborova, Marie; Hrabeta, Jan

    2017-07-01

    Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  17. Histone Deacetylase Inhibitors as Anticancer Drugs

    Directory of Open Access Journals (Sweden)

    Tomas Eckschlager

    2017-07-01

    Full Text Available Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC and histone acetyltransferases (HAT. HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  18. Two active galaxies with tidal tails and companions

    International Nuclear Information System (INIS)

    Keel, W.C.

    1985-01-01

    Spectroscopic, imaging, and radio observations of the tidally disturbed active systems VV 144 and I Zw 96 are presented, and indicate that the prominent optical extensions seen in both cases represent tidal tails rather than matter ejected from their nuclei (jets). This conclusion is based on the presence of stellar spectral features in the tails, lack of significant ionized gas over most of their length, and lack of radio emission outside the nuclei. Discrete knots in these tails are identified with remnant cores of the companion galaxies responsible for the morphological disturbances of the main galaxies and perhaps contributing to their nuclear activity. In both cases, the dynamics of the interactions are unusual in nature or viewing geometry. VV 144 is seen in the common plane of interaction and disk rotation, appearing strongly foreshortened. I Zw 96 shows tails associated with two companions; each is accompanied by changes in tail structure. This may be the result of a binary system of spirals colliding with a giant elliptical galaxy. 18 references

  19. Denitrification in groundwater at uranium mill tailings sites

    International Nuclear Information System (INIS)

    Goering, Timothy J.; Groffman, Armando; Thomson, Bruce

    1992-01-01

    Nitrates are a major contaminant in groundwater at many Uranium Mill Tailings Remedial Action (UMTRA) sites. Microbial denitrification, the transformation of nitrate to nitrogen gas, may be occurring in groundwater at several UMTRA sites. Denitrification is a biologically mediated process whereby facultative anaerobes use nitrate for respiration under anaerobic conditions. Denitrifying bacteria are ubiquitous in soils, sediments, and water. Denitrification requires nitrate, organic carbon, oxygen-limiting conditions, and trace nutrients, especially phosphorus. The lack of organic carbon is the most common limiting factor for denitrification. Denitrification occurs under a limited range of temperature and pH. The uranium milling processes used at UMTRA sites provided a readily available source of carbon and nitrates for denitrifying bacteria. At the Maybell, Colorado, site, the denitrifying organisms Pseudomonas, Flavobacterium and Acinetobacter were identified in core samples of materials from beneath the tailings. In addition, microcosm experiments simulating aquifer conditions beneath the tailings pile showed an average 40 percent decrease in nitrate concentrations over 13 days. At the New Rifle, Colorado, site, aquifer conditions appear favorable for denitrification. Nitrate and organic carbon are readily available in the groundwater, and redox conditions beneath and downgradient of the tailings pile are relatively anoxic. Downgradient from the tailings, total nitrogen is being removed from the groundwater system at a greater rate than the geochemically conservative anion, chloride. This removal may be due to denitrification and adsorption of ammonium onto clay and silt particles. (author)

  20. Denitrification in groundwater at uranium mill tailings sites

    Energy Technology Data Exchange (ETDEWEB)

    Goering, Timothy J [Jacobs Engineering Group, Inc., Albuquerque, NM (United States); Groffman, Armando [Roy F. Weston, Inc., Albuquerque, NM (United States); Thomson, Bruce [University of New Mexico, Albuquerque, NM (United States)

    1992-07-01

    Nitrates are a major contaminant in groundwater at many Uranium Mill Tailings Remedial Action (UMTRA) sites. Microbial denitrification, the transformation of nitrate to nitrogen gas, may be occurring in groundwater at several UMTRA sites. Denitrification is a biologically mediated process whereby facultative anaerobes use nitrate for respiration under anaerobic conditions. Denitrifying bacteria are ubiquitous in soils, sediments, and water. Denitrification requires nitrate, organic carbon, oxygen-limiting conditions, and trace nutrients, especially phosphorus. The lack of organic carbon is the most common limiting factor for denitrification. Denitrification occurs under a limited range of temperature and pH. The uranium milling processes used at UMTRA sites provided a readily available source of carbon and nitrates for denitrifying bacteria. At the Maybell, Colorado, site, the denitrifying organisms Pseudomonas, Flavobacterium and Acinetobacter were identified in core samples of materials from beneath the tailings. In addition, microcosm experiments simulating aquifer conditions beneath the tailings pile showed an average 40 percent decrease in nitrate concentrations over 13 days. At the New Rifle, Colorado, site, aquifer conditions appear favorable for denitrification. Nitrate and organic carbon are readily available in the groundwater, and redox conditions beneath and downgradient of the tailings pile are relatively anoxic. Downgradient from the tailings, total nitrogen is being removed from the groundwater system at a greater rate than the geochemically conservative anion, chloride. This removal may be due to denitrification and adsorption of ammonium onto clay and silt particles. (author)

  1. Presentations of the CONRAD tailings seminar : exploring the past, present and future of tailings technologies

    International Nuclear Information System (INIS)

    2004-01-01

    This symposium explored oil sand tailings activities in Canada and their associated technologies. It was attended by active and prospective tailings researchers and developers of tailings technology who addressed timely issues regarding mature fine tailings, consolidated tailings, thickened tailings, and emerging tailings technologies. The collaborative research projects that are underway at the Oil Sands Tailings Research Facility were also discussed along with other topics such as tailings ponds management, water treatment, water quality and water supply security. All 16 presentations featured at this conference were indexed separately for inclusion in this database

  2. HAMLET interacts with histones and chromatin in tumor cell nuclei.

    Science.gov (United States)

    Düringer, Caroline; Hamiche, Ali; Gustafsson, Lotta; Kimura, Hiroshi; Svanborg, Catharina

    2003-10-24

    HAMLET is a folding variant of human alpha-lactalbumin in an active complex with oleic acid. HAMLET selectively enters tumor cells, accumulates in their nuclei and induces apoptosis-like cell death. This study examined the interactions of HAMLET with nuclear constituents and identified histones as targets. HAMLET was found to bind histone H3 strongly and to lesser extent histones H4 and H2B. The specificity of these interactions was confirmed using BIAcore technology and chromatin assembly assays. In vivo in tumor cells, HAMLET co-localized with histones and perturbed the chromatin structure; HAMLET was found associated with chromatin in an insoluble nuclear fraction resistant to salt extraction. In vitro, HAMLET bound strongly to histones and impaired their deposition on DNA. We conclude that HAMLET interacts with histones and chromatin in tumor cell nuclei and propose that this interaction locks the cells into the death pathway by irreversibly disrupting chromatin organization.

  3. More tail lesions among undocked than tail docked pigs in a conventional herd

    DEFF Research Database (Denmark)

    Lahrmann, H. P.; Busch, M. E.; D'Eath, R. B.

    2017-01-01

    The vast majority of piglets reared in the European Union (EU) and worldwide is tail docked to reduce the risk of being tail bitten, even though EU animal welfare legislation bans routine tail docking. Many conventional herds experience low levels of tail biting among tail docked pigs, however...

  4. Research on Long Tail Recommendation Algorithm

    Science.gov (United States)

    Hu, Xuezhi; Zhang, Chuang; Wu, Ming; Zeng, Yang

    2017-10-01

    Most recommendation systems in the major electronic commerce platforms are influenced by the long tail effect more or less. There are sufficient researches of how to assess recommendation effect while no criteria to evaluate long tail recommendation rate. In this study, we first discussed the existing problems of recommending long tail products through specific experiments. Then we proposed a long tail evaluation criteria and compared the performance in long tail recommendation between different models.

  5. Developing selective histone deacetylases (HDACs inhibitors through ebselen and analogs

    Directory of Open Access Journals (Sweden)

    Wang Y

    2017-05-01

    Full Text Available Yuren Wang,1 Jason Wallach,2 Stephanie Duane,1 Yuan Wang,1 Jianghong Wu,1 Jeffrey Wang,1 Adeboye Adejare,2 Haiching Ma1 1Reaction Biology Corp., Malvern, 2Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA, USA Abstract: Histone deacetylases (HDACs are key regulators of gene expression in cells and have been investigated as important therapeutic targets for cancer and other diseases. Different subtypes of HDACs appear to play disparate roles in the cells and are associated with specific diseases. Therefore, substantial effort has been made to develop subtype-selective HDAC inhibitors. In an effort to discover existing scaffolds with HDAC inhibitory activity, we screened a drug library approved by the US Food and Drug Administration and a National Institutes of Health Clinical Collection compound library in HDAC enzymatic assays. Ebselen, a clinical safe compound, was identified as a weak inhibitor of several HDACs, including HDAC1, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, and HDAC9 with half maximal inhibitory concentrations approximately single digit of µM. Two ebselen analogs, ebselen oxide and ebsulfur (a diselenide analog of ebselen, also inhibited these HDACs, however with improved potencies on HDAC8. Benzisothiazol, the core structure of ebsulfur, specifically inhibited HDAC6 at a single digit of µM but had no inhibition on other HDACs. Further efforts on structure–activity relationship based on the core structure of ebsulfur led to the discovery of a novel class of potent and selective HDAC6 inhibitors with RBC-2008 as the lead compound with single-digit nM potency. This class of histone deacetylase inhibitor features a novel pharmacophore with an ebsulfur scaffold selectively targeting HDAC6. Consistent with its inhibition on HDAC6, RBC-2008 significantly increased the acetylation levels of α-tubulin in PC-3 cells. Furthermore, treatment with these compounds led to

  6. Histones of Chlamydomonas reinhardtii. Synthesis, acetylation, and methylation

    International Nuclear Information System (INIS)

    Waterborg, J.H.; Robertson, A.J.; Tatar, D.L.; Borza, C.M.; Davie, J.R.

    1995-01-01

    Histones of the green alga Chlamydomonas reinhardtii were prepared by a new method and fractionated by reversed-phase high-performance liquid chromatography. Acid-urea-Triton gel analysis and tritiated acetate labeling demonstrated high levels of steady-state acetylation for the single histone H3 protein, in contrast to low levels on histones H4 and H2B. Twenty percent of histone H3 is subject to dynamic acetylation with, on average, three acetylated lysine residues per protein molecule. Histone synthesis in light-dark-synchronized cultures was biphasic with pattern differences between two histone H1 variants, between two H2A variants, and between H2B and ubiquitinated H2B. Automated protein sequence analysis of histone H3 demonstrated a site-specific pattern of steady-state acetylation between 7 and 17% at five of the six amino-terminal lysines and of monomethylation between 5 and 81% at five of the eight amino-terminal lysines in a pattern that may limit dynamic acetylation. An algal histone H3 sequence was confirmed by protein sequencing with a since threonine as residue 28 instead of the serine(28)-alanine(29) sequence, present in all other known plant and animal H3 histones

  7. Targeting post-translational modifications of histones for cancer therapy.

    Science.gov (United States)

    Hsu, Y-C; Hsieh, Y-H; Liao, C-C; Chong, L-W; Lee, C-Y; Yu, Y-L; Chou, R-H

    2015-10-30

    Post-translational modifications (PTMs) on histones including acetylation, methylation, phosphorylation, citrullination, ubiquitination, ADP ribosylation, and sumoylation, play important roles in different biological events including chromatin dynamics, DNA replication, and transcriptional regulation. Aberrant histones PTMs leads to abnormal gene expression and uncontrolled cell proliferation, followed by development of cancers. Therefore, targeting the enzymes required for specific histone PTMs holds a lot of potential for cancer treatment. In this review article, we retrospect the latest studies in the regulations of acetylation, methylation, and phosphorylation of histones. We also summarize inhibitors/drugs that target these modifications for cancer treatment.

  8. The Effect of Histone Hyperacetylation on Viability of Basal-Like Breast Cancer Cells MDA-MB-231

    Directory of Open Access Journals (Sweden)

    Aliasghar Rahimian

    2017-06-01

    Full Text Available Background The Basal-Like breast cancer, is always known for lack of expression of estrogen receptor (ER, progesterone receptor (PR and as well, absence of epidermal growth factor receptor 2 (HER2 gene amplification. Improper expression pattern of ER, PR, and Her2, makes Basal-Like breast tumors resistant to the current hormonal and anti HER2 treatments. In recent decades, several studies have been conducted to investigate the regulatory role of chemical modifications of core histones in gene expression. Their results have shown that histone acetylation is involved in regulation of cell survival. Acetylation of core histones is regulated by the epigenetic-modifying enzymes named Histone Deacetylases (HDACs. As a new approach to control the viability of breast tumor cells resistant to the hormonal and anti-HER2 treatments, we have targeted the HDACs. Using Trichostatin A (TSA as a known HDACs inhibitor, we have tried to hyperacetylate the core histones of MDA-MB-231 cells as an in vitro model of Basal-Like breast tumors. Then we have investigated the effect of histone hyperacetylation on viability of MDA-MB-231 cells. Methods MDA-MB-231 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum (FBS and were incubated at 37°C, in a humidified incubator with 5% CO2 atmosphere. Then cells were treated with different concentrations of TSA including: 50, 100, 200, 400, 800 and 1000 nM or control (1% DMSO. After 24 and 48 hours, viability of cells was evaluated by MTT assay. Results After 24 and 48h exposure to different concentrations of TSA, MDA-MB-231 cells showed a maximum tolerable dose. At higher concentrations, TSA decreased the percentage of cell viability through a time-dose dependent manner. IC50 value for 48h treatment was 600 nM. Conclusions Our results indicate that HDACs inhibition and subsequently hyperacetylation of histones, leads to cytotoxic effects on breast tumor cells resistant to the current treatments. Following

  9. Subnucleosomes and their relationships to the arrangement of histone binding sites along nucleosome deoxyribonucleic acid

    International Nuclear Information System (INIS)

    Nelson, D.A.; Mencke, A.J.; Chambers, S.A.; Oosterhof, D.K.; Rill, R.L.

    1982-01-01

    Micrococcal nuclease cleaves within nucleosomes at sites spaced about 10.4 base pairs (bp) apart. Cleavages at sites equivalent to 30-35 bp from the ends of 146-bp cores cause spontaneous loss of an H2a-H2b pair associated with 30-40 bp length DNA. Cleavages at certain other sites do not affect the nucleosome integrity unless a solvent perturbant such as urea is added. Chromatin moderately digested with micrococcal nuclease, when fractionated by sedimentation or electrophoresis in the presence of 3 M urea, yielded four previously unobserved subnucleosomes with the following histone/DNA compositions: (H3) 2 (H4) 2 (H2a)(H2b)/95-115 bp; (H3)(H4)/70-80 bp DNA; (H2a)(H2b)/50-60 bp DNA; and (H1)/60-70 bp DNA. All but the latter subnucleosome were also obtained upon DNase I digestion of purified nucleosome cores labeled on the 5' ends with 32 P. Only subnucleosomes that retained H2a and H2b also retained labeled ends. These results show that H2a and H2b are paired on the terminal 30-40 bp of core DNA, as suggested from analyses of histone-DNA cross-link products by Mirzabekov and coworkers. Considerations of the orgins and compositions of subnucleosomes and of cross-linking data suggest an expanded model for the locations of histone binding sites along nucleosome core DNA. The principal features of this model are (i) strong electrostatic binding sites of H2a and H2b occur at positions approximately 20-30 bp from the core ends, (ii) strong electrostatic binding sites of H3 and H4 occur primarily on the central 40 bp of core DNA, (iii) strong nonelectrostatic, urea-sensitive binding sites of H3 and H4 occur at positions approximately 30-50 bp from the core ends, and (iv) urea-sensitive binding sites of H2a or H2b may occur on the terminal 10-20 bp of core DNA

  10. Genome-wide analysis of regions similar to promoters of histone genes

    KAUST Repository

    Chowdhary, Rajesh; Bajic, Vladimir B.; Dong, Difeng; Wong, Limsoon; Liu, Jun S

    2010-01-01

    of histone and histone-coregulated gene transcription initiation. While these hypotheses still remain to be verified, we believe that these form a useful resource for researchers to further explore regulation of human histone genes and human genome

  11. EPC1/TIP60-mediated histone acetylation facilitates spermiogenesis in mice

    DEFF Research Database (Denmark)

    Dong, Yixin; Isono, Kyo Ichi; Ohbo, Kazuyuki

    2017-01-01

    Global histone hyperacetylation is suggested to play a critical role for replacement of histones by transition proteins and protamines to compact the genome during spermiogenesis. However, the underlying mechanisms for hyperacetylation- mediated histone replacement remains poorly understood. Here...

  12. Proteomics Core

    Data.gov (United States)

    Federal Laboratory Consortium — Proteomics Core is the central resource for mass spectrometry based proteomics within the NHLBI. The Core staff help collaborators design proteomics experiments in a...

  13. Dewatering tailings impoundments : interior drains

    International Nuclear Information System (INIS)

    Charlie, W.A.; Doehring, D.O.; Durnford, D.S.

    1984-01-01

    For the design of a new uranium tailings impoundment in the western United States, it was proposed that an interior drainage system be considered to economically and reliably minimize potential short- and long-term environmental impacts. The objectives were to decrease the effective hydraulic head on the clay liner, to dewater and stabilize the tailings, and to increase the amount of water recycled to the mill. In addition, desaturation of the impoundment would induce capillary pressure (negative porewater pressure), further reducing the potential movement of dissolved pollutants. This paper presents saturated and unsaturated seepage principles and reviews the concept, criteria and design of the various interior drainage systems considered

  14. Quantum chemical modeling of enzymatic reactions: the case of histone lysine methyltransferase.

    Science.gov (United States)

    Georgieva, Polina; Himo, Fahmi

    2010-06-01

    Quantum chemical cluster models of enzyme active sites are today an important and powerful tool in the study of various aspects of enzymatic reactivity. This methodology has been applied to a wide spectrum of reactions and many important mechanistic problems have been solved. Herein, we report a systematic study of the reaction mechanism of the histone lysine methyltransferase (HKMT) SET7/9 enzyme, which catalyzes the methylation of the N-terminal histone tail of the chromatin structure. In this study, HKMT SET7/9 serves as a representative case to examine the modeling approach for the important class of methyl transfer enzymes. Active site models of different sizes are used to evaluate the methodology. In particular, the dependence of the calculated energies on the model size, the influence of the dielectric medium, and the particular choice of the dielectric constant are discussed. In addition, we examine the validity of some technical aspects, such as geometry optimization in solvent or with a large basis set, and the use of different density functional methods. Copyright 2010 Wiley Periodicals, Inc.

  15. BRCA1 Is a Histone-H2A-Specific Ubiquitin Ligase

    Directory of Open Access Journals (Sweden)

    Reinhard Kalb

    2014-08-01

    Full Text Available The RING domain proteins BRCA1 and BARD1 comprise a heterodimeric ubiquitin (E3 ligase that is required for the accumulation of ubiquitin conjugates at sites of DNA damage and for silencing at DNA satellite repeat regions. Despite its links to chromatin, the substrate and underlying function of the BRCA1/BARD1 ubiquitin ligase remain unclear. Here, we show that BRCA1/BARD1 specifically ubiquitylates histone H2A in its C-terminal tail on lysines 127 and 129 in vitro and in vivo. The specificity for K127-129 is acquired only when H2A is within a nucleosomal context. Moreover, site-specific targeting of the BRCA1/BARD1 RING domains to chromatin is sufficient for H2Aub foci formation in vivo. Our data establish BRCA1/BARD1 as a histone-H2A-specific E3 ligase, helping to explain its localization and activities on chromatin in cells.

  16. Antifungal properties of wheat histones (H1-H4) and purified wheat histone H1

    Science.gov (United States)

    Wheat (Triticum sp.) histones H1, H2, H3, and H4 were extracted. H1 was further purified. Their activities against fungi with varying degrees of wheat pathogenicity were determined. They included Aspergillus flavus, A. fumigatus, A. niger, F. oxysporum, F. verticillioides, F. solani, F. graminearu...

  17. Structural Basis of Histone Demethylase KDM6B Histone 3 Lysine 27 Specificity

    DEFF Research Database (Denmark)

    Jones, Sarah E; Olsen, Lars; Gajhede, Michael

    2018-01-01

    KDM subfamily 6 enzymes KDM6A and KDM6B specifically catalyze demethylation of di- and trimethylated lysine on histone 3 lysine 27 (H3K27me3/2) and play an important role in repression of developmental genes. Despite identical amino acid sequence in the immediate surroundings of H3K9me3/2 (ARKS...

  18. Effects of nickel, chromate, and arsenite on histone 3 lysine methylation

    International Nuclear Information System (INIS)

    Zhou Xue; Li Qin; Arita, Adriana; Sun Hong; Costa, Max

    2009-01-01

    Occupational exposure to nickel (Ni), chromium (Cr), and arsenic (As) containing compounds has been associated with lung cancer and other adverse health effects. Their carcinogenic properties may be attributable in part, to activation and/or repression of gene expression induced by changes in the DNA methylation status and histone tail post-translational modifications. Here we show that individual treatment with nickel, chromate, and arsenite all affect the gene activating mark H3K4 methylation. We found that nickel (1 mM), chromate (10 μM), and arsenite (1 μM) significantly increase tri-methyl H3K4 after 24 h exposure in human lung carcinoma A549 cells. Seven days of exposure to lower levels of nickel (50 and 100 μM), chromate (0.5 and 1 μM) or arsenite (0.1, 0.5 and 1 μM) also increased tri-methylated H3K4 in A549 cells. This mark still remained elevated and inherited through cell division 7 days following removal of 1 μM arsenite. We also demonstrate by dual staining immunofluorescence microscopy that both H3K4 tri-methyl and H3K9 di-methyl marks increase globally after 24 h exposure to each metal treatment in A549 cells. However, the tri-methyl H3K4 and di-methyl H3K9 marks localize in different regions in the nucleus of the cell. Thus, our study provides further evidence that a mechanism(s) of carcinogenicity of nickel, chromate, and arsenite metal compounds may involve alterations of various histone tail modifications that may in turn affect the expression of genes that may cause transformation

  19. Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease

    DEFF Research Database (Denmark)

    Cloos, Paul A C; Christensen, Jesper; Agger, Karl

    2008-01-01

    The enzymes catalyzing lysine and arginine methylation of histones are essential for maintaining transcriptional programs and determining cell fate and identity. Until recently, histone methylation was regarded irreversible. However, within the last few years, several families of histone...... demethylases erasing methyl marks associated with gene repression or activation have been identified, underscoring the plasticity and dynamic nature of histone methylation. Recent discoveries have revealed that histone demethylases take part in large multiprotein complexes synergizing with histone deacetylases......, histone methyltransferases, and nuclear receptors to control developmental and transcriptional programs. Here we review the emerging biochemical and biological functions of the histone demethylases and discuss their potential involvement in human diseases, including cancer....

  20. Chemical Probes of Histone Lysine Methyltransferases

    Science.gov (United States)

    2015-01-01

    Growing evidence suggests that histone methyltransferases (HMTs, also known as protein methyltransferases (PMTs)) play an important role in diverse biological processes and human diseases by regulating gene expression and the chromatin state. Therefore, HMTs have been increasingly recognized by the biomedical community as a class of potential therapeutic targets. High quality chemical probes of HMTs, as tools for deciphering their physiological functions and roles in human diseases and testing therapeutic hypotheses, are critical for advancing this promising field. In this review, we focus on the discovery, characterization, and biological applications of chemical probes for HMTs. PMID:25423077

  1. Predicting radon flux from uranium mill tailings

    International Nuclear Information System (INIS)

    Freeman, H.D.; Hartley, J.N.

    1983-11-01

    Pacific Northwest Laboratory (PNL), under contract to the US Department of Energy (DOE) Uranium Mill Tailings Remedial Action Project (UMTRAP) office, is developing technology for the design of radon barriers for uranium mill tailings piles. To properly design a radon cover for a particular tailings pile, the radon flux emanating from the bare tailings must be known. The tailings characteristics required to calculate the radon flux include radium-226 content, emanating power, bulk density, and radon diffusivity. This paper presents theoretical and practical aspects of estimating the radon flux from an uranium tailings pile. Results of field measurements to verify the calculation methodology are also discussed. 24 references, 4 figures, 4 tables

  2. Molecular mechanisms for the regulation of histone mRNA stem-loop-binding protein by phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Jun; Tan, Dazhi; DeRose, Eugene F.; Perera, Lalith; Dominski, Zbigniew; Marzluff, William F.; Tong, Liang; Tanaka Hall, Traci M. [NIH; (UNC); (Columbia)

    2014-08-06

    Replication-dependent histone mRNAs end with a conserved stem loop that is recognized by stem-loop–binding protein (SLBP). The minimal RNA-processing domain of SLBP is phosphorylated at an internal threonine, and Drosophila SLBP (dSLBP) also is phosphorylated at four serines in its 18-aa C-terminal tail. We show that phosphorylation of dSLBP increases RNA-binding affinity dramatically, and we use structural and biophysical analyses of dSLBP and a crystal structure of human SLBP phosphorylated on the internal threonine to understand the striking improvement in RNA binding. Together these results suggest that, although the C-terminal tail of dSLBP does not contact the RNA, phosphorylation of the tail promotes SLBP conformations competent for RNA binding and thereby appears to reduce the entropic penalty for the association. Increased negative charge in this C-terminal tail balances positively charged residues, allowing a more compact ensemble of structures in the absence of RNA.

  3. Specificity of interaction between carcinogenic polynuclear aromatic hydrocarbons and nuclear proteins: widespread occurrence of a restricted pattern of histone-binding in intact cells

    International Nuclear Information System (INIS)

    MacLeod, M.C.; Pelling, J.C.; Slaga, T.J.; Nikbakht-Noghrei, P.A.; Mansfield, B.K.; Selkirk, J.K.

    1982-01-01

    Metabolic activation of benzo(a)pyrene [B(a)P] produces a number of potentially reactive metabolites. The endproducts of one metabolic pathway, 7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydro-B(a)P (BPDE) are responsible for essentially all DNA adduct formation in animal cells treated with B(a)P, and a particular stereoisomer, designated (+)-anti-BPDE is thought to be the ultimate carcinogenic derivative of B(a)P. In hamster embryo cell nuclei treated with (+)-anti-BPDE, two of the histones of the nucleosomal core, H3 and H2A, are covalently modified, while the remaining core histones, H4 and H2B, are essentially unmodified. All four purified core histones, however, serve as targets. 7,12-dimethylbenz(a)anthracene and 3-methylcholanthrene show the same pattern of histone binding in hamster embryo cells. Treatment of mouse embryo cells with [ 3 H]-BPDE results in covalent binding of the hydrocarbon to histones H3 and H2A among the many cellular targets, while histones H2B and H4 are not bound. Similar binding patterns are seen in mouse embryo cells, a permanent murine, fibroblastic cell line, and a human mammary epithelial cell line, T47D, treated with [ 3 H]B(a)P. Again, the histones are unevenly labeled, displaying the H3 and H2A pattern. Histone-binding in the human cells may also be mediated by BPDE. Similar BPDE binding patterns were observed in other murine and human cell lines and in primary cultures of murine epidermal epithelial cells. The restriction of histone H2B and H4 binding appears to be general when intact cultured cells are studied. This specificity was not observed in a mixed reconstituted system in which rat liver microsomes were used to activate B(a)P. This finding reinforces reservations concerning the use of microsomal systems to probe the interactions of carcinogens with macromolecules and the relationships of adduct formation with the processes of carcinogenesis

  4. Ruin problems and tail asymptotics

    DEFF Research Database (Denmark)

    Rønn-Nielsen, Anders

    The thesis Ruin Problems and Tail Asymptotics provides results on ruin problems for several classes of Markov processes. For a class of diffusion processes with jumps an explicit expression for the joint Laplace transform of the first passage time and the corresponding undershoot is derived...

  5. Liner used in tailings ponds

    International Nuclear Information System (INIS)

    Dinchak, W.G.

    1984-01-01

    A composite liner has been developed for use in hazardous waste impoundments and in tailings ponds where uranium is involved. The liner offers a high degree of reliability against seepage, is durable, and provides a firm working surface. The advantages of the liner are discussed

  6. Portfolio selection with heavy tails

    NARCIS (Netherlands)

    Hyung, N.; Vries, de C.G.

    2007-01-01

    Consider the portfolio problem of choosing the mix between stocks and bonds under a downside risk constraint. Typically stock returns exhibit fatter tails than bonds corresponding to their greater downside risk. Downside risk criteria like the safety first criterion therefore often select corner

  7. Portfolio Selection with Heavy Tails

    NARCIS (Netherlands)

    N. Hyung (Namwon); C.G. de Vries (Casper)

    2004-01-01

    textabstractConsider the portfolio problem of choosing the mix between stocks and bonds under a downside risk constraint. Typically stock returns exhibit fatter tails than bonds corresponding to their greater downside risk. Downside risk criteria like the safety first criterion therefore of ten

  8. Tails, Fears and Risk Premia

    DEFF Research Database (Denmark)

    Bollerslev, Tim; Todorov, Victor

    solely be explained by the level of the volatil- ity. Our empirical investigations are essentially model-free. We estimate the expected values of the tails under the statistical probability measure from "medium" size jumps in high-frequency intraday prices and an extreme value theory approximation...

  9. Capital regulation and tail risk

    NARCIS (Netherlands)

    Perotti, E.; Ratnovski, L.; Vlahu, R.

    2011-01-01

    The paper studies risk mitigation associated with capital regulation, in a context when banks may choose tail risk assets. We show that this undermines the traditional result that higher capital reduces excess risk-taking driven by limited liability. When capital raising is costly, poorly

  10. Capital regulation and tail risk

    NARCIS (Netherlands)

    Perotti, E.; Ratnovski, L.; Vlahu, R.

    2011-01-01

    The paper studies risk mitigation associated with capital regulation, in a context where banks may choose tail risk assets. We show that this undermines the traditional result that higher capital reduces excess risk taking driven by limited liability. Moreover, higher capital may have an unintended

  11. DLM for T-Tails

    CSIR Research Space (South Africa)

    Van Zyl, Lourens H

    2007-06-01

    Full Text Available This paper describes the extension of the DLM to account for effects that are critical to the modelling of T-tail flutter. The boundary condition is made more general to account for yaw/dihedral and sideslip/dihedral coupling and the calculation...

  12. Class IIa histone deacetylases are conserved regulators of circadian function.

    Science.gov (United States)

    Fogg, Paul C M; O'Neill, John S; Dobrzycki, Tomasz; Calvert, Shaun; Lord, Emma C; McIntosh, Rebecca L L; Elliott, Christopher J H; Sweeney, Sean T; Hastings, Michael H; Chawla, Sangeeta

    2014-12-05

    Class IIa histone deacetylases (HDACs) regulate the activity of many transcription factors to influence liver gluconeogenesis and the development of specialized cells, including muscle, neurons, and lymphocytes. Here, we describe a conserved role for class IIa HDACs in sustaining robust circadian behavioral rhythms in Drosophila and cellular rhythms in mammalian cells. In mouse fibroblasts, overexpression of HDAC5 severely disrupts transcriptional rhythms of core clock genes. HDAC5 overexpression decreases BMAL1 acetylation on Lys-537 and pharmacological inhibition of class IIa HDACs increases BMAL1 acetylation. Furthermore, we observe cyclical nucleocytoplasmic shuttling of HDAC5 in mouse fibroblasts that is characteristically circadian. Mutation of the Drosophila homolog HDAC4 impairs locomotor activity rhythms of flies and decreases period mRNA levels. RNAi-mediated knockdown of HDAC4 in Drosophila clock cells also dampens circadian function. Given that the localization of class IIa HDACs is signal-regulated and influenced by Ca(2+) and cAMP signals, our findings offer a mechanism by which extracellular stimuli that generate these signals can feed into the molecular clock machinery. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Co-regulation of histone-modifying enzymes in cancer.

    Directory of Open Access Journals (Sweden)

    Abul B M M K Islam

    Full Text Available Cancer is characterized by aberrant patterns of expression of multiple genes. These major shifts in gene expression are believed to be due to not only genetic but also epigenetic changes. The epigenetic changes are communicated through chemical modifications, including histone modifications. However, it is unclear whether the binding of histone-modifying proteins to genomic regions and the placing of histone modifications efficiently discriminates corresponding genes from the rest of the genes in the human genome. We performed gene expression analysis of histone demethylases (HDMs and histone methyltransferases (HMTs, their target genes and genes with relevant histone modifications in normal and tumor tissues. Surprisingly, this analysis revealed the existence of correlations in the expression levels of different HDMs and HMTs. The observed HDM/HMT gene expression signature was specific to particular normal and cancer cell types and highly correlated with target gene expression and the expression of genes with histone modifications. Notably, we observed that trimethylation at lysine 4 and lysine 27 separated preferentially expressed and underexpressed genes, which was strikingly different in cancer cells compared to normal cells. We conclude that changes in coordinated regulation of enzymes executing histone modifications may underlie global epigenetic changes occurring in cancer.

  14. Histone acetyltransferases : challenges in targeting bi-substrate enzymes

    NARCIS (Netherlands)

    Wapenaar, Hannah; Dekker, Frank J

    2016-01-01

    Histone acetyltransferases (HATs) are epigenetic enzymes that install acetyl groups onto lysine residues of cellular proteins such as histones, transcription factors, nuclear receptors, and enzymes. HATs have been shown to play a role in diseases ranging from cancer and inflammatory diseases to

  15. Chemical mechanisms of histone lysine and arginine modifications

    OpenAIRE

    Smith, Brian C.; Denu, John M.

    2008-01-01

    Histone lysine and arginine residues are subject to a wide array of post-translational modifications including methylation, citrullination, acetylation, ubiquitination, and sumoylation. The combinatorial action of these modifications regulates critical DNA processes including replication, repair, and transcription. In addition, enzymes that modify histone lysine and arginine residues have been correlated with a variety of human diseases including arthritis, cancer, heart disease, diabetes, an...

  16. The histone H5 variant in Xenopus laevis

    NARCIS (Netherlands)

    Moorman, A. F.; de Boer, P. A.; Linders, M. T.; Charles, R.

    1984-01-01

    The presumptive histone H5 of Xenopus laevis has been characterized by SDS and acid-urea-Triton polyacrylamide gel electrophoresis and compared with chicken histone H5. Chicken H5 has a lower electrophoretic mobility compared to that of Xenopus H5 in both gel systems. It is shown, using a polyclonal

  17. Histone methylation and aging: Lessons learned from model systems

    Science.gov (United States)

    McCauley, Brenna S.; Dang, Weiwei

    2014-01-01

    Aging induces myriad cellular and, ultimately, physiological changes that cause a decline in an organism's functional capabilities. Although the aging process and pathways that regulate it have been extensively studied, only in the last decade have we begun to appreciate that dynamic histone methylation may contribute to this process. In this review, we discuss recent work implicating histone methylation in aging. Loss of certain histone methyltransferases and demethylases changes lifespan in invertebrates, and alterations in histone methylation in aged organisms regulate lifespan and aging phenotypes, including oxidative stress-induced hormesis in yeast, insulin signaling in Caenorhabiditis elegans and mammals, and the senescence-associated secretory phenotype in mammals. In all cases where histone methylation has been shown to impact aging and aging phenotypes, it does so by regulating transcription, suggesting that this is a major mechanism of its action in this context. Histone methylation additionally regulates or is regulated by other cellular pathways that contribute to or combat aging. Given the numerous processes that regulate aging and histone methylation, and are in turn regulated by them, the role of histone methylation in aging is almost certainly underappreciated. PMID:24859460

  18. Reconstitution of Nucleosomes with Differentially Isotope-labeled Sister Histones.

    Science.gov (United States)

    Liokatis, Stamatios

    2017-03-26

    Asymmetrically modified nucleosomes contain the two copies of a histone (sister histones) decorated with distinct sets of Post-translational Modifications (PTMs). They are newly identified species with unknown means of establishment and functional implications. Current analytical methods are inadequate to detect the copy-specific occurrence of PTMs on the nucleosomal sister histones. This protocol presents a biochemical method for the in vitro reconstitution of nucleosomes containing differentially isotope-labeled sister histones. The generated complex can be also asymmetrically modified, after including a premodified histone pool during refolding of histone subcomplexes. These asymmetric nucleosome preparations can be readily reacted with histone-modifying enzymes to study modification cross-talk mechanisms imposed by the asymmetrically pre-incorporated PTM using nuclear magnetic resonance (NMR) spectroscopy. Particularly, the modification reactions in real-time can be mapped independently on the two sister histones by performing different types of NMR correlation experiments, tailored for the respective isotope type. This methodology provides the means to study crosstalk mechanisms that contribute to the formation and propagation of asymmetric PTM patterns on nucleosomal complexes.

  19. Biotinylation is a natural, albeit rare, modification of human histones

    Science.gov (United States)

    Kuroishi, Toshinobu; Rios-Avila, Luisa; Pestinger, Valerie; Wijeratne, Subhashinee S. K.; Zempleni, Janos

    2011-01-01

    Previous studies suggest that histones H3 and H4 are posttranslationally modified by binding of the vitamin biotin, catalyzed by holocarboxylase synthetase (HCS). Albeit a rare epigenetic mark, biotinylated histones were repeatedly shown to be enriched in repeat regions and repressed loci, participating in the maintenance of genome stability and gene regulation. Recently, a team of investigators failed to detect biotinylated histones and proposed that biotinylation is not a natural modification of histones, but rather an assay artifact. Here, we describe the results of experiments, including the comparison of various analytical protocols, antibodies, cell lines, classes of histones, and radiotracers. These studies provide unambiguous evidence that biotinylation is a natural, albeit rare, histone modification. Less than 0.001% of human histones H3 and H4 are biotinylated, raising concerns that the abundance might too low to elicit biological effects in vivo. We integrated information from this study, previous studies, and ongoing research efforts to present a new working model in which biological effects are caused by a role of HCS in multiprotein complexes in chromatin. In this model, docking of HCS in chromatin causes the occasional binding of biotin to histones as a tracer for HCS binding sites. PMID:21930408

  20. Heparin defends against the toxicity of circulating histones in sepsis.

    Science.gov (United States)

    Wang, Feifei; Zhang, Naipu; Li, Biru; Liu, Lanbo; Ding, Lei; Wang, Ying; Zhu, Yimin; Mo, Xi; Cao, Qing

    2015-06-01

    Although circulating histones were demonstrated as major mediators of death in septic mice models, their roles in septic patients are not clarified. The present study sought to evaluate the clinical relevance of the circulating histone levels in septic children, and the antagonizing effects of heparin on circulating histones. Histone levels in the plasma of septic children were significantly higher than healthy controls, and positively correlated with disease severity. Histone treatment could activate NF-κB pathway of the endothelial cells and induce the secretion of large amount of cytokines that further amplify inflammation, subsequently leading to organ damage. Co-injection of low dose heparin with lethal dose histones could protect mouse from organ damage and death by antagonizing circulating histones, and similar effects were also observed in other septic models. Collectively, these findings indicated that circulating histones might serve as key factors in the pathogenesis of sepsis and their levels in plasma might be a marker for disease progression and prognosis. Furthermore, low dose heparin might be an effective therapy to hamper sepsis progression and reduce the mortality.

  1. UTAP, U Tailings Assessment Program

    International Nuclear Information System (INIS)

    Holmes, Ron

    1998-01-01

    1 - Description of program or function: UTAP carries out probabilistic analyses of the behaviour and environmental effects of uranium mill tailings, following close-out of milling operations. The models have been designed to allow predictions to be made for distances up to 50 kilometers in all directions from the tailings area. The models include features which include the ability to incorporate different receptors and site characteristics and to deal with input parameters which vary with time. 2 - Method of solution: UTAP is composed of a number of modules. These may be classified as either component or control modules. Component modules (or models) are the programs directly concerned with the simulation of a uranium tailings physical system; that is the computer implementation of the mathematical models representing the uranium tailings pile and surrounding environment. Control modules provide the infrastructure for probabilistic analysis using the component modules. These functions include probabilistic sampling of input parameters such as constant, normal, log-normal, uniform, log-uniform, triangular, Weibull, Beta, arbitrary and correlated. The sampling method used is straight Monte Carlo. The radionuclides modelled are: natural uranium, total thorium, radium-226, radon-222 and lead-210. The pH of the reference uranium tailings site and a chained river-lake system are also modelled. For the afore- mentioned radionuclides the following pathways of dose to the receptors modelled: water consumption, fish consumption, radon inhalation, dust inhalation, vegetable consumption, animal produce consumption and ground-shine. 3 - Restrictions on the complexity of the problem: The maximum number of steps through time allowed is 300

  2. Immune activation by histones: plusses and minuses in inflammation.

    Science.gov (United States)

    Pisetsky, David S

    2013-12-01

    Histones are highly cationic proteins that are essential components of the cell nucleus, interacting with DNA to form the nucleosome and regulating transcription. Histones, however, can transit from the cell nucleus during cell death and, once in an extracellular location, can serve as danger signals and activate immune cells. An article in this issue of the European Journal of Immunology [Eur. J. Immunol. 2013. 43: 3336-3342] reports that histones can activate monocyte-derived DCs via the NRLP3 inflammasome to induce the production of IL-1β. As such, histones, which can also stimulate TLRs, may drive events in the immunopathogenesis of a wide range of acute and chronic diseases marked by sterile inflammation. While the mechanism of this stimulation is not known, the positive charge of histones may provide a structural element to promote interaction with cells and activation of downstream signaling systems. © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Acid-Urea Gel Electrophoresis and Western Blotting of Histones.

    Science.gov (United States)

    Hazzalin, Catherine A; Mahadevan, Louis C

    2017-01-01

    Acid-urea gel electrophoresis offers significant advantages over SDS-PAGE for analysis of post-translational protein modifications, being capable of resolving proteins of similar size but varying in charge. Hence, it can be used to separate protein variants with small charge-altering differences in primary sequence, and is particularly useful in the analysis of histones whose charge variation arises from post-translational modification, such as phosphorylation or acetylation. On acid-urea gels, histones that carry multiple modifications, each with a characteristic charge, are resolved into distinct bands, the so-called "histone ladder." Thus, the extent and distribution of different modification states of histones can be visualized. Here, we describe the analysis of histone H3 by acid-urea gel electrophoresis and western blotting.

  4. The role of extracellular histones in haematological disorders.

    Science.gov (United States)

    Alhamdi, Yasir; Toh, Cheng-Hock

    2016-06-01

    Over the past decades, chromosomal alterations have been extensively investigated for their pathophysiological relevance in haematological malignancies. In particular, epigenetic modifications of intra-nuclear histones are now known as key regulators of healthy cell cycles that have also evolved into novel therapeutic targets for certain blood cancers. Thus, for most haematologists, histones are DNA-chained proteins that are buried deep within chromatin. However, the plot has deepened with recent revelations on the function of histones when unchained and released extracellularly upon cell death or from activated neutrophils as part of neutrophil extracellular traps (NETs). Extracellular histones and NETs are increasingly recognized for profound cytotoxicity and pro-coagulant effects. This article highlights the importance of recognizing this new paradigm of extracellular histones as a key player in host defence through its damage-associated molecular patterns, which could translate into novel diagnostic and therapeutic biomarkers in various haematological and critical disorders. © 2016 John Wiley & Sons Ltd.

  5. Engineering assessment of inactive uranium mill tailings, Durango Site, Durango, Colorado

    International Nuclear Information System (INIS)

    1981-06-01

    Ford, Bacon and Davis Utah Inc. has reevaluated the Durango site in order to revise the November 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Durango, Colorado. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the nearly 1.6 million tons of tailings at the Durango site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The four alternative actions presented in this engineering assessment range from millsite and off-site decontamination with the addition of 3 m of stabilization cover material (Option I), to removal of the tailings to remote disposal sites and decontamination of the tailings site (Options II through IV). Cost estimates for the seven options range from about $10,700,000 for stabilization in-place, to about $21,800,000 for disposal at a distance of about 10 mi. Three principal alternatives for the reprocessing of the Durango tailings were examined: (a) heap leaching; (b) treatment at an existing mill; and (c) reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be about $30/lb U 3 O 8 by either heap leach or conventional plant processes

  6. Engineering assessment of inactive uranium mill tailings: Monument Valley Site, Monument Valley, Arizona

    Energy Technology Data Exchange (ETDEWEB)

    1981-10-01

    Ford, Bacon and Davis Utah Inc. has reevalated the Monument Valley site in order to revise the March 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Monument Valley, Arizona. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposure of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 1.1 million tons of tailings at the Monument Valley site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The four alternative actions presented in this engineering assessment range from millsite decontamination with the addition of 3 m of stabilization cover material (Option I), to removal of the tailings to remote disposal sites and decontamination of the tailings site (Options II through IV). Cost estimates for the four options range from about $6,600,000 for stabilization in-place, to about $15,900,000 for disposal at a distance of about 15 mi. Three principal alternatives for reprocessing the Monument Valley tailings were examined: heap leaching; Treatment at an existing mill; and reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovery is economically unattractive.

  7. Engineering assessment of inactive uranium mill tailings: Monument Valley Site, Monument Valley, Arizona

    International Nuclear Information System (INIS)

    1981-10-01

    Ford, Bacon and Davis Utah Inc. has reevalated the Monument Valley site in order to revise the March 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Monument Valley, Arizona. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposure of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 1.1 million tons of tailings at the Monument Valley site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The four alternative actions presented in this engineering assessment range from millsite decontamination with the addition of 3 m of stabilization cover material (Option I), to removal of the tailings to remote disposal sites and decontamination of the tailings site (Options II through IV). Cost estimates for the four options range from about $6,600,000 for stabilization in-place, to about $15,900,000 for disposal at a distance of about 15 mi. Three principal alternatives for reprocessing the Monument Valley tailings were examined: heap leaching; Treatment at an existing mill; and reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovery is economically unattractive

  8. Twin Tail/Delta Wing Configuration Buffet Due to Unsteady Vortex Breakdown Flow

    Science.gov (United States)

    Kandil, Osama A.; Sheta, Essam F.; Massey, Steven J.

    1996-01-01

    The buffet response of the twin-tail configuration of the F/A-18 aircraft; a multidisciplinary problem, is investigated using three sets of equations on a multi-block grid structure. The first set is the unsteady, compressible, full Navier-Stokes equations. The second set is the coupled aeroelastic equations for bending and torsional twin-tail responses. The third set is the grid-displacement equations which are used to update the grid coordinates due to the tail deflections. The computational model consists of a 76 deg-swept back, sharp edged delta wing of aspect ratio of one and a swept-back F/A-18 twin-tails. The configuration is pitched at 32 deg angle of attack and the freestream Mach number and Reynolds number are 0.2 and 0.75 x 10(exp 6) respectively. The problem is solved for the initial flow conditions with the twin tail kept rigid. Next, the aeroelastic equations of the tails are turned on along with the grid-displacement equations to solve for the uncoupled bending and torsional tails response due to the unsteady loads produced by the vortex breakdown flow of the vortex cores of the delta wing. Two lateral locations of the twin tail are investigated. These locations are called the midspan and inboard locations.

  9. Segregation and differential settling in flocculated tailings

    Energy Technology Data Exchange (ETDEWEB)

    Farinato, R.S.; Mahmoudkhani, A.; Fenderson, T.; Watson, P. [Kemira, Atlanta, GA (United States)

    2010-07-01

    Untreated oil sands tailings have a high solids content, have poor dewaterability, and contain no aggregates. This PowerPoint presentation investigated segregation and differential settling in flocculated tailings. Tailings were treated with gypsum and various polymers. Cylinder settling, dynamic rheometry, particle size analysis, and microscopy techniques were used to characterize the composite tailings. The particles sizes of the samples were evaluated in relation to shear rate, bed depth, and treatment. The study showed that the gypsum-treated tailings had small aggregates, size stratification, a high solids content, and poor dewaterability. The polymer N-treated tailings had the lowest solids content, good dewaterability, and weak aggregates. The polymer A-treated tailings had a low solids content, very good dewaterability, and strong aggregates. The addition of a coagulant to the polymer-A treated tailings provided weaker aggregates and a higher solids content. tabs., figs.

  10. Health risks from uranium mill tailings

    International Nuclear Information System (INIS)

    Russell, J.L.

    1992-01-01

    This paper reviews the risk to public health and the environment from uranium mill tailings. The steps taken by the Environmental Protection Agency (EPA) to reduce this risk from tailing are summarized

  11. Potential non-oncological applications of histone deacetylase inhibitors.

    Science.gov (United States)

    Ververis, Katherine; Karagiannis, Tom C

    2011-01-01

    Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutic drugs. Their clinical utility in oncology stems from their intrinsic cytotoxic properties and combinatorial effects with other conventional cancer therapies. To date, the histone deacetylase inhibitors suberoylanilide hydroxamic acid (Vorinostat, Zolinza®) and depsipeptide (Romidepsin, Istodax®) have been approved by the US Food and Drug Administration for the treatment of refractory cutaneous T-cell lymphoma. Further, there are currently over 100 clinical trials involving the use of histone deacetylase inhibitors in a wide range of solid and hematological malignancies. The therapeutic potential of histone deacetylase inhibitors has also been investigated for numerous other diseases. For example, the cytotoxic properties of histone deacetylase inhibitors are currently being harnessed as a potential treatment for malaria, whereas the efficacy of these compounds for HIV relies on de-silencing latent virus. The anti-inflammatory properties of histone deacetylase inhibitors are the predominant mechanisms for other diseases, such as hepatitis, systemic lupus erythematosus and a wide range of neurodegenerative conditions. Additionally, histone deacetylase inhibitors have been shown to be efficacious in animal models of cardiac hypertrophy and asthma. Broad-spectrum histone deacetylase inhibitors are clinically available and have been used almost exclusively in preclinical systems to date. However, it is emerging that class- or isoform-specific compounds, which are becoming more readily available, may be more efficacious particularly for non-oncological applications. The aim of this review is to provide an overview of the effects and clinical potential of histone deacetylase inhibitors in various diseases. Apart from applications in oncology, the discussion is focused on the potential efficacy of histone deacetylase inhibitors for the treatment of neurodegenerative diseases, cardiac

  12. Single Nucleotide Polymorphisms in the HIRA Gene Affect Litter Size in Small Tail Han Sheep

    Directory of Open Access Journals (Sweden)

    Mei Zhou

    2018-05-01

    Full Text Available Maintenance of appropriate levels of fecundity is critical for efficient sheep production. Opportunities to increase sheep litter size include identifying single gene mutations with major effects on ovulation rate and litter size. Whole-genome sequencing (WGS data of 89 Chinese domestic sheep from nine different geographical locations and ten Australian sheep were analyzed to detect new polymorphisms affecting litter size. Comparative genomic analysis of sheep with contrasting litter size detected a novel set of candidate genes. Two SNPs, g.71874104G>A and g.71833755T>C, were genotyped in 760 Small Tail Han sheep and analyzed for association with litter size. The two SNPs were significantly associated with litter size, being in strong linkage disequilibrium in the region 71.80–71.87 Mb. This haplotype block contains one gene that may affect litter size, Histone Cell Cycle Regulator (HIRA. HIRA mRNA levels in sheep with different lambing ability were significantly higher in ovaries of Small Tail Han sheep (high fecundity than in Sunite sheep (low fecundity. Moreover, the expression levels of HIRA in eight tissues of uniparous Small Tail Han sheep were significantly higher than in multiparous Small Tail Han sheep (p < 0.05. HIRA SNPs significantly affect litter size in sheep and are useful as genetic markers for litter size.

  13. Yeast linker histone Hho1p is required for efficient RNA polymerase I processivity and transcriptional silencing at the ribosomal DNA

    OpenAIRE

    Levy, Anat; Eyal, Miri; Hershkovits, Gitit; Salmon-Divon, Mali; Klutstein, Michael; Katcoff, Don Jay

    2008-01-01

    Nucleosome core particles in eukaryotes are linked by a stretch of DNA that is usually associated with a linker histone. Here, we show in yeast, that the presence of yeast linker histone Hho1p represses expression of a pol II transcribed gene (MET15) embedded in the rDNA. In vivo deletions of Hho1p sequences showed that the second globular domain is sufficient for that repression, whereas the presence of the N terminus is required for its derepression. In contrast, a run-on assay confirmed by...

  14. Risk assessment of tailings facility dam failure

    OpenAIRE

    Hadzi-Nikolova, Marija; Mirakovski, Dejan; Stefanova, Violeta

    2011-01-01

    This paper presents the consequences of tailings facility dam failure and therefore the needs for its risk assessment. Tailings are fine-grained wastes of the mining industry, output as slurries, due to mixing with water during mineral processing. Tailings dams vary a lot as it is affected by: tailings characteristics and mill output, site characteristics as: topography, hydrology, geology, groundwater, seismicity and available material and disposal methods. The talings which accumulat...

  15. Cloning and characterization of the major histone H2A genes completes the cloning and sequencing of known histone genes of Tetrahymena thermophila.

    Science.gov (United States)

    Liu, X; Gorovsky, M A

    1996-01-01

    A truncated cDNA clone encoding Tetrahymena thermophila histone H2A2 was isolated using synthetic degenerate oligonucleotide probes derived from H2A protein sequences of Tetrahymena pyriformis. The cDNA clone was used as a homologous probe to isolate a truncated genomic clone encoding H2A1. The remaining regions of the genes for H2A1 (HTA1) and H2A2 (HTA2) were then isolated using inverse PCR on circularized genomic DNA fragments. These partial clones were assembled into intact HTA1 and HTA2 clones. Nucleotide sequences of the two genes were highly homologous within the coding region but not in the noncoding regions. Comparison of the deduced amino acid sequences with protein sequences of T. pyriformis H2As showed only two and three differences respectively, in a total of 137 amino acids for H2A1, and 132 amino acids for H2A2, indicating the two genes arose before the divergence of these two species. The HTA2 gene contains a TAA triplet within the coding region, encoding a glutamine residue. In contrast with the T. thermophila HHO and HTA3 genes, no introns were identified within the two genes. The 5'- and 3'-ends of the histone H2A mRNAs; were determined by RNase protection and by PCR mapping using RACE and RLM-RACE methods. Both genes encode polyadenylated mRNAs and are highly expressed in vegetatively growing cells but only weakly expressed in starved cultures. With the inclusion of these two genes, T. thermophila is the first organism whose entire complement of known core and linker histones, including replication-dependent and basal variants, has been cloned and sequenced. PMID:8760889

  16. Cylinder Symmetric Measures with the Tail Property

    NARCIS (Netherlands)

    Balkema, A.A.

    2006-01-01

    Abstract: A Pareto distribution has the property that any tail of the distribution has the same shape as the original distribution. The exponential distribution and the uniform distribution have the tail property too. The tail property characterizes the univariate generalized Pareto distributions.

  17. Recombinant thrombomodulin protects mice against histone-induced lethal thromboembolism.

    Directory of Open Access Journals (Sweden)

    Mayumi Nakahara

    Full Text Available INTRODUCTION: Recent studies have shown that histones, the chief protein component of chromatin, are released into the extracellular space during sepsis, trauma, and ischemia-reperfusion injury, and act as major mediators of the death of an organism. This study was designed to elucidate the cellular and molecular basis of histone-induced lethality and to assess the protective effects of recombinant thrombomodulin (rTM. rTM has been approved for the treatment of disseminated intravascular coagulation (DIC in Japan, and is currently undergoing a phase III clinical trial in the United States. METHODS: Histone H3 levels in plasma of healthy volunteers and patients with sepsis and DIC were measured using enzyme-linked immunosorbent assay. Male C57BL/6 mice were injected intravenously with purified histones, and pathological examinations were performed. The protective effects of rTM against histone toxicity were analyzed both in vitro and in mice. RESULTS: Histone H3 was not detectable in plasma of healthy volunteers, but significant levels were observed in patients with sepsis and DIC. These levels were higher in non-survivors than in survivors. Extracellular histones triggered platelet aggregation, leading to thrombotic occlusion of pulmonary capillaries and subsequent right-sided heart failure in mice. These mice displayed symptoms of DIC, including thrombocytopenia, prolonged prothrombin time, decreased fibrinogen, fibrin deposition in capillaries, and bleeding. Platelet depletion protected mice from histone-induced death in the first 30 minutes, suggesting that vessel occlusion by platelet-rich thrombi might be responsible for death during the early phase. Furthermore, rTM bound to extracellular histones, suppressed histone-induced platelet aggregation, thrombotic occlusion of pulmonary capillaries, and dilatation of the right ventricle, and rescued mice from lethal thromboembolism. CONCLUSIONS: Extracellular histones cause massive

  18. Histone deacetylase inhibitors (HDACIs: multitargeted anticancer agents

    Directory of Open Access Journals (Sweden)

    Ververis K

    2013-02-01

    Full Text Available Katherine Ververis,1 Alison Hiong,1 Tom C Karagiannis,1,* Paul V Licciardi2,*1Epigenomic Medicine, Alfred Medical Research and Education Precinct, 2Allergy and Immune Disorders, Murdoch Childrens Research Institute, Melbourne, VIC, Australia*These authors contributed equally to this workAbstract: Histone deacetylase (HDAC inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza and depsipeptide (romidepsin, Istodax. More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the

  19. Histone Deacetylase Inhibitor Alleviates the Neurodegenerative Phenotypes and Histone Dysregulation in Presenilins-Deficient Mice

    Directory of Open Access Journals (Sweden)

    Ting Cao

    2018-05-01

    Full Text Available Histone acetylation has been shown to play a crucial role in memory formation, and histone deacetylase (HDAC inhibitor sodium butyrate (NaB has been demonstrated to improve memory performance and rescue the neurodegeneration of several Alzheimer’s Disease (AD mouse models. The forebrain presenilin-1 and presenilin-2 conditional double knockout (cDKO mice showed memory impairment, forebrain degeneration, tau hyperphosphorylation and inflammation that closely mimics AD-like phenotypes. In this article, we have investigated the effects of systemic administration of NaB on neurodegenerative phenotypes in cDKO mice. We found that chronic NaB treatment significantly restored contextual memory but did not alter cued memory in cDKO mice while such an effect was not permanent after treatment withdrawal. We further revealed that NaB treatment did not rescue reduced synaptic numbers and cortical shrinkage in cDKO mice, but significantly increased the neurogenesis in subgranular zone of dentate gyrus (DG. We also observed that tau hyperphosphorylation and inflammation related protein glial fibrillary acidic protein (GFAP level were decreased in cDKO mice by NaB. Furthermore, GO and pathway analysis for the RNA-Seq data demonstrated that NaB treatment induced enrichment of transcripts associated with inflammation/immune processes and cytokine-cytokine receptor interactions. RT-PCR confirmed that NaB treatment inhibited the expression of inflammation related genes such as S100a9 and Ccl4 found upregulated in the brain of cDKO mice. Surprisingly, the level of brain histone acetylation in cDKO mice was dramatically increased and was decreased by the administration of NaB, which may reflect dysregulation of histone acetylation underlying memory impairment in cDKO mice. These results shed some lights on the possible molecular mechanisms of HDAC inhibitor in alleviating the neurodegenerative phenotypes of cDKO mice and provide a promising target for treating AD.

  20. histoneHMM: Differential analysis of histone modifications with broad genomic footprints

    Czech Academy of Sciences Publication Activity Database

    Heinig, M.; Colomé-Tatché, M.; Taudt, A.; Rintisch, C.; Schafer, S.; Pravenec, Michal; Hubner, N.; Vingron, M.; Johannes, F.

    2015-01-01

    Roč. 16, Feb 22 (2015), s. 60 ISSN 1471-2105 R&D Projects: GA MŠk(CZ) 7E10067; GA ČR(CZ) GA13-04420S Institutional support: RVO:67985823 Keywords : ChIP - seq * histone modifications * Hidden Markov model * computational biology * differential analysis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.435, year: 2015

  1. Dysregulation of Histone Acetyltransferases and Deacetylases in Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Yonggang Wang

    2014-01-01

    Full Text Available Cardiovascular disease (CVD remains a leading cause of mortality worldwide despite advances in its prevention and management. A comprehensive understanding of factors which contribute to CVD is required in order to develop more effective treatment options. Dysregulation of epigenetic posttranscriptional modifications of histones in chromatin is thought to be associated with the pathology of many disease models, including CVD. Histone acetyltransferases (HATs and deacetylases (HDACs are regulators of histone lysine acetylation. Recent studies have implicated a fundamental role of reversible protein acetylation in the regulation of CVDs such as hypertension, pulmonary hypertension, diabetic cardiomyopathy, coronary artery disease, arrhythmia, and heart failure. This reversible acetylation is governed by enzymes that HATs add or HDACs remove acetyl groups respectively. New evidence has revealed that histone acetylation regulators blunt cardiovascular and related disease states in certain cellular processes including myocyte hypertrophy, apoptosis, fibrosis, oxidative stress, and inflammation. The accumulating evidence of the detrimental role of histone acetylation in cardiac disease combined with the cardioprotective role of histone acetylation regulators suggests that the use of histone acetylation regulators may serve as a novel approach to treating the millions of patients afflicted by cardiac diseases worldwide.

  2. Aging and radiation induced alternations in liver histones

    International Nuclear Information System (INIS)

    Kozurkova, M.; Misurova, E.; Kropacova, K.

    1994-01-01

    Age-related changes in histones in the liver of normal rats and in rats irradiated with 5.7 Gy gamma rays were examined. Quantitative histone changes in growing and aging rats (from 1 to 28 months of age) were found to be mild only. As they paralleled the DNA changes, the histone /DNA ratio remained stable with age. In total extracted histones there was a decrease in the H1 proportion in older groups with preceding increase in the H1 grad proportion. Thirty minutes after irradiation the amount of histones was reduced with age, probably due to an impaired extractability of histones. As the quantitative DNA changes were milder, the histone?DNA ratio decreased in aging liver after irradiation. Similar patterns of changes in proportion of the H1 fraction and H1 grad sub-fraction were observed in irradiated and nonirradiated animals in the former with an earlier onset. Irradiation, therefore, accelerated spontaneous age-related alternations. (author)

  3. Numerical modelling for stability of tailings dams

    OpenAIRE

    Auchar, Muhammad; Mattsson, Hans; Knutsson, Sven

    2013-01-01

    A tailings dam is a large embankment structure that is constructed to store the waste from the mining industry. Stability problems may occur in a tailings dam due to factors such as quick rate of raising, internal erosion and liquefaction. The failure of a tailings dam may cause loss of human life and environmental degradation. Tailings Dams must not only be stable during the time the tailings storage facility is in operation, but also long time after the mine is closed. In Sweden, the licens...

  4. SHOCKING TAILS IN THE MAJOR MERGER ABELL 2744

    Energy Technology Data Exchange (ETDEWEB)

    Owers, Matt S.; Couch, Warrick J. [Center for Astrophysics and Supercomputing, Swinburne University of Technology, Hawthorn, VIC 3122 (Australia); Nulsen, Paul E. J.; Randall, Scott W., E-mail: mowers@aao.gov.au [Harvard Smithsonian Center for Astrophysics, 60 Garden Street, Cambridge, MA 02138 (United States)

    2012-05-01

    We identify four rare 'jellyfish' galaxies in Hubble Space Telescope imagery of the major merger cluster Abell 2744. These galaxies harbor trails of star-forming knots and filaments which have formed in situ in gas tails stripped from the parent galaxies, indicating they are in the process of being transformed by the environment. Further evidence for rapid transformation in these galaxies comes from their optical spectra, which reveal starburst, poststarburst, and active galactic nucleus features. Most intriguingly, three of the jellyfish galaxies lie near intracluster medium features associated with a merging 'Bullet-like' subcluster and its shock front detected in Chandra X-ray images. We suggest that the high-pressure merger environment may be responsible for the star formation in the gaseous tails. This provides observational evidence for the rapid transformation of galaxies during the violent core passage phase of a major cluster merger.

  5. Circulating histones are mediators of trauma-associated lung injury.

    Science.gov (United States)

    Abrams, Simon T; Zhang, Nan; Manson, Joanna; Liu, Tingting; Dart, Caroline; Baluwa, Florence; Wang, Susan Siyu; Brohi, Karim; Kipar, Anja; Yu, Weiping; Wang, Guozheng; Toh, Cheng-Hock

    2013-01-15

    Acute lung injury is a common complication after severe trauma, which predisposes patients to multiple organ failure. This syndrome largely accounts for the late mortality that arises and despite many theories, the pathological mechanism is not fully understood. Discovery of histone-induced toxicity in mice presents a new dimension for elucidating the underlying pathophysiology. To investigate the pathological roles of circulating histones in trauma-induced lung injury. Circulating histone levels in patients with severe trauma were determined and correlated with respiratory failure and Sequential Organ Failure Assessment (SOFA) scores. Their cause-effect relationship was studied using cells and mouse models. In a cohort of 52 patients with severe nonthoracic blunt trauma, circulating histones surged immediately after trauma to levels that were toxic to cultured endothelial cells. The high levels were significantly associated with the incidence of acute lung injury and SOFA scores, as well as markers of endothelial damage and coagulation activation. In in vitro systems, histones damaged endothelial cells, stimulated cytokine release, and induced neutrophil extracellular trap formation and myeloperoxidase release. Cellular toxicity resulted from their direct membrane interaction and resultant calcium influx. In mouse models, cytokines and markers for endothelial damage and coagulation activation significantly increased immediately after trauma or histone infusion. Pathological examinations showed that lungs were the predominantly affected organ with edema, hemorrhage, microvascular thrombosis, and neutrophil congestion. An anti-histone antibody could reduce these changes and protect mice from histone-induced lethality. This study elucidates a new mechanism for acute lung injury after severe trauma and proposes that circulating histones are viable therapeutic targets for improving survival outcomes in patients.

  6. Circulating Histones Are Mediators of Trauma-associated Lung Injury

    Science.gov (United States)

    Abrams, Simon T.; Zhang, Nan; Manson, Joanna; Liu, Tingting; Dart, Caroline; Baluwa, Florence; Wang, Susan Siyu; Brohi, Karim; Kipar, Anja; Yu, Weiping

    2013-01-01

    Rationale: Acute lung injury is a common complication after severe trauma, which predisposes patients to multiple organ failure. This syndrome largely accounts for the late mortality that arises and despite many theories, the pathological mechanism is not fully understood. Discovery of histone-induced toxicity in mice presents a new dimension for elucidating the underlying pathophysiology. Objectives: To investigate the pathological roles of circulating histones in trauma-induced lung injury. Methods: Circulating histone levels in patients with severe trauma were determined and correlated with respiratory failure and Sequential Organ Failure Assessment (SOFA) scores. Their cause–effect relationship was studied using cells and mouse models. Measurements and Main Results: In a cohort of 52 patients with severe nonthoracic blunt trauma, circulating histones surged immediately after trauma to levels that were toxic to cultured endothelial cells. The high levels were significantly associated with the incidence of acute lung injury and SOFA scores, as well as markers of endothelial damage and coagulation activation. In in vitro systems, histones damaged endothelial cells, stimulated cytokine release, and induced neutrophil extracellular trap formation and myeloperoxidase release. Cellular toxicity resulted from their direct membrane interaction and resultant calcium influx. In mouse models, cytokines and markers for endothelial damage and coagulation activation significantly increased immediately after trauma or histone infusion. Pathological examinations showed that lungs were the predominantly affected organ with edema, hemorrhage, microvascular thrombosis, and neutrophil congestion. An anti-histone antibody could reduce these changes and protect mice from histone-induced lethality. Conclusions: This study elucidates a new mechanism for acute lung injury after severe trauma and proposes that circulating histones are viable therapeutic targets for improving survival

  7. Thermal stabilization of uranium mill tailings

    International Nuclear Information System (INIS)

    Dreesen, D.R.; Williams, J.M.; Cokal, E.J.

    1981-01-01

    The sintering of tailings at high temperatures (1200 0 C) has shown promise as a conditioning approach that greatly reduces the 222 Rn emanation of uranium mill tailings. The structure of thermally stabilized tailings has been appreciably altered producing a material that will have minimal management requirements and will be applicable to on-site processing and disposal. The mineralogy of untreated tailings is presented to define the structure of the original materials. Quartz predominates in most tailings samples; however, appreciable quantities of gypsum, clay, illite, or albites are found in some tailings. Samples from the Durango and Shiprock sites have plagioclase-type aluminosilicates and non-aluminum silicates as major components. The iron-rich vanadium tailings from the Salt Lake City site contain appreciable quantities of α-hematite and chloroapatite. The reduction in radon emanation power and changes in mineralogy as a function of sintering temperature are presented

  8. Ecotoxicity of Mine Tailings: Unrehabilitated Versus Rehabilitated.

    Science.gov (United States)

    Maboeta, M S; Oladipo, O G; Botha, S M

    2018-05-01

    Earthworms are bioindicators of soil pollution. The ecotoxicity of tailings from selected gold mines in South Africa was investigated utilizing Eisenia andrei bioassays and biomarkers. Samples were obtained from unrehabilitated, rehabilitated and naturally vegetated sites. Biomass, neutral red retention time (NRRT), survival and reproduction were assessed using standardized protocols. Earthworm biomass, NRRT and reproductive success in rehabilitated tailings (comparable to naturally vegetated site) were significantly higher (p tailings. In addition, significantly lower (p tailings compared to the unrehabilitated. Further, significantly lower (p tailings than the rehabilitated and naturally vegetated sites. Overall, reduced ecotoxicity effects were confirmed in rehabilitated compared to unrehabilitated tailings. This suggests that rehabilitation as a post-mining restorative strategy has strong positive influence on mine tailings.

  9. Mineralogy and geochemistry of uranium mill tailings

    International Nuclear Information System (INIS)

    Pagel, M.; Somot, S.

    2002-01-01

    We have investigated three main types of uranium mill tailings: (1) acid mill tailings (Mounana, Gabon), (2) neutralized acid mill tailings (Ecarpiere and Jouac, France) and (3) alkaline mill tailings (Lodeve, France). We have focused especially on radium behaviour which is of major environmental concern in these tailings, but other metals were also studied. It is shown that in type 1 , trapping of 226 Ra by anglesite and barite is dominant whereas in types 2 and 3, 226 Ra is mainly or significantly scavenged by Fe- Mn oxyhydroxides. This study points out the importance of keeping conditions in which these oxyhydroxides will be stable for the long-term. Uranium would be also released during acidification of the tailings. This shows the importance to know more about the behavior of Ra during the crystallization of oxyhydroxides and during tailings diagenesis. Therefore, it is very important to study the sorption of Ra by clay minerals or late authigeneous minerals such as barite. (author)

  10. Summary of the engineering assessment of inactive uranium mill tailings: Falls City site, Falls City, Texas

    International Nuclear Information System (INIS)

    1981-10-01

    Ford, Bacon and Davis Utah Inc. has reevaluated the Falls City site in order to update the December 1977 engineering assessment of the problems resulting from the existence of radioactive uranum mill tailings at Falls City, Texas. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrolgy and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 2.5 million tons of tailings at the Falls City site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The four alternative actions presented in this engineering assessment range from millsite decontamination with the addition of 3 m of stabilization cover material, to removal of the tailings to remote disposal sites and decontamination of the tailings site. Cost estimates for the four options range from about $21,700,000 for stabilization in place, to about $35,100,000 for disposal at a distance of about 15 mi. Three principal alternatives for the reprocessing of the Falls City tailings were examined: heap leaching; treatment at an existing mill; reprocessing at a new conventional mill constructed for tailings reprocessing. The tailings piles are presently being rewashed for uranium recovery by Solution Engineering, Inc. The cost for further reprocessing would be about $250/lb of U 3 O 8 . The spot market price for uranium was $25/lb early in 1981. Therefore, reprocessing the tailings for uranium recovery does not appear to be economically attractive for the foreseeable future

  11. Summary of the engineering assessment of inactive uranium mill tailings. Vitro site, Salt Lake City, Utah

    International Nuclear Information System (INIS)

    1981-04-01

    This report is a summary of a parent report (issued under separate cover) entitled Engineering Assessment of Inactive Uranium Mill Tailings for Vitro Site, Salt Lake City, Utah. Bacon and Davis Utah Inc. has reevaluated the Vitro site in order to revise the April 1976 assessment of the problems resulting from the existence of radioactive uranium mill tailings at Salt Lake City, Utah. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 1.9 million tons of tailings at the Vitro site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The four alternative actions presented in this engineering assessment range from millsite and off-site decontamination with the addition of 3 m of stabilization cover material (Option 1), to removal of the tailings to remote disposal sites, and decontamination of the tailings site (Options II through IV). Cost estimates for the four options range from about $36,400,000 for stabilization in-place, to about $91,000,000 for disposal at a distance of about 85 mi. Three principal alternatives for the reprocessing of the Vitro tailings were examined: heap leaching; treatment at an existing mill; and reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be about $200/lb by heap leach and $130/lb by conventional plant processes. Spot market price for uranium was $28.00 in November 1980. Therefore, reprocessing the tailings for uranium recovery appears to be economically unattractive at present

  12. Syntheses and modulations in the chromatin contents of histones H1/sup o/ and H1 during G1 and S phases in Chinese hamsters cells

    International Nuclear Information System (INIS)

    D'Anna, J.A.; Gurley, L.R.; Tobey, R.A.

    1982-01-01

    Flow cytometry, conventional autoradiography, and autoradiography employing high concentrations of high specific activity [ 3 H]thymidine indicate that (1) treatment of Chinese hamster ovary (line CHO) cells with butyrate truly blocks cells in G 1 and (2) cells blocked in G 1 by isoleucine deprivation remain blocked in G 1 when they are released into complete medium containing butyrate. Measurements of H1/sup o/ content relative to core histones and H1/sup o/:H1 ratios indicate that H1/sup o/ is enhanced somewhat in G 1 cells arrested by isoleucine deprivation; however, (1) treatment with butyrate greatly increases the H1/sup o/ content in G 1 -blocked cells, and (2) the enhancement is very sensitive to butyrate concentration. Measurements of relative histone contents in the isolated chromatin of synchronized cultures also suggest that the acid-soluble content of histone H1 (relative to core histones) becomes greatly depleted in the isolated chromatin when synchronized cells are blocked in early S phase by sequential use of isoleucine deprivation and hydroxyurea blockade. We also have measured [ 3 H]lysine incorporation, various protein ratios, and relative rates of deposition of newly synthesized H1/sup o/, H1, and H4 onto chromatin during G 1 and S in the absence of butyrate. The results suggest a dynamic picture of chromatin organization in which (1) newly synthesized histone H1/sup o/ binds to chromatin during traverse of G 1 and S phases and (2) histone H1 dissociates from (or becomes loosely bound to) chromatin during prolonged early S-phase block with hydroxyurea

  13. Specific distribution of the Saccharomyces cerevisiae linker histone homolog HHO1p in the chromatin

    OpenAIRE

    Freidkin, Ilya; Katcoff, Don J.

    2001-01-01

    In virtually all eukaryotic organisms, linker DNA between nucleosomes is associated with a histone termed linker histone or histone H1. In Saccharomyces cerevisiae, HHO1 encodes a putative linker histone with very significant homology to histone H1. The encoded protein is expressed in the nucleus, but has not been shown to affect global chromatin structure, nor has its deletion shown any detectable phenotype. In vitro chromatin assembly experiments with recombinant HHO1p have shown that it is...

  14. Asymmetry in the burial of hydrophobic residues along the histone chains of Eukarya, Archaea and a transcription factor

    Directory of Open Access Journals (Sweden)

    Silverman B David

    2005-10-01

    Full Text Available Abstract Background The histone fold is a common structural motif of proteins involved in the chromatin packaging of DNA and in transcription regulation. This single chain fold is stabilized by either homo- or hetero-dimer formation in archaea and eukarya. X-ray structures at atomic resolution have shown the eukaryotic nucleosome core particle to consist of a central tetramer of two bound H3-H4 dimers flanked by two H2A-H2B dimers. The c-terminal region of the H3 histone fold involved in coupling the two eukaryotic dimers of the tetramer, through a four-fold helical bundle, had previously been shown to be a region of reduced burial of hydrophobic residues within the dimers, and thereby provide a rationale for the observed reduced stability of the H3-H4 dimer compared with that of the H2A-H2B dimer. Furthermore, comparison between eukaryal and archaeal histones had suggested that this asymmetry in the distribution of hydrophobic residues along the H3 histone chains could be due to selective evolution that enhanced the coupling between the eukaryotic dimers of the tetramer. Results and discussion The present work describes calculations utilizing the X-ray structures at atomic resolution of a hyperthermophile from Methanopyrus kandleri (HMk and a eukaryotic transcription factor from Drosophila melanogaster (DRm, that are structurally homologous to the eukaryotic (H3-H42 tetramer. The results for several other related structures are also described. Reduced burial of hydrophobic residues, at the homologous H3 c-terminal regions of these structures, is found to parallel the burial at the c-terminal regions of the H3 histones and is, thereby, expected to affect dimer stability and the processes involving histone structural rearrangement. Significantly different sequence homology between the two histones of the HMk doublet with other archaeal sequences is observed, and how this might have occurred during selection to enhance tetramer stability is

  15. Which is the most preventive measure against tail damage in finisher pigs: tail docking, straw provision or lowered stocking density?

    DEFF Research Database (Denmark)

    Larsen, Mona Lilian Vestbjerg; Andersen, Heidi Mai-Lis; Pedersen, Lene Juul

    2018-01-01

    One challenge of intensive pig production is tail damage caused by tail biting, and farmers often decrease the prevalence of tail damage through tail docking. However, tail docking is not an optimal preventive measure against tail damage and thus, it would be preferable to replace it. The aim of ...

  16. Engineering assessment of inactive uranium mill tailings, Green River Site, Green River, Utah

    International Nuclear Information System (INIS)

    1981-08-01

    Ford, Bacon and Davis Utah Inc. has reevaluated the Green River site in order to revise the December 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Green River, Utah. This evaluation has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative remedial actions. Radon gas released from the 123,000 tons of tailings at the Green River site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors

  17. Histones and their phosphorylation during germination of rice seeds

    International Nuclear Information System (INIS)

    Iqbal Ahmed, C.M.; Padayatti, J.D.

    1980-01-01

    Histones from nuclei of rice embryos were identified by their mobilities on 15% acid-urea polyacrylamide gel electrophoreogram, incorporation of ( 3 H)lysine and ( 14 C) arginine and lack of incorporation of ( 3 H)tryptophan. The ratio of histone to DNA in ungerminated embryos was 2.7 which decreased during germination reaching unity by 48 hr. There was preferential phosphorylation of lysine-rich histones, which paralleled the synthesis of DNA. In the presence of cytosine arabinoside and mitomycin-C, which inhibited the synthesis of DNA to the extend of 75-80% the phosphorylation of lysine-rich histone was reduced by 50-60% suggesting the dependence of phosphorylation on the ongoing synthesis of DNA. (auth.)

  18. Characterization of oils sands thickened tailings

    Energy Technology Data Exchange (ETDEWEB)

    Scott, J.D.; Jeeravipoolvarn, S.; Donahue, R.; Ozum, B. [Alberta Univ., Edmonton, AB (Canada). Dept. of Civil and Environmental Engineering

    2008-07-01

    This presentation discussed the characterization of oils sands thickened tailings. The problem statement was defined as the fact that many laboratory procedures to characterize fine tailings do not take into account the extraction process, and instead use standardized laboratory tests. The purpose of this presentation was to demonstrate how different extraction processes affect the fine tailings geotechnical properties and water chemistry. Properties that were characterized included particle size analysis from hydrometer-sieve tests; per cent clay from methylene blue tests; per cent clay from mineralogy tests; Atterberg limits; water chemistry; and morphology by scanning electron microscopy. The presentation discussed the origin of fines (silt and clay) in tailings; where fine particles come from; tailings materials; mineralogy of tailings; the hydrometer-sieve test on fine tailings and thickened tailings; and the methylene blue test. It was concluded that the great majority of clay minerals in the tailings come from the clay-shale discontinuous seams and layers. For thickened tailings, the dispersed and non-dispersed hydrometer tests show considerable difference in the amount of clay size material. tabs., figs.

  19. Uranium mill tailings neutralization: contaminant complexation and tailings leaching studies

    International Nuclear Information System (INIS)

    Opitz, B.E.; Dodson, M.E.; Serne, R.J.

    1985-05-01

    Laboratory experiments were performed to compare the effectiveness of limestone (CaCO 3 ) and hydrated lime [Ca(OH) 2 ] for improving waste water quality through the neutralization of acidic uranium mill tailings liquor. The experiments were designed to also assess the effects of three proposed mechanisms - carbonate complexation, elevated pH, and colloidal particle adsorption - on the solubility of toxic contaminants found in a typical uranium mill waste solution. Of special interest were the effects each of these possible mechanisms had on the solution concentrations of trace metals such as Cd, Co, Mo, Zn, and U after neutralization. Results indicated that the neutralization of acidic tailings to a pH of 7.3 using hydrated lime provided the highest overall waste water quality. Both the presence of a carbonate source or elevating solution pH beyond pH = 7.3 resulted in a lowering of previously achieved water quality, while adsorption of contaminants onto colloidal particles was not found to affect the solution concentration of any constituent investigated. 24 refs., 8 figs., 19 tabs

  20. Targeting Histone Abnormality in Triple Negative Breast Cancer

    Science.gov (United States)

    2015-08-01

    κB pathway in triple negative breast cancer . 8th International Nitric Oxide Conference & 6th International Nitrite/ Nitrate Conference, Cleveland, OH...1 AWARD NUMBER: W81XWH-14-1-0237 TITLE: Targeting Histone Abnormality in Triple-Negative Breast Cancer PRINCIPAL INVESTIGATOR: Yi...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Histone Abnormality in Triple-Negative Breast Cancer 5b. GRANT NUMBER W81XWH-14-1-0237 5c

  1. Biochemical studies on histones of the central nervous system. 1

    International Nuclear Information System (INIS)

    Schmitt, M.; Matthies, H.

    1979-01-01

    Rat brain histones were acetylated in vivo by intraventricular injection of [ 14 C]-acetate. More than 90% of the label is the result of a true acetylation. Enzymatic proteolysis of the labelled histone fraction and subsequent chromatographic investigation of the digestion products showed about 60% of the recovered radioactive material to be epsilon-acetyl lysine, whereas 22% of the radioactivity was found in an unidentified spot. (author)

  2. Tail-Cuff Technique and Its Influence on Central Blood Pressure in the Mouse.

    Science.gov (United States)

    Wilde, Elena; Aubdool, Aisah A; Thakore, Pratish; Baldissera, Lineu; Alawi, Khadija M; Keeble, Julie; Nandi, Manasi; Brain, Susan D

    2017-06-27

    Reliable measurement of blood pressure in conscious mice is essential in cardiovascular research. Telemetry, the "gold-standard" technique, is invasive and expensive and therefore tail-cuff, a noninvasive alternative, is widely used. However, tail-cuff requires handling and restraint during measurement, which may cause stress affecting blood pressure and undermining reliability of the results. C57Bl/6J mice were implanted with radio-telemetry probes to investigate the effects of the steps of the tail-cuff technique on central blood pressure, heart rate, and temperature. This included comparison of handling techniques, operator's sex, habituation, and influence of hypertension induced by angiotensin II. Direct comparison of measurements obtained by telemetry and tail-cuff were made in the same mouse. The results revealed significant increases in central blood pressure, heart rate, and core body temperature from baseline following handling interventions without significant difference among the different handling technique, habituation, or sex of the investigator. Restraint induced the largest and sustained increase in cardiovascular parameters and temperature. The tail-cuff readings significantly underestimated those from simultaneous telemetry recordings; however, "nonsimultaneous" telemetry, obtained in undisturbed mice, were similar to tail-cuff readings obtained in undisturbed mice on the same day. This study reveals that the tail-cuff technique underestimates the core blood pressure changes that occur simultaneously during the restraint and measurement phases. However, the measurements between the 2 techniques are similar when tail-cuff readings are compared with telemetry readings in the nondisturbed mice. The differences between the simultaneous recordings by the 2 techniques should be recognized by researchers. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  3. Histone Acetylome-wide Association Study of Autism Spectrum Disorder.

    Science.gov (United States)

    Sun, Wenjie; Poschmann, Jeremie; Cruz-Herrera Del Rosario, Ricardo; Parikshak, Neelroop N; Hajan, Hajira Shreen; Kumar, Vibhor; Ramasamy, Ramalakshmi; Belgard, T Grant; Elanggovan, Bavani; Wong, Chloe Chung Yi; Mill, Jonathan; Geschwind, Daniel H; Prabhakar, Shyam

    2016-11-17

    The association of histone modification changes with autism spectrum disorder (ASD) has not been systematically examined. We conducted a histone acetylome-wide association study (HAWAS) by performing H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) on 257 postmortem samples from ASD and matched control brains. Despite etiological heterogeneity, ≥68% of syndromic and idiopathic ASD cases shared a common acetylome signature at >5,000 cis-regulatory elements in prefrontal and temporal cortex. Similarly, multiple genes associated with rare genetic mutations in ASD showed common "epimutations." Acetylome aberrations in ASD were not attributable to genetic differentiation at cis-SNPs and highlighted genes involved in synaptic transmission, ion transport, epilepsy, behavioral abnormality, chemokinesis, histone deacetylation, and immunity. By correlating histone acetylation with genotype, we discovered >2,000 histone acetylation quantitative trait loci (haQTLs) in human brain regions, including four candidate causal variants for psychiatric diseases. Due to the relative stability of histone modifications postmortem, we anticipate that the HAWAS approach will be applicable to multiple diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Structural Mechanisms of Nucleosome Recognition by Linker Histones.

    Science.gov (United States)

    Zhou, Bing-Rui; Jiang, Jiansheng; Feng, Hanqiao; Ghirlando, Rodolfo; Xiao, T Sam; Bai, Yawen

    2015-08-20

    Linker histones bind to the nucleosome and regulate the structure of chromatin and gene expression. Despite more than three decades of effort, the structural basis of nucleosome recognition by linker histones remains elusive. Here, we report the crystal structure of the globular domain of chicken linker histone H5 in complex with the nucleosome at 3.5 Å resolution, which is validated using nuclear magnetic resonance spectroscopy. The globular domain sits on the dyad of the nucleosome and interacts with both DNA linkers. Our structure integrates results from mutation analyses and previous cross-linking and fluorescence recovery after photobleach experiments, and it helps resolve the long debate on structural mechanisms of nucleosome recognition by linker histones. The on-dyad binding mode of the H5 globular domain is different from the recently reported off-dyad binding mode of Drosophila linker histone H1. We demonstrate that linker histones with different binding modes could fold chromatin to form distinct higher-order structures. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Histone deacetylase inhibition abolishes stress-induced spatial memory impairment.

    Science.gov (United States)

    Vargas-López, Viviana; Lamprea, Marisol R; Múnera, Alejandro

    2016-10-01

    Acute stress induced before spatial training impairs memory consolidation. Although non-epigenetic underpinning of such effect has been described, the epigenetic mechanisms involved have not yet been studied. Since spatial training and intense stress have opposite effects on histone acetylation balance, it is conceivable that disruption of such balance may underlie acute stress-induced spatial memory consolidation impairment and that inhibiting histone deacetylases prevents such effect. Trichostatin-A (TSA, a histone deacetylase inhibitor) was used to test its effectiveness in preventing stress' deleterious effect on memory. Male Wistar rats were trained in a spatial task in the Barnes maze; 1-h movement restraint was applied to half of them before training. Immediately after training, stressed and non-stressed animals were randomly assigned to receive either TSA (1mg/kg) or vehicle intraperitoneal injection. Twenty-four hours after training, long-term spatial memory was tested; plasma and brain tissue were collected immediately after the memory test to evaluate corticosterone levels and histone H3 acetylation in several brain areas. Stressed animals receiving vehicle displayed memory impairment, increased plasma corticosterone levels and markedly reduced histone H3 acetylation in prelimbic cortex and hippocampus. Such effects did not occur in stressed animals treated with TSA. The aforementioned results support the hypothesis that acute stress induced-memory impairment is related to histone deacetylation. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Biochemical Analysis Reveals the Multifactorial Mechanism of Histone H3 Clipping by Chicken Liver Histone H3 Protease

    KAUST Repository

    Chauhan, Sakshi; Mandal, Papita; Tomar, Raghuvir S.

    2016-01-01

    Proteolytic clipping of histone H3 has been identified in many organisms. Despite several studies, the mechanism of clipping, the substrate specificity, and the significance of this poorly understood epigenetic mechanism are not clear. We have

  7. Neutron scattering studies of the H2a-H2b and (H3-H4)2 histone complexes

    International Nuclear Information System (INIS)

    Carlson, R.D.

    1984-01-01

    Neutron scattering experiments have shown that both the (H3-H4)2 and H2a-H2b histone complexes are quite asymmetric in solution. The (H3-H4)2 tetramer is an oblate or flattened structure, with a radius of gyration almost as large as that of the core octamer. If the tetramer is primarily globular, it must have an axial ratio of about 1:5. It is more likely, however, that this asymmetry results in part from N-terminal arms that extend outward approximately within the major plane of the particle. If this is the case, less asymmetric models for the globular part of the tetramer, including a dislocated disk of the type proposed by Klug et al. (23), can be made consistent with the scattering data. The H2a-H2b dimer, on the other hand, is an elongated structure. The low resolution data are in good agreement with those calculated for a cylindrical model 64 X 27 A, but other elongated models fit those data almost as well, including one that approximates free N-terminal arms at each end. Free arms are not necessary, but they must extend from the ends if they exist. A contrast matching experiment done with 50% deuterated H2b and undeuterated H2a in the reconstituted dimer showed that these two histones must each be rather elongated within the complex and are not just confined to one end. The amount of scattering contrast between the undeuterated and 50% deuterated histones was sufficient to suggest further experiments using complexes reconstituted from mixtures of undeuterated and partially deuterated histones which will help elucidate their arrangement within the histone complexes and within the octamer core of the nucleosome core particle

  8. Radon emanation characteristics of uranium mill tailings

    International Nuclear Information System (INIS)

    Nielson, K.K.; Freeman, H.D.; Hartley, J.N.; Mauch, M.L.; Rogers, V.C.

    1982-01-01

    Radon emanation from uranium mill tailings was examined with respect to the mechanisms of emanation and the physical properties of the tailings which affect emanation. Radon emanation coefficients were measured at ambient moisture on 135 samples from the 1981 field test site at the Grand Junction tailings pile. These coefficients showed a similar trend with moisture to those observed previously with uranium ores, and averaged 0.10 + or - 0.02 at dryness and 0.38 + or - 0.04 for all samples having greater than five weight-percent moisture. Small differences were noted between the maximum values of the coefficients for the sand and slime fractions of the tailings. Separate measurements on tailings from the Vitro tailings pile exhibited much lower emanation coefficients for moist samples, and similar coefficients for dry samples. Alternative emanation measurement techniques were examined and procedures are recommended for use in future work

  9. Post-Training Intrahippocampal Inhibition of Class I Histone Deacetylases Enhances Long-Term Object-Location Memory

    Science.gov (United States)

    Hawk, Joshua D.; Florian, Cedrick; Abel, Ted

    2011-01-01

    Long-term memory formation involves covalent modification of the histone proteins that package DNA. Reducing histone acetylation by mutating histone acetyltransferases impairs long-term memory, and enhancing histone acetylation by inhibiting histone deacetylases (HDACs) improves long-term memory. Previous studies using HDAC inhibitors to enhance…

  10. Molecular ions in comet tails

    International Nuclear Information System (INIS)

    Wyckoff, S.; Wehinger, P.A.

    1976-01-01

    Band intensities of the molecular ions CH + , CO + , N 2 + , and H 2 O + have been determined on an absolute scale from tail spectra of comet Kohoutek (1973f) and comet Bradfield (1974b). Photoionization and photodissociation rates have been computed for CH, CO, and N 2 . Also emission rate excitation g-factors for (1) photoionization plus excitation and (2) resonance fluorescence have been computed for the observed ions. It is shown that resonance fluorescence is the dominant excitation mechanism for observed comet tail ions at rapprox. =1 AU. Band system luminosities and molecular ion abundances within a projected nuclear distance rho 4 km have been determined for CH + , CO + , N 2 + , and H 2 O + in comet Kohoutek, and for H 2 O + in comet Bradfield. Estimates are also given for column densities of all observed ions at rhoapprox. =10 4 km on the tailward side of the coma. The observed H 2 O + column densities were found to be roughly the same in comet Kohoutek and comet Bradfield et equal heliocentric distances, while CO + was found to be approximately 100 times more abundant than H 2 O + , N 2 + , and CH + at rhoapprox. =10 4 km in comet Kohoutek. Finally, the relative abundances of the observed ions and of the presumed parent neutral species are briefly discussed

  11. Oil sands tailings management project

    Energy Technology Data Exchange (ETDEWEB)

    Godwalt, C. [Alberta WaterSMART, Calgary, AB (Canada); Kotecha, P. [Suncor Energy Inc, Calgary, AB (Canada); Aumann, C. [Alberta Innovates - Technology Futures, Alberta Governement, AB (Canada)

    2010-11-15

    The Oil sands leadership initiative (OSLI) works with the Government of Alberta on the development of the oil sands industry, considering environmental, economical and social aspects. Water management was identified as one of most important areas to focus on. Alberta WaterSMART was requested to support the development and the management of projects resulting from the work done or underway in this field. The development of a regional water management solution stood out as the most interesting solution to obtain significant results. In the Athabasca Region, oil sands producers work independently on their water sourcing and disposal with particular attention to fresh water conservation and economics. The Athabasca River represents a source for mines and distant saline aquifers are the target of steam assisted gravity drainage (SAGD) operators. As part of a four-phase project aiming to study the environmental and economic footprint (EEF) benefit of alternatives for Athabasca oil sands production water supply and disposal, the purpose of the tailings water management project was to identify tailings treatment technologies that are ready to be implemented, and to design and evaluate solutions in order to improve regional oil sands production water sourcing and disposal. Alternatives were evaluated based on their total EEF, applying a lifecycle assessment methodology with a particular attention on the quantification of important performance indicators. 25 refs., 8 tabs., 40 figs.

  12. Oil sands tailings management project

    International Nuclear Information System (INIS)

    Godwalt, C.; Kotecha, P.; Aumann, C.

    2010-11-01

    The Oil sands leadership initiative (OSLI) works with the Government of Alberta on the development of the oil sands industry, considering environmental, economical and social aspects. Water management was identified as one of most important areas to focus on. Alberta WaterSMART was requested to support the development and the management of projects resulting from the work done or underway in this field. The development of a regional water management solution stood out as the most interesting solution to obtain significant results. In the Athabasca Region, oil sands producers work independently on their water sourcing and disposal with particular attention to fresh water conservation and economics. The Athabasca River represents a source for mines and distant saline aquifers are the target of steam assisted gravity drainage (SAGD) operators. As part of a four-phase project aiming to study the environmental and economic footprint (EEF) benefit of alternatives for Athabasca oil sands production water supply and disposal, the purpose of the tailings water management project was to identify tailings treatment technologies that are ready to be implemented, and to design and evaluate solutions in order to improve regional oil sands production water sourcing and disposal. Alternatives were evaluated based on their total EEF, applying a lifecycle assessment methodology with a particular attention on the quantification of important performance indicators. 25 refs., 8 tabs., 40 figs.

  13. Assessing Risks of Mine Tailing Dam Failures

    Science.gov (United States)

    Concha Larrauri, P.; Lall, U.

    2017-12-01

    The consequences of tailings dam failures can be catastrophic for communities and ecosystems in the vicinity of the dams. The failure of the Fundão tailings dam at the Samarco mine in 2015 killed 19 people with severe consequences for the environment. The financial and legal consequences of a tailings dam failure can also be significant for the mining companies. For the Fundão tailings dam, the company had to pay 6 billion dollars in fines and twenty-one executives were charged with qualified murder. There are tenths of thousands of active, inactive, and abandoned tailings dams in the world and there is a need to better understand the hazards posed by these structures to downstream populations and ecosystems. A challenge to assess the risks of tailings dams in a large scale is that many of them are not registered in publicly available databases and there is little information about their current physical state. Additionally, hazard classifications of tailings dams - common in many countries- tend to be subjective, include vague parameter definitions, and are not always updated over time. Here we present a simple methodology to assess and rank the exposure to tailings dams using ArcGIS that removes subjective interpretations. The method uses basic information such as current dam height, storage volume, topography, population, land use, and hydrological data. A hazard rating risk was developed to compare the potential extent of the damage across dams. This assessment provides a general overview of what in the vicinity of the tailings dams could be affected in case of a failure and a way to rank tailings dams that is directly linked to the exposure at any given time. One hundred tailings dams in Minas Gerais, Brazil were used for the test case. This ranking approach could inform the risk management strategy of the tailings dams within a company, and when disclosed, it could enable shareholders and the communities to make decisions on the risks they are taking.

  14. PSG gene expression is up-regulated by lysine acetylation involving histone and nonhistone proteins.

    Directory of Open Access Journals (Sweden)

    Soledad A Camolotto

    Full Text Available BACKGROUND: Lysine acetylation is an important post-translational modification that plays a central role in eukaryotic transcriptional activation by modifying chromatin and transcription-related factors. Human pregnancy-specific glycoproteins (PSG are the major secreted placental proteins expressed by the syncytiotrophoblast at the end of pregnancy and represent early markers of cytotrophoblast differentiation. Low PSG levels are associated with complicated pregnancies, thus highlighting the importance of studying the mechanisms that control their expression. Despite several transcription factors having been implicated as key regulators of PSG gene family expression; the role of protein acetylation has not been explored. METHODOLOGY/PRINCIPAL FINDINGS: Here, we explored the role of acetylation on PSG gene expression in the human placental-derived JEG-3 cell line. Pharmacological inhibition of histone deacetylases (HDACs up-regulated PSG protein and mRNA expression levels, and augmented the amount of acetylated histone H3 associated with PSG 5'regulatory regions. Moreover, PSG5 promoter activation mediated by Sp1 and KLF6, via the core promoter element motif (CPE, -147/-140, was markedly enhanced in the presence of the HDAC inhibitor trichostatin A (TSA. This effect correlated with an increase in Sp1 acetylation and KLF6 nuclear localization as revealed by immunoprecipitation and subcellular fractionation assays. The co-activators PCAF, p300, and CBP enhanced Sp1-dependent PSG5 promoter activation through their histone acetylase (HAT function. Instead, p300 and CBP acetyltransferase domain was dispensable for sustaining co-activation of PSG5 promoter by KLF6. CONCLUSIONS/SIGNIFICANCE: Results are consistent with a regulatory role of lysine acetylation on PSG expression through a relaxed chromatin state and an increase in the transcriptional activity of Sp1 and KLF6 following an augmented Sp1 acetylation and KLF6 nuclear localization.

  15. Lymphocytes From Patients With Type 1 Diabetes Display a Distinct Profile of Chromatin Histone H3 Lysine 9 Dimethylation

    Science.gov (United States)

    Miao, Feng; Smith, David D.; Zhang, Lingxiao; Min, Andrew; Feng, Wei; Natarajan, Rama

    2008-01-01

    OBJECTIVE—The complexity of interactions between genes and the environment is a major challenge for type 1 diabetes studies. Nuclear chromatin is the interface between genetics and environment and the principal carrier of epigenetic information. Because histone tail modifications in chromatin are linked to gene transcription, we hypothesized that histone methylation patterns in cells from type 1 diabetic patients can provide novel epigenetic insights into type 1 diabetes and its complications. RESEARCH DESIGN AND METHODS—We used chromatin immunoprecipitation (ChIP) linked to microarray (ChIP-chip) approach to compare genome-wide histone H3 lysine 9 dimethylation (H3K9me2) patterns in blood lymphocytes and monocytes from type 1 diabetic patients versus healthy control subjects. Bioinformatics evaluation of methylated candidates was performed by Ingenuity Pathway Analysis (IPA) tools. RESULTS—A subset of genes in the type 1 diabetic cohort showed significant increase in H3K9me2 in lymphocytes but not in monocytes. CLTA4, a type 1 diabetes susceptibility gene, was one of the candidates displaying increased promoter H3K9me2 in type 1 diabetes. IPA identified two high-scoring networks that encompassed genes showing altered H3K9me2. Many of them were associated with autoimmune and inflammation-related pathways, such as transforming growth factor-β, nuclear factor-κB, p38 mitogen-activated protein kinase, toll-like receptor, and interleukin-6. IPA also revealed biological relationships between these networks and known type 1 diabetes candidate genes. CONCLUSIONS—The concerted and synergistic alteration of histone methylation within the identified network in lymphocytes might have an effect on the etiology of type 1 diabetes and its complications. These studies provide evidence of a novel association between type 1 diabetes and altered histone methylation of key genes that are components of type 1 diabetes–related biological pathways and also a new

  16. Average configuration of the geomagnetic tail

    International Nuclear Information System (INIS)

    Fairfield, D.H.

    1979-01-01

    Over 3000 hours of Imp 6 magnetic field data obtained between 20 and 33 R/sub E/ in the geomagnetic tail have been used in a statistical study of the tail configuration. A distribution of 2.5-min averages of B/sub z/ as a function of position across the tail reveals that more flux crosses the equatorial plane near the dawn and dusk flanks (B-bar/sub z/=3.γ) than near midnight (B-bar/sub z/=1.8γ). The tail field projected in the solar magnetospheric equatorial plane deviates from the x axis due to flaring and solar wind aberration by an angle α=-0.9 Y/sub SM/-2.7, where Y/sub SM/ is in earth radii and α is in degrees. After removing these effects, the B/sub y/ component of the tail field is found to depend on interplanetary sector structure. During an 'away' sector the B/sub y/ component of the tail field is on average 0.5γ greater than that during a 'toward' sector, a result that is true in both tail lobes and is independent of location across the tail. This effect means the average field reversal between northern and southern lobes of the tail is more often 178 0 rather than the 180 0 that is generally supposed

  17. Unique structural features facilitate lizard tail autotomy.

    Science.gov (United States)

    Sanggaard, Kristian W; Danielsen, Carl Chr; Wogensen, Lise; Vinding, Mads S; Rydtoft, Louise M; Mortensen, Martin B; Karring, Henrik; Nielsen, Niels Chr; Wang, Tobias; Thøgersen, Ida B; Enghild, Jan J

    2012-01-01

    Autotomy refers to the voluntary shedding of a body part; a renowned example is tail loss among lizards as a response to attempted predation. Although many aspects of lizard tail autotomy have been studied, the detailed morphology and mechanism remains unclear. In the present study, we showed that tail shedding by the Tokay gecko (Gekko gecko) and the associated extracellular matrix (ECM) rupture were independent of proteolysis. Instead, lizard caudal autotomy relied on biological adhesion facilitated by surface microstructures. Results based on bio-imaging techniques demonstrated that the tail of Gekko gecko was pre-severed at distinct sites and that its structural integrity depended on the adhesion between these segments.

  18. Unique structural features facilitate lizard tail autotomy

    DEFF Research Database (Denmark)

    Sanggaard, Kristian W; Danielsen, Carl Chr; Wogensen, Lise

    2012-01-01

    Autotomy refers to the voluntary shedding of a body part; a renowned example is tail loss among lizards as a response to attempted predation. Although many aspects of lizard tail autotomy have been studied, the detailed morphology and mechanism remains unclear. In the present study, we showed...... that tail shedding by the Tokay gecko (Gekko gecko) and the associated extracellular matrix (ECM) rupture were independent of proteolysis. Instead, lizard caudal autotomy relied on biological adhesion facilitated by surface microstructures. Results based on bio-imaging techniques demonstrated that the tail...

  19. Summary of the engineering assessment of inactive uranium mill tailings: Slick Rock sites, Slick Rock, Colorado

    International Nuclear Information System (INIS)

    1981-09-01

    Ford, Bacon and Davis Utah, Inc., has reevaluated the Slick Rock sites in order to revise the October 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Slick Rock, Colorado. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 387,000 tons of tailings at the Slick Rock sites constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The five alternative actions presented in this engineering assessment include millsite decontamination with the addition of 3 m of stabilization cover material, consolidation of the piles, and removal of the tailings to remote disposal sites and decontamination of the tailings sites. Cost estimates for the five options range from about $6,800,000 for stabilization in-place, to about $11,000,000 for disposal at a distance of about 6.5 mi. Three principal alternatives for the reprocessing of the Slick Rock tailings were examined: heap leaching; treatment at an existing mill; and reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be over $800/lb of U 3 O 8 whether by conventional or heap leach plant processes. The spot market price for uranium was $25/lb early in 1981. Therefore, reprocessing the tailings for uranium recovery is not economically attractive at present, nor for the foreseeable future

  20. Engineering assessment of inactive uranium mill tailings: Slick Rock sites, Slick Rock, Colorado

    International Nuclear Information System (INIS)

    1981-09-01

    Ford, Bacon and Davis Utah, Inc., has reevaluated the Slick Rock sites in order to revise the October 1977 engineering radioactive uranium mill tailings at Slick Rock, Colorado. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 387,000 tons of tailings at the Slick Rock sites constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The five alternative actions presented in this engineering assessment include millsite decontamination with the addition of 3 m of stabilization cover material, consolidation of the piles, and removal of the tailings to remote disposal sites and decontamination of the tailings sites. Cost estimates for the five options range from about $6,800,000 for stabilization in-place, to about $11,000,000 for disposal at a distance of about 6.5 mi. Three principal alternatives for the reprocessing of the Slick Rock tailings were examined: heap leaching; treatment at an existing mill; and reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be over $800/lb of U 3 O 8 whether by conventional or heap leach plant processes. The spot market price for uranium was $25/lb early in 1981. Therefore, reprocessing the tailings for uranium recovery is not economically attractive at present, nor for the foreseeable future

  1. Engineering assessment of inactive uranium mill tailings: Maybell Site, Maybell, Colorado. Summary

    International Nuclear Information System (INIS)

    1981-09-01

    Ford, Bacon and Davis Utah Inc. has reevaluated the Maybell site in order to revise the October 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Maybell, Colorado. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 2.6 million dry tons of tailings at the Maybell site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The two alternative actions presented in this engineering assessment range from millsite decontamination with the addition of 3 m of stabilization cover material (Option I), to disposal of the tailings in a nearby open pit mine and decontamination of the tailings site (Option II). Cost estimates for the two options are about $11,700,000 for stabilization in-place and about $22,700,000 for disposal within a distance of 2 mi. Three principal alternatives for the reprocessing of the Maybell tailings were examined: (a) heap leaching; (b) treatment at an existing mill; and (c) reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be about $125 and $165/lb of U 3 O 8 by heap leach and conventional plant processes, respectively. The spot market price for uranium was $25/lb early in 1981. Therefore, reprocessing the tailings for uranium recovery is not economically attractive at present

  2. Engineering assessment of inactive uranium mill tailings. Vitro site, Salt Lake City, Utah

    International Nuclear Information System (INIS)

    1981-04-01

    Ford, Bacon and Davis Utah Inc. has reevaluated the Vitro site in order to revise the April 1976 assessment of the problems resulting from the existence of radioactive uranium mill tailings at Salt Lake City, Utah. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 1.9 million tons of tailings at the Vitro site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The four alternative actions presented in this engineering assessment range from millsite and off-site decontamination with the addition of 3 m of stabilization cover material (Option I), to removal of the tailings to remote disposal sites, and decontamination of the tailings site (Options II through IV). Cost estimates for the four options range from about $36,400,000 for stabilization in-place, to about $91,000,000 for disposal at a distance of about 85 mi. Three principal alternatives for the reprocessing of the Vitro tailings were examined: heap leaching; treatment at an existing mill; and reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be about $200/lb by heap leach and $130/lb by conventional plant processes. Spot market price for uranium was $28.00 in November 1980. Therefore, reprocessing the tailings for uranium recovery appears to be economically unattractive at present

  3. Engineering assessment of inactive uranium mill tailings: Phillips/United Nuclear site, Ambrosia Lake, New Mexico

    International Nuclear Information System (INIS)

    1981-10-01

    Ford, Bacon and Davis Utah, Inc., has reevaluated the Phillips/United Nuclear site in order to revise the December 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Ambrosia Lake, New Mexico. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from 2.6 million dry tons of tailings at the Phillips/United Nuclear site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The four alternative actions presented in this engineering assessment range from millsite decontamination with the addition of 3 m of stabilization cover material, to removal of the tailings to remote disposal sites and decontamination of the tailings site. Cost estimates for the four options range from about $21,500,000 for stabilization in-place, to about $45,200,000 for disposal at a distance of about 15 mi. Three principal alternatives for the reprocessing of the Phillips/United Nuclear tailings were examined: heap leaching; treatment at an existing mill; and reprocessing at a new conventional mill constructed for tailings reprocessing.The cost of the uranium recovered would be about $87/lb of U 3 O 8 by either heap leach or conventional plant process. The spot market price for uranium was $25/lb early in 1981. Reprocessing the Phillips/United Nuclear tailings for uranium recovery does not appear to be economically attractive under present or foreseeable market conditions

  4. Engineering assessment of inactive uranium mill tailings, Shiprock site, Shiprock, New Mexico

    International Nuclear Information System (INIS)

    1981-07-01

    Ford, Bacon and Davis Utah Inc. has reevaluated the Shiprock site in order to revise the March 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Shiprock, New Mexico. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 1.5 million dry tons of tailings at the Shiprock site constitutes the most significant environental impact, although windblown tailings and external gamma radiation also are factors. The eight alternative actions presented in this engineering assessment range from millsite decontamination with the addition of 3 m of stabilization cover material (Option I), to removal of the tailings to remote disposal sites and decontamination of the tailings site (Options II through VIII). Cost estimates for the eight options range from about $13,400,000 for stabilization in place to about $37,900,000 for disposal at a distance of about 16 miles. Three principal alternatives for the reprocessing of the Shiprock tailings were examined: (a) heap leaching; (b) treatment at an existing mill; and (c) reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be about $230/lb by heap leach and $250/lb by conventional plant processes. The spot market price for uranium was $25/lb early in 1981. Therefore, reprocessing the tailings for uranium recovery is not economically attractive

  5. Engineering assessment of inactive uranium mill tailings: Mexican Hat Site, Mexican Hat, Utah

    International Nuclear Information System (INIS)

    1981-09-01

    Ford, Bacon and Davis Utah Inc. has reevaluated the Mexican Hat site in order to revise the March 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Mexican Hat, Utah. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 2.2 million tons of tailings at the Mexican Hat site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The four alternative actions presented in this engineering assessment range from millsite decontamination with the addition of 3 m of stabilization cover material to removal of the tailings to remote disposal sites and decontamination of the tailings site. Cost estimates for the four options range from about $15,200,000 for stabilization in place, to about $45,500,000 for disposal at a distance of about 16 mi. Three principal alternatives for the reprocessing of the Mexican Hat tailings were examined: heap leaching; treatment at an existing mill; and reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be about $115/lb of U 3 O 8 whether by heap leach or conventional plant processes. The spot market price for uranium was $25/lb early in 1981. Reprocessing the Mexican Hat tailings for uranium recovery is not economically attractive under present conditions

  6. Engineering assessment of inactive uranium mill tailings: Maybell Site, Maybell, Colorado

    International Nuclear Information System (INIS)

    1981-09-01

    Ford, Bacon and Davis Utah Inc. has reevaluated the Maybell site in order to revise the October 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Maybell, Colorado. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 2.6 million dry tons of tailings at the Maybell site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The two alternative actions presented in this engineering assessment range from millsite decontamination with the addition of 3 m of stabilization cover material (Option I), to disposal of the tailings in a nearby open pit mine and decontamination of the tailings site (Option II). Cost estimates for the two options are about $11,700,000 for stabilization in-place and about $22,700,000 for disposal within a distance of 2 mi. Three principal alternatives for the reprocessing of the Maybell tailings were examined: (a) heap leaching; (b) treatment at an existing mill; and (c) reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be about $125 and $165/lb of U 3 O 8 by heap leach and conventional plant processes, respectively. The spot market price for uranium was $25/lb early in 1981. Therefore, reprocessing the tailings for uranium recovery is not economically attractive at present

  7. Engineering assessment of inactive uranium mill tailings: Slick Rock sites, Slick Rock, Colorado

    Energy Technology Data Exchange (ETDEWEB)

    None

    1981-09-01

    Ford, Bacon and Davis Utah, Inc., has reevaluated the Slick Rock sites in order to revise the October 1977 engineering radioactive uranium mill tailings at Slick Rock, Colorado. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 387,000 tons of tailings at the Slick Rock sites constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The five alternative actions presented in this engineering assessment include millsite decontamination with the addition of 3 m of stabilization cover material, consolidation of the piles, and removal of the tailings to remote disposal sites and decontamination of the tailings sites. Cost estimates for the five options range from about $6,800,000 for stabilization in-place, to about $11,000,000 for disposal at a distance of about 6.5 mi. Three principal alternatives for the reprocessing of the Slick Rock tailings were examined: heap leaching; treatment at an existing mill; and reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be over $800/lb of U/sub 3/O/sub 8/ whether by conventional or heap leach plant processes. The spot market price for uranium was $25/lb early in 1981. Therefore, reprocessing the tailings for uranium recovery is not economically attractive at present, nor for the foreseeable future.

  8. Summary of the engineering assessment of inactive uranium mill tailings: Monument Valley site, Monument Valley, Arizona

    International Nuclear Information System (INIS)

    1981-10-01

    Ford, Bacon and Davis Utah Inc. has reevaluated the Monument Valley site in order to revise the March 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Monument Valley, Arizona. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 1.1 million tons of tailings at the Monument Valley site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The four alternative actions presented in this engineering assessment range from millsite decontamination with the addition of 3 m of stabilization cover material to removal of the tailings to remote disposal sites and decontamination of the tailings site. Cost estimates for the four options range from about $6,600,000 for stabilization in-place, to about $15,900,000 for disposal at a distance of about 15 mi. Three principal alternatives for reprocessing the Monument Valley tailings were examined: heap leaching, treatment at an existing mill; and reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be more than $500/lb of U 3 O 8 by heap leach or conventional plant processes. The spot market price for uranium was $25/lb early in 1981. Therefore, reprocessing the tailings for uranium recovery is economically unattractive

  9. Summary of the engineering assessment of inactive uranium mill tailings, Shiprock Site, Shiprock, New Mexico

    International Nuclear Information System (INIS)

    1981-07-01

    Ford, Bacon and Davis Utah Inc. has reevaluated the Shiprock site in order to revise the March 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Shiprock, New Mexico. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 1.5 million dry tons of tailings at the Shiprock site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The eight alternative actions presented in this engineering assessment range from millsite decontamination with the addition of 3 m of the stabilization cover material (Option I), to removal of the tailings to remote disposal sites and decontamination of the tailings site (Options II through VIII). Cost estimates for the eight options range from about $13,400,000 for stabilization in place to about $37,900,000 for disposal at a distance of about 16 miles. Three principal alternatives for the reprocessing of the Shiprock tailings were examined: (a) heap leaching; (b) treatment at an existing mill; and(c) reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be about $230/lb by heap leach and $250/lb by conventional plant processes. The spot market price for uranium was $25/lb early in 1981. Therefore, reprocessing the tailings for uranium recovery is not economically attractive

  10. Engineering assessment of inactive uranium mill tailings: Mexican Hat site, Mexican Hat, Utah. Summary

    International Nuclear Information System (INIS)

    1981-09-01

    Ford, Bacon and Davis Utah Inc. has reevaluated the Mexican Hat site in order to revise the March 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Mexican Hat, Utah. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 2.2 million tons of tailings at the Mexican Hat site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The four alternative actions presented in this engineering assessment range from millsite decontamination with the addition of 3 m of stabilization cover material to removal of the tailings to remote disposal sites and decontamination of the tailings site. Cost estimates for the four options range from about $15,200,000 for stabilization in place, to about $45,500,000 for disposal at a distance of about 16 mi. Three principal alternatives for the reprocessing of the Mexican Hat tailings were examined: (a) heap leaching; treatment at an existing mill; and reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be about $115/lb of U 3 O 8 whether by heap leach or conventional plant processes. The spot market price for uranium was $25/lb early in 1981. Reprocessing the Mexican Hat tailings for uranium recovery is not economically attractive under present conditions

  11. Summary of the engineering assessment of inactive uranium mill tailings, Riverton Site, Riverton, Wyoming

    International Nuclear Information System (INIS)

    1981-08-01

    Ford, Bacon, and Davis Utah Inc. has reevaluated the Riverton site in order to revise the December 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Riverton, Wyoming. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 900,000 tons of tailings materials at the Riverton site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The nine alternative actions presented in this engineering assessment range from millsite decontamination with the addition of 3 m of stabilization cover material (Option I), to removal of the tailings to remote disposal sites and decontaminations of the tailings site (Options II through IX). Cost estimates for the nine options range from about $16,600,000 for stabilization in-place, to about $23,200,000 for disposal at a distance of 18 to 25 mi. Three principal alternatives for the reprocessing of the Riverton tailings were examined: (a) heap leaching; (b) treatment at an existing mill; and (c) reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be about $260 and $230/lb of U 3 O 8 by heap leach and conventional plant processes respectively. The spot market price for uranium was $25/lb early in 1981. Therefore, reprocessing the tailings for uranium recovery does not appear to be economically attractive

  12. Immunomodulatory effects of histone deacetylase inhibitors.

    Science.gov (United States)

    Licciardi, P V; Ververis, K; Tang, M L; El-Osta, A; Karagiannis, T C

    2013-05-01

    Histone deacetylase inhibitors (HDACi) have emerged as a new generation of anticancer therapeutics. The classical broad-spectrum HDACi typically alter the cell cycle distribution and induce cell death, apoptosis and differentiation in malignant and transformed cells. This provides the basis for the clinical potential of HDACi in cancer therapy. Currently two compounds, suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza™) and depsipeptide (Romidepsin, Istodax™) have been approved for by the US Food and Drug Administration for the treatment of refractory cutaneous T-cell lymphoma. Apart from clinical application in oncology, HDACi have also been investigated as potential therapeutics for various pathologies including those of the central nervous system (such as Huntington's disease and multiple sclerosis), cardiac conditions (particularly hypertrophy), arthritis and malaria. Further, evidence is accumulating for potent immunomodulatory effects of classical HDACi which is the focus of this review. We review the antiinflammatory effects of HDACi and in particular findings implicating regulation of the innate and adaptive immune systems by HDAC enzymes. The recent findings highlighting the immunomodulatory function of HDAC11 which relates to balancing immune activation versus tolerance are also discussed.

  13. Interpreting clinical assays for histone deacetylase inhibitors

    International Nuclear Information System (INIS)

    Martinet, Nadine; Bertrand, Philippe

    2011-01-01

    As opposed to genetics, dealing with gene expressions by direct DNA sequence modifications, the term epigenetics applies to all the external influences that target the chromatin structure of cells with impact on gene expression unrelated to the sequence coding of DNA itself. In normal cells, epigenetics modulates gene expression through all development steps. When “imprinted” early by the environment, epigenetic changes influence the organism at an early stage and can be transmitted to the progeny. Together with DNA sequence alterations, DNA aberrant cytosine methylation and microRNA deregulation, epigenetic modifications participate in the malignant transformation of cells. Their reversible nature has led to the emergence of the promising field of epigenetic therapy. The efforts made to inhibit in particular the epigenetic enzyme family called histone deacetylases (HDACs) are described. HDAC inhibitors (HDACi) have been proposed as a viable clinical therapeutic approach for the treatment of leukemia and solid tumors, but also to a lesser degree for noncancerous diseases. Three epigenetic drugs are already arriving at the patient’s bedside, and more than 100 clinical assays for HDACi are registered on the National Cancer Institute website. They explore the eventual additive benefits of combined therapies. In the context of the pleiotropic effects of HDAC isoforms, more specific HDACi and more informative screening tests are being developed for the benefit of the patients

  14. Transformer core

    NARCIS (Netherlands)

    Mehendale, A.; Hagedoorn, Wouter; Lötters, Joost Conrad

    2008-01-01

    A transformer core includes a stack of a plurality of planar core plates of a magnetically permeable material, which plates each consist of a first and a second sub-part that together enclose at least one opening. The sub-parts can be fitted together via contact faces that are located on either side

  15. Transformer core

    NARCIS (Netherlands)

    Mehendale, A.; Hagedoorn, Wouter; Lötters, Joost Conrad

    2010-01-01

    A transformer core includes a stack of a plurality of planar core plates of a magnetically permeable material, which plates each consist of a first and a second sub-part that together enclose at least one opening. The sub-parts can be fitted together via contact faces that are located on either side

  16. [Effect of TSA and VPA treatment on long-tailed macaque (Macaca fascicularis)-pig interspecies somatic cell nuclear transfer].

    Science.gov (United States)

    Qin, Zu-Xing; Huang, Gao-Bo; Luo, Jun; Ning, Shu-Fang; Lu, Sheng-Sheng; Lu, Ke-Huan

    2012-03-01

    Long-tailed macaque-pig interspecies somatic cell nuclear transfer (iSCNT) is beneficial to yield embryonic stem cells from iSCNT embryos with similar genetic background as human, which can be used as materials for medical and basic research. The primary objective of this study was to investigate the effects of concentrations and treatment duration of two histone deacetylase inhibitors-Trichostatin A (TSA) and Valproic acid (VPA) and two different embryo culture media (PZM-3 and HECM-10) on the in vitro development of iSCNT embryos. The results suggested that when PZM-3 was used as the embryo culture medium, the blastocyst rate of 10 nmol/L TSA treatment for 48 h was significantly higher than the control group (22.78% vs 9.86%, PTSA treatment could enhance the in vitro developmental potential of long-tailed macaque-pig iSCNT embryos.

  17. Lateral movements of a massive tail influence gecko locomotion: an integrative study comparing tail restriction and autotomy

    OpenAIRE

    Jagnandan, Kevin; Higham, Timothy E.

    2017-01-01

    Tails are an intricate component of the locomotor system for many vertebrates. Leopard geckos (Eublepharis macularius) possess a large tail that is laterally undulated during steady locomotion. However, the tail is readily shed via autotomy, resulting in the loss of tail function, loss in body mass, and a cranial shift in the center of mass. To elucidate the function of tail undulations, we investigated changes in limb kinematics after manipulating the tail artificially by restricting tail un...

  18. Performance Comparison between Neutralization Tailings and Flotation Tailings Used for Backfill Mix and Mechanism Analysis

    Directory of Open Access Journals (Sweden)

    Bin Han

    2016-01-01

    Full Text Available A comparison test of different tailings used for underground backfill was conducted, using neutralized tailings from BIOX and flotation tailings of Jinfeng Mine. Laboratory comparison test results show that, with neutralized tailings, when the cement dosage is at 19%, backfill UCS after 7 days, 14 days, and 28 days are 105%–163%, 80%–102%, and 33%–43%, respectively, which are higher than those of flotation tailings. When the cement dosage is at 12%, backfill UCS after 7 days, 14 days, and 28 days are 58%–77%, 50%–60%, and 28%–51%, respectively, which are higher than those of flotation tailings. Slurry fluidity of neutralized tailings is lower than that of flotation tailings, while, in these two tailings, the difference of slump and diffusivity values is less than 6%, which is not a significant difference in slurry fluidity. The reason for neutralized tailings showing higher UCS is as follows: during backfill curing, neutralization tailings produce abundant crystals of CaSO4·2H2O in interlaced structure which helps in combining aggregates closely; CaSO4·2H2O hydrates with C3A C4AF contained in the cement and forms clavate cement bacillus which works as a micro reinforcing steel bar. The test proved that neutralized tailings are more optimal for backfilling.

  19. Characterization and dewatering of flotation technological tailings

    Directory of Open Access Journals (Sweden)

    Grigorova I.

    2014-01-01

    Full Text Available The treatment of flotation tailings is today a subject of interest in mineral processing because of the potential of wasted materials as an actual mineral resource and because of environmental reasons. Decantation ponds are found at almost every mine in the world. They are large earth fill dams containing the residue of the milling process to extract metals from mined ores. Traditional wet tailings disposal has been problematic due to the risk of ground water contamination and the difficulty in rehabilitating storage sites. Tailings dams are at risk of failure due to leakage, instability, liquefaction, and poor design. In the last few years the use of paste technology in the disposal of mine tailings is increasingly studied as an option to conventional tailings dams. The Lucky Invest Concentrator is located in the Eastern Rhodopes Mountain of Bulgaria. Since 1959 lead-zinc ores are dressed. Finally, during the flotation cycle lead and zinc concentrates are produced. The final technological processing waste precipitates in tailing pond. Research and development program has started to established opportunities to obtain dry deposit of the ore processing residue and analyses the feature of new tailing disposal method. The tailings particle size distributions and chemical compositions were determined. The data from laboratory and pilot scale tests clearly illustrate that there are the possibilities to obtaine lead-zinc dewatered tailings. The experimental results show that new cyclone modifications have a potential in dewatering technology of flotation tailings. It appears that dewatering cyclones can be an approach on new tailings pond elimination technology.

  20. Making the long tail work

    DEFF Research Database (Denmark)

    Thuesen, Christian Langhoff; Jensen, Jens Stissing; Gottlieb, Stefan Christoffer

    2009-01-01

    The paper discusses the development and impact of construction research the past 25 years. Theoretically, the paper builds on two fundamental insights: The Pareto principle (the 80-20 rule) and the Thomas theorem: "If men define situations as real, they are real in their consequences" (Thomas......’s predominant view of buildings – as unique – implies that: 1) the nature of the construction processes is chaotic, 2) the buildings are realised through onsite project work rather than through offsite production; and 3) project management is the fundamental management principle. The paper further identifies...... how attempts to develop new construction practices like partnering and lean implicitly reproduce this myth. The result is that construction research the past 25 years has been constructing the long tail in a way that hinders radical development of the construction industry. The paper concludes...

  1. Profitable tail-end production

    Energy Technology Data Exchange (ETDEWEB)

    Pinchbeck, R.H.

    1997-12-31

    This presentation discusses the origins of the present challenge faced in making mature oil fields profitable in the North Sea. It briefly examines the origins of these challenges, which are rooted in the industrial psychology of the North Sea. It develops a methodological formula for the successful re-engineering of inefficiently-run assets, focusing in particular on the personnel management aspects. It identifies some key areas to seek sustainable cost reductions and recognises the importance of renewing the context for investment in tail-end fields. Finally, it speculates about the way in which the learnings developed in the experiences of the last few years will influence the future of the North Sea. 2 refs.

  2. Sensitization to UV-induced apoptosis by the histone deacetylase inhibitor trichostatin A (TSA)

    International Nuclear Information System (INIS)

    Kim, Myoung Sook; Baek, Jin Hyen; Chakravarty, Devulapalli; Sidransky, David; Carrier, France

    2005-01-01

    UV-induced apoptosis is a protective mechanism that is primarily caused by DNA damage. Cyclobutane pyrimidine dimers (CPD) and 6-4 photoproducts are the main DNA adducts triggered by UV radiation. Because the formation of DNA lesions in the chromatin is modulated by the structure of the nucleosomes, we postulated that modification of chromatin compaction could affect the formation of the lesions and consequently apoptosis. To verify this possibility we treated human colon carcinoma RKO cells with the histone deacetylase inhibitor trichostatin A (TSA) prior to exposure to UV radiation. Our data show that pre-treatment with TSA increased UV killing efficiency by more than threefold. This effect correlated with increased formation of CPDs and consequently apoptosis. On the other hand, TSA treatment after UV exposure rather than before had no more effect than UV radiation alone. This suggests that a primed (opened) chromatin status is required to sensitize the cells. Moreover, TSA sensitization to UV-induced apoptosis is p53 dependent. p53 and acetylation of the core histones may thus contribute to UV-induced apoptosis by modulating the formation of DNA lesions on chromatin

  3. Interactions of nickel(II) with histones. Stability and solution structure of complexes with CH3CO-Cys-Ala-Ile-His-NH2, a putative metal binding sequence of histone H3.

    Science.gov (United States)

    Bal, W; Lukszo, J; Jezowska-Bojczuk, M; Kasprzak, K S

    1995-01-01

    Nickel(II) compounds are established human carcinogens, but the molecular mechanisms underlying their activity are only partially known. One mechanism may include mediation by nickel of promutagenic oxidative DNA damage that depends on Ni(II) binding to chromatin. To characterize such binding at the histone moiety of chromatin, we synthesized the peptide CH3CO-Cys-Ala-Ile-His-NH2 (L), a model of the evolutionarily conserved motif in histone H3 with expected affinity for transition metals, and evaluated its reactivity toward Ni(II). Combined spectroscopic (UV/vis, CD, NMR) and potentiometric measurements showed that, at physiological pH, mixtures of Ni(II) and L yielded unusual macrochelate complexes, NiL and NiL2, in which the metal cation was bound through Cys and His side chains in a square-planar arrangement. Above pH 9, a NiH-3L complex was formed, structurally analogous to typical square-planar nickel complexes. These complexes are expected to catalyze oxidation reactions, and therefore, coordination of Ni(II) by the L motif in core histone H3 may be a key event in oxidative DNA base damage observed in the process of Ni(II)-induced carcinogenesis.

  4. Core lifter

    Energy Technology Data Exchange (ETDEWEB)

    Pavlov, N G; Edel' man, Ya A

    1981-02-15

    A core lifter is suggested which contains a housing, core-clamping elements installed in the housing depressions in the form of semirings with projections on the outer surface restricting the rotation of the semirings in the housing depressions. In order to improve the strength and reliability of the core lifter, the semirings have a variable transverse section formed from the outside by the surface of the rotation body of the inner arc of the semiring aroung the rotation axis and from the inner a cylindrical surface which is concentric to the outer arc of the semiring. The core-clamping elements made in this manner have the possibility of freely rotating in the housing depressions under their own weight and from contact with the core sample. These semirings do not have weakened sections, have sufficient strength, are inserted into the limited ring section of the housing of the core lifter without reduction in its through opening and this improve the reliability of the core lifter in operation.

  5. Summary of the Phase II, Title I engineering assessment of inactive uranium mill tailings, Tuba City site, Tuba City, Arizona

    International Nuclear Information System (INIS)

    1977-01-01

    An engineering assessment was performed of the problems resulting from the existence of radioactive uranium mill tailings at the Tuba City millsite in Arizona. Services include the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and other radium-contaminated materials, the evaluation of resulting radiation exposures of individuals residing nearby, the investigation of site hydrology and meteorology and the evaluation and costing of alternative corrective actions. Radon gas release from the tailings on the site constitutes the most significant environmental impact to the inhabited area near the site

  6. Research on uranium tailings disposal technology at CANMET, Ottawa

    International Nuclear Information System (INIS)

    Skeaff, J.M.; Ritcey, G.M.; Jongejan, A.; Silver, M.

    1982-01-01

    In this paper, results from three continuing investigations at CANMET on uranium tailings management are presented. These investigations are: cleaning of tailings by flotation, conversion of municipal wastes into compost for use as topsoil on uranium tailings, methods for the chemical fixation of uranium tailings and a laboratory determination of the rate of release of environmental contaminants from uranium tailings

  7. Red-tailed Hawk movements and use of habitat in the Luquillo Mountains of Puerto Rico

    Science.gov (United States)

    Vilella, Francisco; Nimitz, Wyatt F.

    2012-01-01

    The Red-tailed Hawk (Buteo jamaicensis) is a top predator of upland ecosystems in the Greater Antilles. Little information exists on the ecology of the insular forms of this widely distributed species. We studied movements and resource use of the Red-tailed Hawk from 2000 to 2002 in the montane forests of northeastern Puerto Rico. We captured 32 and used 21 radio-marked Red-tailed Hawks to delineate home range, core area shifts, and macrohabitat use in the Luquillo Mountains. Red-tailed Hawks in the Luquillo Mountains frequently perched near the top of canopy emergent trees and were characterized by wide-ranging capabilities and extensive spatial overlap. Home range size averaged 5,022.6 6 832.1 ha (305–11,288 ha) and core areas averaged 564.8 6 90.7 ha (150–1,230 ha). This species had large mean weekly movements (3,286.2 6 348.5 m) and a preference for roadside habitats. Our findings suggest fragmentation of contiguous forest outside protected areas in Puerto Rico may benefit the Red-tailed Hawk

  8. Heavy mineral concentration from oil sand tailings

    Energy Technology Data Exchange (ETDEWEB)

    Chachula, F.; Erasmus, N. [Titanium Corp. Inc., Regina, SK (Canada)

    2008-07-01

    This presentation described a unique technique to recover heavy minerals contained in the froth treatment tailings produced by oil sand mining extraction operations in Fort McMurray, Alberta. In an effort to process waste material into valuable products, Titanium Corporation is developing technology to recover heavy minerals, primarily zircon, and a portion of bitumen contained in the final stage of bitumen processing. The process technology is being developed to apply to all mined oil sands operations in the Fort McMurray region. In 2004, Titanium Corporation commissioned a pilot research facility at the Saskatchewan Research Council to test dry oil sands tailings. In 2005, a bulk sampling pilot plant was connected to the fresh oil sands tailings pipeline on-site in Fort McMurray, where washed sands containing heavy minerals were processed at a pilot facility. The mineral content in both deposited tailings and fresh pipeline tailings was assessed. Analysis of fresh tailings on a daily basis identified a constant proportion of zircon and higher levels of associated bitumen compared with the material in the deposited tailings. The process flow sheet design was then modified to remove bitumen from the heavy minerals and concentrate the minerals. A newly modified flotation process was shown to be a viable processing route to recover the heavy minerals from froth treatment tailings. 8 refs., 9 tabs., 12 figs.

  9. Electrodialytic remediation of copper mine tailings

    DEFF Research Database (Denmark)

    Hansen, Henrik K.; Rojo, A.; Ottpsen, Lisbeth M.

    2005-01-01

    electrodialytic remediation experiments on copper mine tailings. The results show that electric current could remove copper from watery tailing if the potential gradient was higher than 2V/cm during 21 days. With addition of sulphuric acid, the process was enhanced because the pH decreased to around 4...

  10. Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents.

    Science.gov (United States)

    Ververis, Katherine; Hiong, Alison; Karagiannis, Tom C; Licciardi, Paul V

    2013-01-01

    Histone deacetylase (HDAC) inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents) as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza) and depsipeptide (romidepsin, Istodax). More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the advancement of these drugs, especially to facilitate the rational design of HDAC inhibitors that are effective as antineoplastic agents. This review will discuss the use of HDAC inhibitors as multitargeted therapies for malignancy. Further, we outline the pharmacology and mechanisms of action of HDAC inhibitors while

  11. Extracellular DNA and histones: double-edged swords in immunothrombosis.

    Science.gov (United States)

    Gould, T J; Lysov, Z; Liaw, P C

    2015-06-01

    The existence of extracellular DNA in human plasma, also known as cell-free DNA (cfDNA), was first described in the 1940s. In recent years, there has been a resurgence of interest in the functional significance of cfDNA, particularly in the context of neutrophil extracellular traps (NETs). cfDNA and histones are key components of NETs that aid in the host response to infection and inflammation. However, cfDNA and histones may also exert harmful effects by triggering coagulation, inflammation, and cell death and by impairing fibrinolysis. In this article, we will review the pathologic nature of cfDNA and histones in macrovascular and microvascular thrombosis, including venous thromboembolism, cancer, sepsis, and trauma. We will also discuss the prognostic value of cfDNA and histones in these disease states. Understanding the molecular and cellular pathways regulated by cfDNA and histones may provide novel insights to prevent pathological thrombus formation and vascular occlusion. © 2015 International Society on Thrombosis and Haemostasis.

  12. Histones trigger sterile inflammation by activating the NLRP3 inflammasome.

    Science.gov (United States)

    Allam, Ramanjaneyulu; Darisipudi, Murthy Narayana; Tschopp, Jurg; Anders, Hans-Joachim

    2013-12-01

    Sterile cell death mediated inflammation is linked to several pathological disorders and involves danger recognition of intracellular molecules released by necrotic cells that activate different groups of innate pattern recognition receptors. Toll-like receptors directly interact with their extrinsic or intrinsic agonists and induce multiple proinflammatory mediators. In contrast, the NLRP3 inflammasome is rather thought to represent a downstream element integrating various indirect stimuli into proteolytic cleavage of interleukin (IL)-1β and IL-18. Here, we report that histones released from necrotic cells induce IL-1β secretion in an NLRP3-ASC-caspase-1-dependent manner. Genetic deletion of NLRP3 in mice significantly attenuated histone-induced IL-1β production and neutrophil recruitment. Furthermore, necrotic cells induced neutrophil recruitment, which was significantly reduced by histone-neutralizing antibodies or depleting extracellular histones via enzymatic degradation. These results identify cytosolic uptake of necrotic cell-derived histones as a triggering mechanism of sterile inflammation, which involves NLRP3 inflammasome activation and IL-1β secretion via oxidative stress. © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Selective Biological Responses of Phagocytes and Lungs to Purified Histones.

    Science.gov (United States)

    Fattahi, Fatemeh; Grailer, Jamison J; Lu, Hope; Dick, Rachel S; Parlett, Michella; Zetoune, Firas S; Nuñez, Gabriel; Ward, Peter A

    2017-01-01

    Histones invoke strong proinflammatory responses in many different organs and cells. We assessed biological responses to purified or recombinant histones, using human and murine phagocytes and mouse lungs. H1 had the strongest ability in vitro to induce cell swelling independent of requirements for toll-like receptors (TLRs) 2 or 4. These responses were also associated with lactate dehydrogenase release. H3 and H2B were the strongest inducers of [Ca2+]i elevations in phagocytes. Cytokine and chemokine release from mouse and human phagocytes was predominately a function of H2A and H2B. Double TLR2 and TLR4 knockout (KO) mice had dramatically reduced cytokine release induced in macrophages exposed to individual histones. In contrast, macrophages from single TLR-KO mice showed few inhibitory effects on cytokine production. Using the NLRP3 inflammasome protocol, release of mature IL-1β was predominantly a feature of H1. Acute lung injury following the airway delivery of histones suggested that H1, H2A, and H2B were linked to alveolar leak of albumin and the buildup of polymorphonuclear neutrophils as well as the release of chemokines and cytokines into bronchoalveolar fluids. These results demonstrate distinct biological roles for individual histones in the context of inflammation biology and the requirement of both TLR2 and TLR4. © 2017 S. Karger AG, Basel.

  14. Performance Comparison between Neutralization Tailings and Flotation Tailings Used for Backfill Mix and Mechanism Analysis

    OpenAIRE

    Han, Bin; Sun, Wei; Yu, Shaofeng; Liu, Chao; Yao, Song; Wu, Jianxun

    2016-01-01

    A comparison test of different tailings used for underground backfill was conducted, using neutralized tailings from BIOX and flotation tailings of Jinfeng Mine. Laboratory comparison test results show that, with neutralized tailings, when the cement dosage is at 19%, backfill UCS after 7 days, 14 days, and 28 days are 105%–163%, 80%–102%, and 33%–43%, respectively, which are higher than those of flotation tailings. When the cement dosage is at 12%, backfill UCS after 7 days, 14 days, and 28 ...

  15. Monte Carlo-based tail exponent estimator

    Science.gov (United States)

    Barunik, Jozef; Vacha, Lukas

    2010-11-01

    In this paper we propose a new approach to estimation of the tail exponent in financial stock markets. We begin the study with the finite sample behavior of the Hill estimator under α-stable distributions. Using large Monte Carlo simulations, we show that the Hill estimator overestimates the true tail exponent and can hardly be used on samples with small length. Utilizing our results, we introduce a Monte Carlo-based method of estimation for the tail exponent. Our proposed method is not sensitive to the choice of tail size and works well also on small data samples. The new estimator also gives unbiased results with symmetrical confidence intervals. Finally, we demonstrate the power of our estimator on the international world stock market indices. On the two separate periods of 2002-2005 and 2006-2009, we estimate the tail exponent.

  16. Analysis of Heavy-Tailed Time Series

    DEFF Research Database (Denmark)

    Xie, Xiaolei

    This thesis is about analysis of heavy-tailed time series. We discuss tail properties of real-world equity return series and investigate the possibility that a single tail index is shared by all return series of actively traded equities in a market. Conditions for this hypothesis to be true...... are identified. We study the eigenvalues and eigenvectors of sample covariance and sample auto-covariance matrices of multivariate heavy-tailed time series, and particularly for time series with very high dimensions. Asymptotic approximations of the eigenvalues and eigenvectors of such matrices are found...... and expressed in terms of the parameters of the dependence structure, among others. Furthermore, we study an importance sampling method for estimating rare-event probabilities of multivariate heavy-tailed time series generated by matrix recursion. We show that the proposed algorithm is efficient in the sense...

  17. Why are most EU pigs tail docked?

    DEFF Research Database (Denmark)

    D'eath, R.B.; Niemi, J.K.; Vosough Ahmadi, B.

    2016-01-01

    To limit tail biting incidence, most pig producers in Europe tail dock their piglets. This is despite EU Council Directive 2008/120/EC banning routine tail docking and allowing it only as a last resort. The paper aims to understand what it takes to fulfil the intentions of the Directive...... by examining economic results of four management and housing scenarios, and by discussing their consequences for animal welfare in the light of legal and ethical considerations. The four scenarios compared are: ‘Standard Docked’, a conventional housing scenario with tail docking meeting the recommendations...... for Danish production (0.7 m2/pig); ‘Standard Undocked’, which is the same as ‘Standard Docked’ but with no tail docking, ‘Efficient Undocked’ and ‘Enhanced Undocked’, which have increased solid floor area (0.9 and 1.0 m2/pig, respectively) provision of loose manipulable materials (100 and 200 g/straw per...

  18. Uranium mill tailings remedial action technology

    International Nuclear Information System (INIS)

    Hartley, J.N.; Gee, G.W.

    1984-01-01

    The uranium milling process involves the hydrometallurgical extraction of uranium from ores and the resultant generation of large quantities of waste referred to as tailings. Uranium mill tailings have been identified as requiring remediation because they contain residual radioactive material that is not removed in the milling process. Potential radiation exposure can result from direct contact with the tailings, from radon gas emitted by the tailings, and from radioactive contamination of groundwater. As a result, the technology developed under the US Department of Energy (DOE) Uranium Mill Tailings Remedial Action Project (UMTRAP) and the US Nuclear Regulatory Commission (NRC) Uranium Recovery Program have focused on radon control, groundwater contamination and the long-term protection of the containment system. This paper briefly summarizes the UMTRAP and NRC remedial action technology development. 33 references, 9 figures, 5 tables

  19. Engineering assessment of inactive uranium mill tailings, Shiprock site, Shiprock, New Mexico. Phase II, Title I

    International Nuclear Information System (INIS)

    1977-01-01

    Ford, Bacon and Davis Utah Inc. has performed an engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Shiprock, New Mexico. The Phase II, Title I services include the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and other radium-contaminated materials, the evaluation of resulting radiation exposures of individuals and nearby populations, the investigation of site hydrology and meteorology and the evaluation and costing of alternative corrective actions. Radon gas release from the 1.7 million tons of tailings at the Shiprock site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation are also factors. The 11 alternative actions presented range from completion of the present ongoing EPA site decontamination plan (Option I), to stabilizing in-place with varying depths of cover material (Options II-IV), to removal to an isolated long-term disposal site (Options V-XI). All options include remedial action costs for off-site locations where tailings have been placed. Costs estimates for the 11 options range from $540,000 to $12,500,000. Reprocessing the tailings for uranium is not economically feasible

  20. Engineering assessment of inactive uranium mill tailings, Shiprock site, Shiprock, New Mexico. Phase II, Title I

    Energy Technology Data Exchange (ETDEWEB)

    1977-03-31

    Ford, Bacon and Davis Utah Inc. has performed an engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Shiprock, New Mexico. The Phase II, Title I services include the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and other radium-contaminated materials, the evaluation of resulting radiation exposures of individuals and nearby populations, the investigation of site hydrology and meteorology and the evaluation and costing of alternative corrective actions. Radon gas release from the 1.7 million tons of tailings at the Shiprock site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation are also factors. The 11 alternative actions presented range from completion of the present ongoing EPA site decontamination plan (Option I), to stabilizing in-place with varying depths of cover material (Options II-IV), to removal to an isolated long-term disposal site (Options V-XI). All options include remedial action costs for off-site locations where tailings have been placed. Costs estimates for the 11 options range from $540,000 to $12,500,000. Reprocessing the tailings for uranium is not economically feasible.

  1. Engineering assessment of inactive uranium mill tailings, Durango site, Durango, Colorado. Phase II, Title I

    International Nuclear Information System (INIS)

    1977-11-01

    Ford, Bacon and Davis Utah Inc. has performed an engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Durango, Colorado. The Phase II, Title I services include the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and other radium-contaminated materials, the evaluation of resulting radiation exposures of individuals and nearby populations, the investigation of site hydrology and meteorology and the evaluation and costing of alternative corrective actions. Radon gas release from the 1.555 million tons of tailings at the Durango site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation are also factors. The eight alternative actions presented range from vegetative stabilization (Option I), to contouring and stabilizing in-place with varying depths of cover material (Options II and III), to removal to an isolated long-term disposal site (Options V to VIII). All options include remedial action costs for offsite locations where tailings have been placed. Costs estimated for the eight options range from $4,340,000 to $13,590,000. Reprocessing the tailings for uranium is sufficiently economically attractive to justify reprocessing in conjunction with each of the options

  2. Engineering assessment of inactive uranium mill tailings, Naturita site, Naturita, Colorado. Phase II, Title I

    International Nuclear Information System (INIS)

    1977-11-01

    Ford, Bacon and Davis Utah Inc. has performed an engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Naturita, Colorado. The Phase II, Title I services include the preparation of topographic maps, the performance of core drillings sufficient to determine areas and volumes of tailings, the performance of radiometric measurements to determine the extent of radium contamination, the evaluation of resulting radiation exposures of individuals and nearby populations, the investigation of site hydrology and meteorology, and the costing of alternative corrective actions. Radon gas release from the 704,000 tons of tailings at the Naturita site constitutes the most significant environmental impact although windblown tailings and external gamma radiation are also factors. Ranchers Exploration and Development Company has been licensed by the State of Colorado to reprocess the tailings at a location 3 mi from the present site where they will be stabilized for long-term storage. The remedial action options include remedial action for structures in Naturita and Nucla (Option I) at an estimated cost of $270,000 and remedial action for structures and open land adjacent to the tailings site (Option II) at an estimated cost of $950,000

  3. Engineering assessment of inactive uranium mill tailings, Maybell site, Maybell, Colorado. Phase II, Title I

    International Nuclear Information System (INIS)

    1977-10-01

    Ford, Bacon and Davis Utah Inc. has performed an engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Maybell, Colorado. The Phase II--Title I services include the preparation of topographic maps, the performance of core drillings sufficient to determine areas and volumes of tailings and radiometric measurements to determine radium-contaminated materials, the evaluation of resulting radiation exposures of individuals and nearby populations, the investigation of site hydrology and meteorology and the evaluation and costing of alternative corrective actions. Radon gas release from the 2.6 million tons of tailings at the Maybell site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation are also factors. The three alternative actions presented range from fencing and maintenance (Option I), to placing the tailings in an open-pit mine and adding 2 ft of stabilization cover material (Option III). Cost estimates for the three options range from $250,000 to $4,520,000. Reprocessing the tailings for uranium does not appear to be economically attractive at present

  4. Expressed Centromere Specific Histone 3 (CENH3 Variants in Cultivated Triploid and Wild Diploid Bananas (Musa spp.

    Directory of Open Access Journals (Sweden)

    Kariuki S. Muiruri

    2017-06-01

    Full Text Available Centromeres are specified by a centromere specific histone 3 (CENH3 protein, which exists in a complex environment, interacting with conserved proteins and rapidly evolving satellite DNA sequences. The interactions may become more challenging if multiple CENH3 versions are introduced into the zygote as this can affect post-zygotic mitosis and ultimately sexual reproduction. Here, we characterize CENH3 variant transcripts expressed in cultivated triploid and wild diploid progenitor bananas. We describe both splice- and allelic-[Single Nucleotide Polymorphisms (SNP] variants and their effects on the predicted secondary structures of protein. Expressed CENH3 transcripts from six banana genotypes were characterized and clustered into three groups (MusaCENH-1A, MusaCENH-1B, and MusaCENH-2 based on similarity. The CENH3 groups differed with SNPs as well as presence of indels resulting from retained and/or skipped exons. The CENH3 transcripts from different banana genotypes were spliced in either 7/6, 5/4 or 6/5 exons/introns. The 7/6 and the 5/4 exon/intron structures were found in both diploids and triploids, however, 7/6 was most predominant. The 6/5 exon/introns structure was a result of failure of the 7/6 to splice correctly. The various transcripts obtained were predicted to encode highly variable N-terminal tails and a relatively conserved C-terminal histone fold domain (HFD. The SNPs were predicted in some cases to affect the secondary structure of protein by lengthening or shorting the affected domains. Sequencing of banana CENH3 transcripts predicts SNP variations that affect amino acid sequences and alternatively spliced transcripts. Most of these changes affect the N-terminal tail of CENH3.

  5. Reactor core

    International Nuclear Information System (INIS)

    Azekura, Kazuo; Kurihara, Kunitoshi.

    1992-01-01

    In a BWR type reactor, a great number of pipes (spectral shift pipes) are disposed in the reactor core. Moderators having a small moderating cross section (heavy water) are circulated in the spectral shift pipes to suppress the excess reactivity while increasing the conversion ratio at an initial stage of the operation cycle. After the intermediate stage of the operation cycle in which the reactor core reactivity is lowered, reactivity is increased by circulating moderators having a great moderating cross section (light water) to extend the taken up burnup degree. Further, neutron absorbers such as boron are mixed to the moderator in the spectral shift pipe to control the concentration thereof. With such a constitution, control rods and driving mechanisms are no more necessary, to simplify the structure of the reactor core. This can increase the fuel conversion ratio and control great excess reactivity. Accordingly, a nuclear reactor core of high conversion and high burnup degree can be attained. (I.N.)

  6. Ice Cores

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Records of past temperature, precipitation, atmospheric trace gases, and other aspects of climate and environment derived from ice cores drilled on glaciers and ice...

  7. Tail posture predicts tail biting outbreaks at pen level in weaner pigs

    DEFF Research Database (Denmark)

    Lahrmann, Helle Pelant; Hansen, Christian Fink; D'Eath, Rick

    2018-01-01

    posture and behaviour could be detected at pen level between upcoming tail biting pens (T-pens) and control pens (C-pens). The study included 2301 undocked weaner pigs in 74 pens (mean 31.1 pigs/pen; SD 1.5). Tails were scored three times weekly (wound freshness, wound severity and tail length) between 07......Detecting a tail biting outbreak early is essential to reduce the risk of pigs getting severe tail damage. A few previous studies suggest that tail posture and behavioural differences can predict an upcoming outbreak. The aim of the present study was therefore to investigate if differences in tail......:00 h-14:00 h from weaning until a tail biting outbreak. An outbreak (day 0) occurred when at least four pigs had a tail damage, regardless of wound freshness. On average 7.6 (SD 4.3) pigs had a damaged tail (scratches + wound) in T-pens on day 0. Tail posture and behaviour (activity, eating...

  8. Uranium Mill Tailings Remedial Action 1993 Roadmap

    International Nuclear Information System (INIS)

    1993-01-01

    The 1993 Roadmap for the Uranium Mill Tailings Remedial Action (UMTRA) Project office is a tool to assess and resolve issues. The US Department of Energy (DOE) UMTRA Project Office uses the nine-step roadmapping process as a basis for Surface and Groundwater Project planning. This is the second year the Roadmap document has been used to identify key issues and assumptions, develop logic diagrams, and outline milestones. This document is a key element of the DOE planning process. A multi-interest group used the nine-step process to focus on issues, root cause analysis and resolutions. This core group updated and incorporated comments on the basic assumptions, then used these assumptions to identify issues. The list of assumptions was categorized into the following areas: institutional, regulatory compliance, project management, human resource requirements, and other site-specific assumptions. The group identified 10 issues in the analysis phase. All of the issues are ranked according to importance. The number one issue from the 1992 Roadmap, ''Lack of sufficient human resources,'' remained the number one issue in 1993. The issues and their ranking are as follows: Lack of sufficient human resources; increasing regulatory requirements; unresolved groundwater issues; extension of UMTRCA through September 30, 1998; lack of post-UMTRA and post-cell closure policies; unpredictable amounts and timing of Federal funding; lack of regulatory compliance agreements; problem with states providing their share of remedial action costs; different interests and priorities among participants; and technology development/transfer. The issues are outlined and analyzed in detail in Section 8.0, with a schedule for resolution of these issues in Section 9.0

  9. Effects of various tailings covers on radon gas emanation from pyritic uranium tailings

    International Nuclear Information System (INIS)

    Dave, N.K.; Lim, T.P.

    1987-01-01

    Radon emanation studies were carried out at an inactive pyritic uranium tailings site in Elliot Lake, Ontario, Canada, to evaluate the effects of various existing dry and wet covers on radon flux rates. Measurements were taken using activated charcoal cartridges for various surface covers consisting of bare, vegetated, acidophilic moss with high degree of water saturation, compacted crushed rock and gravel, and winter snow. The results showed that at a given site, there was no significant difference in radon emanation rates between various tailings covers and bare tailings. In particular, no increase In radon emanation rates from vegetated areas compared to bare tailings was observed. Radon emanation rates varied spatially depending on tailings grain size, porosity, moisture content and on pressure and water table variations. The emanation rates were higher for tailings with low water contents compared to those for wet and moss covered tailings

  10. Engineering assessment of inactive uranium mill tailings, Slick Rock sites, Slick Rock, Colorado. Phase II, Title I

    International Nuclear Information System (INIS)

    1977-10-01

    Ford, Bacon and Davis Utah Inc. has performed an engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at the two millsites in Slick Rock, Colorado. The Phase II, Title I services include the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and other radium-contaminated materials, the evaluation of resulting radiation exposures of individuals residing nearby, the investigation of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. The Union Carbide site has 350,000 tons of tailings and the North Continent site now owned by Union Carbide has 37,000 tons of tailings. Both tailings piles have been stabilized in accordance with regulations of the State of Colorado. Radon gas release from the tailings on the sites constitute the most significant environmental impact, although windblown tailings and external gamma radiation are also factors. The sparse population and relatively low radiation levels yield minimal immediate environmental impact. Hence the three alternative actions presented are directed towards restricting access to the sites (Option I), and returning the windblown tailings to the piles and stabilizing the piles with cover material (Option II), and consolidating the two piles on the UC site and stabilizing with 2 ft of cover (Option III). Fencing around the tailings piles is included in all options. Options II and III provide 2 ft of cover material on the tailings. Costs of the options range from $370,000 to $1,100,000. Reprocessing the tailings for uranium is not economically feasible

  11. Engineering assessment of inactive uranium mill tailings, Rifle Site, Rifle, Colorado. Summary of the Phase II, Title I

    International Nuclear Information System (INIS)

    1977-10-01

    Ford, Bacon and Davis Utah Inc. has performed an engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Rifle, Colorado. The Phase II - Title I services include the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and other radium-contaminated materials, the evaluation of resulting radiation exposures of individuals and nearby populations, the investigation of site hydrology and meteorology and the evaluation and costing of alternative corrective actions. Radon gas release from the 3.1 million tons of tailings at the two Rifle sites, constitutes the most significant environmental impact. Windblown tailings, external gamma radiation and localized contamination of surface waters are other environmental effects. The 15 alternative remedial action options presented range from millsite decomtamination and off-site remedial action (Options I and IV), to adding various depths of stabilization cover material (Options II, V, VI, and VII), to removal of the tailings to long-term storage sites and decontamination of the present sites (Options III and VIII through XV). Cost estimates for the first 14 options range from $224,000 to $20,300,000. Option XV, estimated at $32,200,000, includes the cost for moving both Rifle tailings piles and the Grand Junction tailings pile to DeBeque for long-term storage and site decontamination after removal of the piles. Reprocessing of the tailings for uranium appears to be economically attractive at present

  12. Engineering assessment of inactive uranium mill tailings new and old Rifle site, Rifle, Colorado. Phase II, Title I

    International Nuclear Information System (INIS)

    1977-10-01

    Ford, Bacon and Davis Utah Inc. has performed an engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Rifle, Colorado. The Phase II--Title I services include the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and other radium-contaminated materials, the evaluation of resulting radiation exposures of individuals and nearby populations, the investigation of site hydrology and meteorology and the evaluation and costing of alternative corrective actions. Radon gas release from the 3.1 million tons of tailings at the two Rifle sites, constitutes the most significant environmental impact. Windblown tailings, external gamma radiation and localized contamination of surface waters are other environmental effects. The 15 alternative remedial action options presented range from millsite decontamination and off-site remedial action (Options I and IV), to adding various depths of stabilization cover material (Options II, V, VI and VII), to removal of the tailings to long-term storage sites and decontamination of the present sites (Options III and VIII through XV). Cost estimates for the first 14 options range from $224,000 to $20,300,000. Option XV, estimated at $32,200,000, includes the cost for moving both Rifle tailings piles and the Grand Junction tailings pile to DeBeque for long-term storage and site decontamination after removal of the piles. Reprocessing of the tailings for uranium appears to be economically attractive at present

  13. Engineering assessment of inactive uranium mill tailings new and old Rifle site, Rifle, Colorado. Phase II, Title I

    Energy Technology Data Exchange (ETDEWEB)

    None

    1977-10-01

    Ford, Bacon and Davis Utah Inc. has performed an engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Rifle, Colorado. The Phase II--Title I services include the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and other radium-contaminated materials, the evaluation of resulting radiation exposures of individuals and nearby populations, the investigation of site hydrology and meteorology and the evaluation and costing of alternative corrective actions. Radon gas release from the 3.1 million tons of tailings at the two Rifle sites, constitutes the most significant environmental impact. Windblown tailings, external gamma radiation and localized contamination of surface waters are other environmental effects. The 15 alternative remedial action options presented range from millsite decontamination and off-site remedial action (Options I and IV), to adding various depths of stabilization cover material (Options II, V, VI and VII), to removal of the tailings to long-term storage sites and decontamination of the present sites (Options III and VIII through XV). Cost estimates for the first 14 options range from $224,000 to $20,300,000. Option XV, estimated at $32,200,000, includes the cost for moving both Rifle tailings piles and the Grand Junction tailings pile to DeBeque for long-term storage and site decontamination after removal of the piles. Reprocessing of the tailings for uranium appears to be economically attractive at present.

  14. The Role of Histone Protein Modifications and Mutations in Histone Modifiers in Pediatric B-Cell Progenitor Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Janczar, Szymon; Janczar, Karolina; Pastorczak, Agata; Harb, Hani; Paige, Adam J. W.; Zalewska-Szewczyk, Beata; Danilewicz, Marian; Mlynarski, Wojciech

    2017-01-01

    While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include MLL1, CREBBP, NSD2, and SETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis. PMID:28054944

  15. Asymmetric Extreme Tails and Prospective Utility of Momentum Returns

    NARCIS (Netherlands)

    Stork, P.A.; Gregory-Allen, R.; Lu, H.

    2012-01-01

    We use extreme value theory to analyse the tails of a momentum strategy's return distribution. The asymmetry between the fat left tail and thin right tail strongly reduces a momentum strategy's prospective utility levels. © 2012 Elsevier B.V.

  16. Low Proteolytic Clipping of Histone H3 in Cervical Cancer

    Science.gov (United States)

    Sandoval-Basilio, Jorge; Serafín-Higuera, Nicolás; Reyes-Hernandez, Octavio D.; Serafín-Higuera, Idanya; Leija-Montoya, Gabriela; Blanco-Morales, Magali; Sierra-Martínez, Monica; Ramos-Mondragon, Roberto; García, Silvia; López-Hernández, Luz Berenice; Yocupicio-Monroy, Martha; Alcaraz-Estrada, Sofia L.

    2016-01-01

    Chromatin in cervical cancer (CC) undergoes chemical and structural changes that alter the expression pattern of genes. Recently, a potential mechanism, which regulates gene expression at transcriptional levels is the proteolytic clipping of histone H3. However, until now this process in CC has not been reported. Using HeLa cells as a model of CC and human samples from patients with CC, we identify that the H3 cleavage was lower in CC compared with control tissue. Additionally, the histone H3 clipping was performed by serine and aspartyl proteases in HeLa cells. These results suggest that histone H3 clipping operates as part of post-translational modification system in CC. PMID:27698925

  17. About a significance of the avian linker histone (H1) polymorphic ...

    Indian Academy of Sciences (India)

    60

    structural disorder may specify histone H1 interaction with both DNA and partnering proteins through ... from the studies conducted on mammalian model, including the human H1 variants. However ..... Thus, the disparate layout of histone H1.

  18. Two distinct modes for propagation of histone PTMs across the cell cycle

    DEFF Research Database (Denmark)

    Alabert, Constance; Barth, Teresa K; Reverón-Gómez, Nazaret

    2015-01-01

    Epigenetic states defined by chromatin can be maintained through mitotic cell division. However, it remains unknown how histone-based information is transmitted. Here we combine nascent chromatin capture (NCC) and triple-SILAC (stable isotope labeling with amino acids in cell culture) labeling...... to track histone modifications and histone variants during DNA replication and across the cell cycle. We show that post-translational modifications (PTMs) are transmitted with parental histones to newly replicated DNA. Di- and trimethylation marks are diluted twofold upon DNA replication, as a consequence...... of new histone deposition. Importantly, within one cell cycle, all PTMs are restored. In general, new histones are modified to mirror the parental histones. However, H3K9 trimethylation (H3K9me3) and H3K27me3 are propagated by continuous modification of parental and new histones because the establishment...

  19. Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans

    NARCIS (Netherlands)

    Choi, S.W.; Gatza, E.; Hou, G.; Sun, Y; Whitfield, J.; Song, Y.; Oravecz-Wilson, K.; Tawara, I.; Dinarello, C.A.; Reddy, P.

    2015-01-01

    We examined immunological responses in patients receiving histone deacetylase (HDAC) inhibition (vorinostat) for graft-versus-host disease prophylaxis after allogeneic hematopoietic cell transplant. Vorinostat treatment increased histone acetylation in peripheral blood mononuclear cells (PBMCs) from

  20. Evaluation of respirable particle matter in gold mine tailings on the Witwatersrand

    International Nuclear Information System (INIS)

    Ojelede, M.E.; Annegarn, H.J.

    2007-01-01

    Within the Witwatersrand gold mining area of South Africa, wind-blown dust is a significant contributor to atmospheric air pollution brought to the fore with the reworking of old mine tailings. Approximately 40,000 hectares are covered with tailings in the Witwatersrand. Wind-erosion during late austral winter and early spring causes surfaces of these tailings to be exposed, particularly during higher wind speeds and in the absence of rainfall. Local residents complain as the surrounding areas experience unpleasant dust episodes. As a result of urban PM 10 and PM 2.5 respirable particulate matter, increased respiratory ailments, morbidity and mortality, and concerns about the health impacts of wind-blown mine tailings in South Africa have been reported. Since 1981, significant monitoring of dustfall has taken place on the Witwatersrand, however, characterization of the respirable fraction of gold mine tailings material and dustfall is lacking. This paper presented the results of a study that established the content of respirable particulate matter in exposed mine tailings and wind-blown dust, and their likely contributions to ambient air. The initial results of the particulate size distribution of material samples from tailings and dust deposits collected in ambient dustfall-monitors were provided. Particle size distributions from different deposit types include slimes and sand deposits, surface and core material, and wind-winnowed secondary deposits. Fractions of PM 10 in source and deposited material were also discussed. It was concluded that there was a significant fraction of PM 10 material in the mine tailings, and that further work to quantify the population exposure risk is needed. 11 refs., 1 tab., 6 figs

  1. Engineering assessment of inactive uranium mill tailings, Gunnison Site, Gunnison, Colorado: summary

    International Nuclear Information System (INIS)

    1981-09-01

    Ford, Bacon and Davis Utah Inc. has reevaluated the Gunnison site in order to revise the November 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Gunnison, Colorado. This evaluation has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the ivnvestigations of site hydrology and meteorology, and the evaluation and costing of alternative remedial actions. Radon gas released from the combined 540,000 dry tons of tailings and the 435,400 tons of contaminated waste at the Gunnison site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The 10 alternative actions presented in this engineering assessment range from stabilization of the site in its present location with the addition of 3 m of stabilization cover material (Option I), to removal of the tailings to disposal sites along with decontamination of the Gunnison site (Options II through X). Cost estimates for the 10 options range from about $8,900,000 for stabilization in-place, to about $14,000,000 for disposal in the North Alkali Creek area at a distance of about 18 mi. Truck haulage would be used to transport the tailings and contaminated materials from the Gunnison site to the selected disposal site. Three principal alternatives for the reprocessing of the Gunnison tailings were examined: heap leaching; treatment at an existing mill; and reprocessing at a new conventional mill constructed for tailings reprocesssing. The cost of the uranium recovered would be about $250 and $230/lb of U 3 O 8 by heap leach and conventional plant processes, respectively. The spot market price for uranium was $25/lb early in 1981

  2. The emerging role of histone lysine demethylases in prostate cancer

    Directory of Open Access Journals (Sweden)

    Crea Francesco

    2012-08-01

    Full Text Available Abstract Early prostate cancer (PCa is generally treatable and associated with good prognosis. After a variable time, PCa evolves into a highly metastatic and treatment-refractory disease: castration-resistant PCa (CRPC. Currently, few prognostic factors are available to predict the emergence of CRPC, and no curative option is available. Epigenetic gene regulation has been shown to trigger PCa metastasis and androgen-independence. Most epigenetic studies have focused on DNA and histone methyltransferases. While DNA methylation leads to gene silencing, histone methylation can trigger gene activation or inactivation, depending on the target amino acid residues and the extent of methylation (me1, me2, or me3. Interestingly, some histone modifiers are essential for PCa tumor-initiating cell (TIC self-renewal. TICs are considered the seeds responsible for metastatic spreading and androgen-independence. Histone Lysine Demethylases (KDMs are a novel class of epigenetic enzymes which can remove both repressive and activating histone marks. KDMs are currently grouped into 7 major classes, each one targeting a specific methylation site. Since their discovery, KDM expression has been found to be deregulated in several neoplasms. In PCa, KDMs may act as either tumor suppressors or oncogenes, depending on their gene regulatory function. For example, KDM1A and KDM4C are essential for PCa androgen-dependent proliferation, while PHF8 is involved in PCa migration and invasion. Interestingly, the possibility of pharmacologically targeting KDMs has been demonstrated. In the present paper, we summarize the emerging role of KDMs in regulating the metastatic potential and androgen-dependence of PCa. In addition, we speculate on the possible interaction between KDMs and other epigenetic effectors relevant for PCa TICs. Finally, we explore the role of KDMs as novel prognostic factors and therapeutic targets. We believe that studies on histone demethylation may add a

  3. Basic description of tailings from Aitik focusing on mechanical behavior

    OpenAIRE

    Bhanbhro, Riaz; Knutsson, Roger; Rodriguez, Juan; Edeskär, Tommy; Knutsson, Sven

    2013-01-01

    Tailings are artificial granular materials that behave different as compared to natural soil of equal grain sizes. Tailings particle sizes, shapes, gradation and mechanical behavior may influence the performance of tailings dams. Hence it is essential to understand the tailings materials in depth. This article describes present studies being carried out on Aitik tailings. Basic tailings characteristics including specific gravity, phase relationships, particle sizes, particle shapes and direct...

  4. Dissociation of histone and DNA synthesis in x-irradiated HeLa cells

    International Nuclear Information System (INIS)

    Bases, R.; Mendez, F.

    1971-01-01

    Although histone synthesis and DNA synthesis are normally very well coordinated in HeLa cells, their histone synthesis proved relatively resistant to inhibition by ionizing radiation. During the first 24 h after 1,000 R the rate of cellular DNA synthesis progressively fell to small fractions of control values while histone synthesis with much less relative reduction. Acrylamide gel electropherograms of the acid soluble nuclear histones synthesized by irradiated HeLa cells were qualitatively normal

  5. Ilmenite Mineral's Recovery from Beach Sand Tailings

    International Nuclear Information System (INIS)

    Mulaba-Bafubiandi, Antoine F.; Mukendi-Ngalula, David; Waanders, Frans B.

    2002-01-01

    The mineral ilmenite is the major source of rutile for industrial use and is of interest to paint and fertiliser industries. Enormous unutilised tailing dams lie on the eastern coast of the South Africa. Although covered by a simulation of the original indigenous vegetation, these tailings are still ilmenite bearing and of economic value. Tailings emanating from beach sand mineral slimes dams of the Kwazulu-Natal area (South Africa) have been processed. Screening, flotation, spiral concentration and magnetic separation methods were used either separately or successively. The present work sheds light on alternative routes for the extraction of the ilmenite, from these tailings. It moreover points out the usefulness of the Moessbauer spectroscopy in the mineral processing product monitoring. Tailings from the beach sands were used in the present study after the economic industrial minerals zirconia, ilmenite and rutile had been extracted in previous mining operations. About 61% natural ilmenite recovery was observed in the flotation concentrate of a Humphrey Spiral concentrate while a 62% recovery of hematite was found in the flotation tailings. The combination of screening, spiral concentration and magnetic separation, and flotation yielded a product with the highest ilmenite and hematite concentration being 71% and 19%, respectively. A natural ilmenite mineral, containing 87% ilmenite and 13% hematite, could be produced and extracted from the tailings of the flotation process, collected subsequently to the spiral concentration and the initial screening.

  6. The evolution of tail weaponization in amniotes.

    Science.gov (United States)

    Arbour, Victoria M; Zanno, Lindsay E

    2018-01-31

    Weaponry, for the purpose of intraspecific combat or predator defence, is one of the most widespread animal adaptations, yet the selective pressures and constraints governing its phenotypic diversity and skeletal regionalization are not well understood. Here, we investigate the evolution of tail weaponry in amniotes, a rare form of weaponry that nonetheless evolved independently among a broad spectrum of life including mammals, turtles and dinosaurs. Using phylogenetic comparative methods, we test for links between morphology, ecology and behaviour in extant amniotes known to use the tail as a weapon, and in extinct taxa bearing osseous tail armaments. We find robust ecological and morphological correlates of both tail lashing behaviour and bony tail weaponry, including large body size, body armour and herbivory, suggesting these life-history parameters factor into the evolution of antipredator behaviours and tail armaments. We suggest that the evolution of tail weaponry is rare because large, armoured herbivores are uncommon in extant terrestrial faunas, as they have been throughout evolutionary history. © 2018 The Author(s).

  7. Inhibition of histone deacetylases sensitizes glioblastoma cells to lomustine

    DEFF Research Database (Denmark)

    Staberg, Mikkel; Michaelsen, Signe Regner; Rasmussen, Rikke Darling

    2017-01-01

    the sensitizing effect of the HDACi trichostatin A (TSA) to the alkylating agent lomustine (CCNU), which is used in the clinic for the treatment of GBM. METHODS: Twelve primary GBM cell cultures grown as neurospheres were used in this study, as well as one established GBM-derived cell line (U87 MG). Histone...... are problems that call for a prompt development of novel therapeutic strategies. While only displaying modest efficacies as mono-therapy in pre-clinical settings, histone deacetylase inhibitors (HDACi) have shown promising sensitizing effects to a number of cytotoxic agents. Here, we sought to investigate...

  8. Epigenetic control of skull morphogenesis by histone deacetylase 8

    Science.gov (United States)

    Haberland, Michael; Mokalled, Mayssa H.; Montgomery, Rusty L.; Olson, Eric N.

    2009-01-01

    Histone deacetylases (Hdacs) are transcriptional repressors with crucial roles in mammalian development. Here we provide evidence that Hdac8 specifically controls patterning of the skull by repressing a subset of transcription factors in cranial neural crest cells. Global deletion of Hdac8 in mice leads to perinatal lethality due to skull instability, and this is phenocopied by conditional deletion of Hdac8 in cranial neural crest cells. Hdac8 specifically represses the aberrant expression of homeobox transcription factors such as Otx2 and Lhx1. These findings reveal how the identity and patterning of vertebrate-specific portions of the skull are epigenetically controlled by a histone deacetylase. PMID:19605684

  9. Mechanisms of transcriptional repression by histone lysine methylation

    DEFF Research Database (Denmark)

    Hublitz, Philip; Albert, Mareike; Peters, Antoine H F M

    2009-01-01

    . In this report, we review the recent literature to deduce mechanisms underlying Polycomb and H3K9 methylation mediated repression, and describe the functional interplay with activating H3K4 methylation. We summarize recent data that indicate a close relationship between GC density of promoter sequences......, transcription factor binding and the antagonizing activities of distinct epigenetic regulators such as histone methyltransferases (HMTs) and histone demethylases (HDMs). Subsequently, we compare chromatin signatures associated with different types of transcriptional outcomes from stable repression to highly...

  10. Characterization of human papillomavirus type 16 pseudovirus containing histones.

    Science.gov (United States)

    Kim, Hyoung Jin; Kwag, Hye-Lim; Kim, Hong-Jin

    2016-08-27

    Pseudoviruses (PsVs) that encapsidate a reporter plasmid DNA have been used as surrogates for native human papillomavirus (HPV), whose continuous production is technically difficult. HPV PsVs have been designed to form capsids made up of the major capsid protein L1 and the minor capsid proteins L2. HPV PsVs have been produced in 293TT cells transfected with plasmid expressing L1 and L2 protein and plasmid containing the reporter gene. Several studies have suggested that naturally occurring HPV virions contain cellular histones, and histones have also been identified in mature HPV PsVs. However, the effect of the histones on the properties of the PsVs has not been investigated. Using heparin chromatography, we separated mature HPV type 16 PsVs into three fractions (I, II, and III) according to their heparin-binding affinities. The amounts of cellular histone and cellular nucleotides per PsV were found to increase in the order fraction I, II and III. It appeared that PsVs in fraction I contains just small amount of cellular histone in Western blot analysis. The proportions of the three fractions in PsV preparations were 83.4, 7.5, and 9.1 % for fraction I, II, and III PsVs, respectively. In the electron microscope PsVs in fraction I appeared to have a more condensed structure than those in fractions II and III. Under the electron microscope fraction II and III PsVs appeared to be covered by substantial amounts of cellular histone while there was no visible histone covering PsVs of fraction I. Also the levels of reporter gene expression in infections of fraction II and III PsVs to 293TT cells were significantly lower than those in infections of fraction I PsV, and fraction II and III particles had significantly reduced immunogenicity. Our findings suggest that the involvement of large amounts of cellular histones during PsV formation interferes with the structural integrity of the PsVs and affects their immunogenicity. The fraction I particle therefore has the most

  11. Effects of orally applied butyrate bolus on histone acetylation and cytochrome P450 enzyme activity in the liver of chicken – a randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Mátis Gábor

    2013-01-01

    Full Text Available Abstract Background Butyrate is known as histone deacetylase inhibitor, inducing histone hyperacetylation in vitro and playing a predominant role in the epigenetic regulation of gene expression and cell function. We hypothesized that butyrate, endogenously produced by intestinal microbial fermentation or applied as a nutritional supplement, might cause similar in vivo modifications in the chromatin structure of the hepatocytes, influencing the expression of certain genes and therefore modifying the activity of hepatic microsomal drug-metabolizing cytochrome P450 (CYP enzymes. Methods An animal study was carried out in chicken as a model to investigate the molecular mechanisms of butyrate’s epigenetic actions in the liver. Broiler chicks in the early post-hatch period were treated once daily with orally administered bolus of butyrate following overnight starvation with two different doses (0.25 or 1.25 g/kg body weight per day for five days. After slaughtering, cell nucleus and microsomal fractions were separated by differential centrifugation from the livers. Histones were isolated from cell nuclei and acetylation of hepatic core histones was screened by western blotting. The activity of CYP2H and CYP3A37, enzymes involved in biotransformation in chicken, was detected by aminopyrine N-demethylation and aniline-hydroxylation assays from the microsomal suspensions. Results Orally added butyrate, applied in bolus, had a remarkable impact on nucleosome structure of hepatocytes: independently of the dose, butyrate caused hyperacetylation of histone H2A, but no changes were monitored in the acetylation state of H2B. Intensive hyperacetylation of H3 was induced by the higher administered dose, while the lower dose tended to increase acetylation ratio of H4. In spite of the observed modification in histone acetylation, no significant changes were observed in the hepatic microsomal CYP2H and CYP3A37 activity. Conclusion Orally added butyrate in bolus

  12. Histone deacetylase 1, 2, 6 and acetylated histone H4 in B- and T-cell lymphomas

    DEFF Research Database (Denmark)

    Marquard, L.; Poulsen, C.B.; Gjerdrum, L.M.

    2009-01-01

    AIMS: Histone deacetylase (HDAC) inhibitors are novel therapeutics in the treatment of peripheral T-cell lymphoma, unspecified (PTCL) and diffuse large B-cell lymphoma (DLBCL), where, for unknown reasons, T-cell malignancies appear to be more sensitive than B-cell malignancies. The aim was to det......AIMS: Histone deacetylase (HDAC) inhibitors are novel therapeutics in the treatment of peripheral T-cell lymphoma, unspecified (PTCL) and diffuse large B-cell lymphoma (DLBCL), where, for unknown reasons, T-cell malignancies appear to be more sensitive than B-cell malignancies. The aim...... was to determine HDAC expression in DLBCL and PTCL which has not previously been investigated. METHODS AND RESULTS: The expression of HDAC1, HDAC2, HDAC6 and acetylated histone H4 was examined immunohistochemically in 31 DLBCL and 45 PTCL. All four markers showed high expression in both DLBCL and PTCL compared...

  13. Cameco engineered tailings program: linking research with industrial processes for improved tailings performance

    International Nuclear Information System (INIS)

    Kotzer, T.; Hendry, M.J.

    2011-01-01

    The waste product from uranium mining and milling that generates the greatest public and regulatory concern is tailings. The tailings contain all of the mined material except uranium plus a host of processing reagents. These minerals and compounds have the potential to harm the local environment if not deposited in a fashion that is both geochemically and geotechnically stable. Environmental leadership impels Cameco Corporation to ensure that the methods used to dispose of tailings are at the forefront of best available technologies whereby tailings production results in a product with geotechnical and geochemical characteristics that minimize the environmental impact associated with long-term storage of this product. Cameco has developed an Engineered Tailings (ET) program to ensure optimization of long-term tailings performance and minimal impacts of elements of concern (EOCs) to the receiving environment, regardless of the ore being milled. Within this program chemical and physical performance of tailings from geochemical and geotechnical investigations and baseline environmental data, integrated with regulatory requirements and corporate commitments, will be used to evaluate and set criteria for mill- and tailings management facilities-based chemical and physical tailings characteristics, identify key knowledge gaps, prioritize areas of concern and implement appropriate responses. This paper provides an overview of the Engineered Tailings program, the research being conducted as part of the ET program, and how it links with present and future Cameco operations. (author)

  14. Histone deacetylase inhibitors induced differentiation and accelerated mineralization of pulp-derived cells.

    LENUS (Irish Health Repository)

    Duncan, Henry F

    2012-03-01

    Histone deacetylase inhibitors (HDACis) alter the homeostatic balance between 2 groups of cellular enzymes, histone deacetylases (HDACs) and histone acetyltransferases (HATs), increasing transcription and influencing cell behavior. This study investigated the potential of 2 HDACis, valproic acid (VPA) and trichostatin A (TSA), to promote reparative processes in pulp cells as assayed by viability, cell cycle, and mineralization analyses.

  15. Further evidence for poly-ADP-ribosylated histones as DNA suppressors

    International Nuclear Information System (INIS)

    Yu, F.L.; Geronimo, I.H.; Bender, W.; Meginniss, K.E.

    1986-01-01

    For many years histones have been considered to be the gene suppressors in eukaryotic cells. Recently, the authors have found strong evidence indicating that poly-ADP-ribosylated histones, rather than histones, are the potent inhibitors of DNA-dependent RNA synthesis. They now report additional evidence for this concept: 1) using histone inhibitor isolated directly from nuclei, the authors are able to confirm their earlier findings that the inhibitor substances are sensitive to pronase, snake venom phosphodiesterase digestion and 0.1N KOH hydrolysis, and are resistant to DNase I and RNase A digestion, 2) the O.D. 260/O.D.280 ratio of the histone inhibitor is between pure protein and nuclei acid, suggesting the inhibitor substance is a nucleoprotein hybrid. This result directly supports the fact that the isolated histone inhibitor is radioactive poly (ADP-ribose) labeled, 3) commercial histones show big differences in inhibitor activity. The authors believe this reflects the variation in poly-ADP-ribosylation among commercial histones, and 4) 0.1N KOH hydrolysis eliminates the poly (ADP-ribose) radioactivity from the acceptor proteins as well as histone inhibitor activity. Yet, on gel, the inhibitor shows identical histone bands and stain intensity before and after hydrolysis, indicating the histones per se are qualitatively and quantitatively unaffected by alkaline treatment. This result strongly suggests that histones themselves are not capable of inhibiting DNA-dependent RNA synthesis

  16. Neutrophil Extracellular Trap-Related Extracellular Histones Cause Vascular Necrosis in Severe GN.

    Science.gov (United States)

    Kumar, Santhosh V R; Kulkarni, Onkar P; Mulay, Shrikant R; Darisipudi, Murthy N; Romoli, Simone; Thomasova, Dana; Scherbaum, Christina R; Hohenstein, Bernd; Hugo, Christian; Müller, Susanna; Liapis, Helen; Anders, Hans-Joachim

    2015-10-01

    Severe GN involves local neutrophil extracellular trap (NET) formation. We hypothesized a local cytotoxic effect of NET-related histone release in necrotizing GN. In vitro, histones from calf thymus or histones released by neutrophils undergoing NETosis killed glomerular endothelial cells, podocytes, and parietal epithelial cells in a dose-dependent manner. Histone-neutralizing agents such as antihistone IgG, activated protein C, or heparin prevented this effect. Histone toxicity on glomeruli ex vivo was Toll-like receptor 2/4 dependent, and lack of TLR2/4 attenuated histone-induced renal thrombotic microangiopathy and glomerular necrosis in mice. Anti-glomerular basement membrane GN involved NET formation and vascular necrosis, whereas blocking NET formation by peptidylarginine inhibition or preemptive anti-histone IgG injection significantly reduced all aspects of GN (i.e., vascular necrosis, podocyte loss, albuminuria, cytokine induction, recruitment or activation of glomerular leukocytes, and glomerular crescent formation). To evaluate histones as a therapeutic target, mice with established GN were treated with three different histone-neutralizing agents. Anti-histone IgG, recombinant activated protein C, and heparin were equally effective in abrogating severe GN, whereas combination therapy had no additive effects. Together, these results indicate that NET-related histone release during GN elicits cytotoxic and immunostimulatory effects. Furthermore, neutralizing extracellular histones is still therapeutic when initiated in established GN. Copyright © 2015 by the American Society of Nephrology.

  17. The DEAD-Box Protein CYT-19 Uses Arginine Residues in Its C-Tail To Tether RNA Substrates.

    Science.gov (United States)

    Busa, Veronica F; Rector, Maxwell J; Russell, Rick

    2017-07-18

    DEAD-box proteins are nonprocessive RNA helicases that play diverse roles in cellular processes. The Neurospora crassa DEAD-box protein CYT-19 promotes mitochondrial group I intron splicing and functions as a general RNA chaperone. CYT-19 includes a disordered, arginine-rich "C-tail" that binds RNA, positioning the helicase core to capture and unwind nearby RNA helices. Here we probed the C-tail further by varying the number and positions of arginines within it. We found that removing sets of as few as four of the 11 arginines reduced RNA unwinding activity (k cat /K M ) to a degree equivalent to that seen upon removal of the C-tail, suggesting that a minimum or "threshold" number of arginines is required. In addition, a mutant with 16 arginines displayed RNA unwinding activity greater than that of wild-type CYT-19. The C-tail modifications impacted unwinding only of RNA helices within constructs that included an adjacent helix or structured RNA element that would allow C-tail binding, indicating that the helicase core remained active in the mutants. In addition, changes in RNA unwinding efficiency of the mutants were mirrored by changes in functional RNA affinity, as determined from the RNA concentration dependence of ATPase activity, suggesting that the C-tail functions primarily to increase RNA affinity. Interestingly, the salt concentration dependence of RNA unwinding activity is unaffected by C-tail composition, suggesting that the C-tail uses primarily hydrogen bonding, not electrostatic interactions, to bind double-stranded RNA. Our results provide insights into how an unstructured C-tail contributes to DEAD-box protein activity and suggest parallels with other families of RNA- and DNA-binding proteins.

  18. Summary of the engineering assessment of inactive uranium mill tailings: Phillips/United Nuclear site, Ambrosia Lake, New Mexico

    International Nuclear Information System (INIS)

    1981-10-01

    Ford, Bacon and Davis Utah, Inc., has reevaluated the Phillips/United Nuclear site in order to revise the December 1977 engineering assessment of the problems resulting from the existence of radioactive uranium mill tailings at Ambrosia Lake, New Mexico. This engineering assessment has included the preparation of topographic maps, the performance of core drillings and radiometric maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas released from the 2.6 million dry tons of tailings at the Phillips/United Nuclear site constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The four alternative actions presented in this engineering assessment range from millsite decontamination with the addition of 3 m of stabilization cover material, to removal of the tailings to remote disposal sites and decontamination of the tailings site. Cost estimates for the four options range from about $21,500,000 for stabilization in-place, to about $45,200,000 for disposal at a distance of about 15 mi. Three principal alternatives for the reprocessing of the Phillips/United Nuclear tailings were examined: heap leaching; treatment at an existing mill; reprocessing at a new conventional mill constructed for tailings reprocessing. The cost of the uranium recovered would be about $87/lb of U 3 O 8 by either heap leach or conventional plant process. The spot market price for uranium was $25/lb early in 1981. Reprocessing the Phillips/United Nuclear tailings for uranium recovery does not appear to be economically attractive under present or foreseeable market conditions

  19. Collisional relaxation of electron tail distribution

    International Nuclear Information System (INIS)

    Yamagiwa, Mitsuru; Okamoto, Masao.

    1985-05-01

    Relaxation due to the Coulomb collisions of the electron velocity distribution function with a high energy tail is investigated in detail. In the course of the relaxation, a 'saddle' point can be created in velocity space owing to upsilon -3 dependence of the deflection rate and a positive slope or a 'dip' appears in the tail direction. The time evolution of the electron tail is studied analytically. A comparison is made with numerical results by using a Fokker-Planck code. Also discussed is the kinetic instability concerned with the positive slope during the relaxation. (author)

  20. Role of chromatin structure modulation by the histone deacetylase inhibitor trichostatin A on the radio-sensitivity of ataxia telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

    Meschini, Roberta, E-mail: meschini@unitus.it; Morucci, Elisa; Berni, Andrea; Lopez-Martinez, Wilner; Palitti, Fabrizio

    2015-07-15

    Highlights: • Role of chromatin compaction on chromosomal instability. • Reduced radiation-induced clastogenicity in Ataxia telangiectasia cell lines. • Histone tails hyperacetylation reduces heterochromatin content favouring DSBs repair. - Abstract: At present, a lot is known about biochemical aspects of double strand breaks (DBS) repair but how chromatin structure affects this process and the sensitivity of DNA to DSB induction is still an unresolved question. Ataxia telangiectasia (A-T) patients are characterised by very high sensitivity to DSB-inducing agents such as ionising radiation. This radiosensitivity is revealed with an enhancement of chromosomal instability as a consequence of defective DNA repair for a small fraction of breaks located in the heterochromatin, where they are less accessible. Besides, recently it has been reported that Ataxia Telangiectasia Mutated (ATM) mediated signalling modifies chromatin structure. In order to study the impact of chromatin compaction on the chromosomal instability of A-T cells, the response to trichostatin-A, an histone deacetylase inhibitor, in normal and A-T lymphoblastoid cell lines was investigated testing its effect on chromosomal aberrations, cell cycle progression, DNA damage and repair after exposure to X-rays. The results suggest that the response to both trichostatin-A pre- and continuous treatments is independent of the presence of either functional or mutated ATM protein, as the reduction of chromosomal damage was found also in the wild-type cell line. The presence of trichostatin-A before exposure to X-rays could give rise to prompt DNA repair functioning on chromatin structure already in an open conformation. Differently, trichostatin-A post-treatment causing hyperacetylation of histone tails and reducing the heterochromatic DNA content might diminish the requirement for ATM and favour DSBs repair reducing chromosomal damage only in A-T cells. This fact could suggest that trichostatin-A post

  1. Histone deacetylase inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.

    Science.gov (United States)

    Lee, Eunjo; Song, Min-Ji; Lee, Hae-Ahm; Kang, Seol-Hee; Kim, Mina; Yang, Eun Kyoung; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung; Kim, Inkyeom

    2016-09-01

    CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.

  2. Quantitative analysis of histone modifications: formaldehyde is a source of pathological n(6-formyllysine that is refractory to histone deacetylases.

    Directory of Open Access Journals (Sweden)

    Bahar Edrissi

    Full Text Available Aberrant protein modifications play an important role in the pathophysiology of many human diseases, in terms of both dysfunction of physiological modifications and the formation of pathological modifications by reaction of proteins with endogenous electrophiles. Recent studies have identified a chemical homolog of lysine acetylation, N(6-formyllysine, as an abundant modification of histone and chromatin proteins, one possible source of which is the reaction of lysine with 3'-formylphosphate residues from DNA oxidation. Using a new liquid chromatography-coupled to tandem mass spectrometry method to quantify all N(6-methyl-, -acetyl- and -formyl-lysine modifications, we now report that endogenous formaldehyde is a major source of N(6-formyllysine and that this adduct is widespread among cellular proteins in all compartments. N(6-formyllysine was evenly distributed among different classes of histone proteins from human TK6 cells at 1-4 modifications per 10(4 lysines, which contrasted strongly with lysine acetylation and mono-, di-, and tri-methylation levels of 1.5-380, 5-870, 0-1400, and 0-390 per 10(4 lysines, respectively. While isotope labeling studies revealed that lysine demethylation is not a source of N(6-formyllysine in histones, formaldehyde exposure was observed to cause a dose-dependent increase in N(6-formyllysine, with use of [(13C,(2H2]-formaldehyde revealing unchanged levels of adducts derived from endogenous sources. Inhibitors of class I and class II histone deacetylases did not affect the levels of N(6-formyllysine in TK6 cells, and the class III histone deacetylase, SIRT1, had minimal activity (<10% with a peptide substrate containing the formyl adduct. These data suggest that N(6-formyllysine is refractory to removal by histone deacetylases, which supports the idea that this abundant protein modification could interfere with normal regulation of gene expression if it arises at conserved sites of physiological protein secondary

  3. A new epigenetic marker: The replication-coupled, cell cycle-dependent, dual modification of the histone H4 tail

    Czech Academy of Sciences Publication Activity Database

    Fidlerová, Helena; Kalinová, Jana; Blechová, Miroslava; Velek, Jiří; Raška, Ivan

    2009-01-01

    Roč. 167, č. 1 (2009), s. 76-82 ISSN 1047-8477 R&D Projects: GA ČR(CZ) GA304/06/1691 Grant - others:GA MŠk(CZ) LC535 Program:LC Institutional research plan: CEZ:AV0Z50110509; CEZ:AV0Z40550506 Keywords : epigenetics * H4K16 * H4K20 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.673, year: 2009

  4. Esperanto for histones: CENP-A, not CenH3, is the centromeric histone H3 variant.

    Science.gov (United States)

    Earnshaw, W C; Allshire, R C; Black, B E; Bloom, K; Brinkley, B R; Brown, W; Cheeseman, I M; Choo, K H A; Copenhaver, G P; Deluca, J G; Desai, A; Diekmann, S; Erhardt, S; Fitzgerald-Hayes, M; Foltz, D; Fukagawa, T; Gassmann, R; Gerlich, D W; Glover, D M; Gorbsky, G J; Harrison, S C; Heun, P; Hirota, T; Jansen, L E T; Karpen, G; Kops, G J P L; Lampson, M A; Lens, S M; Losada, A; Luger, K; Maiato, H; Maddox, P S; Margolis, R L; Masumoto, H; McAinsh, A D; Mellone, B G; Meraldi, P; Musacchio, A; Oegema, K; O'Neill, R J; Salmon, E D; Scott, K C; Straight, A F; Stukenberg, P T; Sullivan, B A; Sullivan, K F; Sunkel, C E; Swedlow, J R; Walczak, C E; Warburton, P E; Westermann, S; Willard, H F; Wordeman, L; Yanagida, M; Yen, T J; Yoda, K; Cleveland, D W

    2013-04-01

    The first centromeric protein identified in any species was CENP-A, a divergent member of the histone H3 family that was recognised by autoantibodies from patients with scleroderma-spectrum disease. It has recently been suggested to rename this protein CenH3. Here, we argue that the original name should be maintained both because it is the basis of a long established nomenclature for centromere proteins and because it avoids confusion due to the presence of canonical histone H3 at centromeres.

  5. Phase II, Title I, engineering assessment of inactive uranium mill tailings, Riverton Site, Riverton, Wyoming

    International Nuclear Information System (INIS)

    1977-12-01

    An engineering assessment was performed of the problems resulting from the existence of radioactive uranium mill tailings at the Spook Site, Converse County, Wyoming. Services include the performance of core drillings, soil, water and other sample analyses, radiometric measurements to determine areas with radium-contaminated materials, the evaluation of resulting radiation exposures of individuals and nearby populations, the investigation of site geology, hydrology, and meteorology and the evaluation and costing of alternative corrective actions. Radon gas release from the 187,000 tons of tailings at the Spook Site constitutes the main environmental impact, which is negligible. The two alternative actions presented are better fencing of the site in its present state, and placing tailings and contaminated on-site materials and soil in the open-pit mine and covering the resulting pile with 2 ft of overburden materials. The cost estimates for the options are $81,000 and $142,000, respectively

  6. Cameco engineered tailings program: linking applied research with industrial processes for improved tailings performance

    International Nuclear Information System (INIS)

    Kotzer, T.G.

    2010-01-01

    'Full text:' Mine tailings at Cameco's operations are by-products of milling uranium ore having variable concentrations of uranium, metals, oxyanions and trace elements or elements of concern (EOC). Cameco has undertaken an Engineered Tailings (ET) program to optimize tailings performance and minimize environmental EOC impacts, regardless of the milled ore source. Applied geochemical and geotechnical tailings research is key within the ET program. In-situ drilling and experimental programs are used to understand long-term tailings behaviour and help validate source term predictions. Within this, the ET program proactively aids in the development of mill-based processes for production of tailings having improved long-term stability. (author)

  7. Some properties of Suncor oil sands tailings

    Energy Technology Data Exchange (ETDEWEB)

    Guo, C.; Wells, P.S. [Suncor Energy, Fort McMurray, AB (Canada)

    2010-07-01

    This PowerPoint presentation discussed a pond assessment program conducted by Suncor to determine the properties of mature fine tailings (MFT) and composite tailings (CT) at reclaimed and unreclaimed sites. Mudline and sonar depth sounding techniques were used to determine solids contents. A wire line sampler provided point depth samples used for laboratory analyses. Continuous drill samples were obtained in order to characterize bottom fines and clay content. A flow penetration tests was used to determine the undrained shear strength of the soft tailings. A 3-D block model was then used to estimate soft material properties and to generate material distribution volumes and tonnages for different property ranges. The study showed that the block modelling techniques provide a more accurate tailings pond assessment than traditional approaches. While slow, ongoing static consolidation was observed, surface capping and artificial dewatering are required to provide trafficable ground for the final reclamation of the sites. tabs., figs.

  8. Unique structural features facilitate lizard tail autotomy.

    Directory of Open Access Journals (Sweden)

    Kristian W Sanggaard

    Full Text Available Autotomy refers to the voluntary shedding of a body part; a renowned example is tail loss among lizards as a response to attempted predation. Although many aspects of lizard tail autotomy have been studied, the detailed morphology and mechanism remains unclear. In the present study, we showed that tail shedding by the Tokay gecko (Gekko gecko and the associated extracellular matrix (ECM rupture were independent of proteolysis. Instead, lizard caudal autotomy relied on biological adhesion facilitated by surface microstructures. Results based on bio-imaging techniques demonstrated that the tail of Gekko gecko was pre-severed at distinct sites and that its structural integrity depended on the adhesion between these segments.

  9. BIOMECHANICS. Why the seahorse tail is square.

    Science.gov (United States)

    Porter, Michael M; Adriaens, Dominique; Hatton, Ross L; Meyers, Marc A; McKittrick, Joanna

    2015-07-03

    Whereas the predominant shapes of most animal tails are cylindrical, seahorse tails are square prisms. Seahorses use their tails as flexible grasping appendages, in spite of a rigid bony armor that fully encases their bodies. We explore the mechanics of two three-dimensional-printed models that mimic either the natural (square prism) or hypothetical (cylindrical) architecture of a seahorse tail to uncover whether or not the square geometry provides any functional advantages. Our results show that the square prism is more resilient when crushed and provides a mechanism for preserving articulatory organization upon extensive bending and twisting, as compared with its cylindrical counterpart. Thus, the square architecture is better than the circular one in the context of two integrated functions: grasping ability and crushing resistance. Copyright © 2015, American Association for the Advancement of Science.

  10. Elemental characterization of Tummalapalle uranium mill tailing

    International Nuclear Information System (INIS)

    Patra, A.C.; Sahoo, S.K.; Thakur, V.K.; Dubey, J.S.; Jha, S.K.; Tripathi, R.M.; Sharma, D.B.

    2018-01-01

    Elements are present in environmental matrices at varying concentrations. Their levels may increase due to anthropogenic activities like transportation, industrial activities, agriculture, urbanization and human activities. Trace elements can be classified as potentially toxic (eg. cadmium, arsenic, mercury, lead, nickel), probably essential (eg. cobalt, vanadium) and essential (eg. iron, zinc, copper, selenium, manganese). Due to the expansion of the Indian Nuclear Power Programme, new uranium mining sites are coming up. Mining and milling produce large quantities of low active mill tailings contained in engineered Tailings Ponds. The tailings are amenable for interaction with the geochemical forces and can act as potential sources of contamination. Thus it is necessary to ascertain the concentrations of elements that are present therein. In this paper we aim to characterize the uranium tailings generated from Tummalapalle uranium mining facility in Kadappa district, Andhra Pradesh, India

  11. On Estimation and Testing for Pareto Tails

    Czech Academy of Sciences Publication Activity Database

    Jordanova, P.; Stehlík, M.; Fabián, Zdeněk; Střelec, L.

    2013-01-01

    Roč. 22, č. 1 (2013), s. 89-108 ISSN 0204-9805 Institutional support: RVO:67985807 Keywords : testing against heavy tails * asymptotic properties of estimators * point estimation Subject RIV: BB - Applied Statistics, Operational Research

  12. Toxic effects of extracellular histones and their neutralization by vitreous in retinal detachment.

    Science.gov (United States)

    Kawano, Hiroki; Ito, Takashi; Yamada, Shingo; Hashiguchi, Teruto; Maruyama, Ikuro; Hisatomi, Toshio; Nakamura, Makoto; Sakamoto, Taiji

    2014-05-01

    Histones are DNA-binding proteins and are involved in chromatin remodeling and regulation of gene expression. Histones can be released after tissue injuries, and the extracellular histones cause cellular damage and organ dysfunction. Regardless of their clinical significance, the role and relevance of histones in ocular diseases are unknown. We studied the role of histones in eyes with retinal detachment (RD). Vitreous samples were collected during vitrectomy, and the concentration of histone H3 was measured by enzyme-linked immunosorbent assay. The location of the histones and related molecules was examined in a rat RD model. The release of histones and their effects on rat retinal progenitor cells R28 and ARPE-19 were evaluated in vitro. In addition, the protective role of the vitreous body against histones was tested. The intravitreal concentration of histones was higher in eyes with RD (mean, 30.9 ± 9.8 ng/ml) than in control eyes (below the limit of detection, Phistone H3 was observed on the outer side of the detached retina and was associated with photoreceptor death. Histone H3 was released from cultured R28 by oxidative stress. Histones at a concentration 10 μg/ml induced the production of interleukin-8 in ARPE-19 cells (2.5-fold increase, PHistones were toxic to cells at concentrations of ≥ 20 μg/ml. Vitreous body or hyaluronan decreased toxicity of histones by inhibiting diffusion of histones. These results indicate that histones are released from retinas with RD and may modulate the subretinal microenvironment by functioning as damage-associated molecular pattern molecules, thereby inducing proinflammatory cytokines or cell toxicity. In addition, the important role of the vitreous body and hyaluronan in protecting the retina from these toxic effects is suggested.

  13. Reactor core

    International Nuclear Information System (INIS)

    Matsuura, Tetsuaki; Nomura, Teiji; Tokunaga, Kensuke; Okuda, Shin-ichi

    1990-01-01

    Fuel assemblies in the portions where the gradient of fast neutron fluxes between two opposing faces of a channel box is great are kept loaded at the outermost peripheral position of the reactor core also in the second operation cycle in the order to prevent interference between a control rod and the channel box due to bending deformation of the channel box. Further, the fuel assemblies in the second row from the outer most periphery in the first operation cycle are also kept loaded at the second row in the second operation cycle. Since the gradient of the fast neutrons in the reactor core is especially great at the outer circumference of the reactor core, the channel box at the outer circumference is bent such that the surface facing to the center of the reactor core is convexed and the channel box in the second row is also bent to the identical direction, the insertion of the control rod is not interfered. Further, if the positions for the fuels at the outermost periphery and the fuels in the second row are not altered in the second operation cycle, the gaps are not reduced to prevent the interference between the control rod and the channel box. (N.H.)

  14. Electrodialytic remediation of suspended mine tailings

    DEFF Research Database (Denmark)

    Hansen, Henrik K.; Rojo, Adrian; Pino, Denisse

    2008-01-01

    This work shows the laboratory results of nine electrodialytic remediation experiments on copper mine tailings. A newly designed remediation cell, where the solids were kept in suspension by airflow, was tested. The results show that electric current could remove copper from suspended tailings...... efficiency from 1% to 80% compared to experiments with no stirring but with the same operational conditions. This showed the crucial importance of having the solids in suspension and not settled during the remediation....

  15. Electrodialytic Remediation of Copper Mine Tailings

    DEFF Research Database (Denmark)

    Hansen, H.K.; Rojo, A.; Ottosen, L.M.

    2012-01-01

    This work compares and evaluates sixteen electrodialytic laboratory remediation experiments on copper mine tailings. Different parameters were analysed, such as remediation time, addition of desorbing agents, and the use of pulsed electrical fields.......This work compares and evaluates sixteen electrodialytic laboratory remediation experiments on copper mine tailings. Different parameters were analysed, such as remediation time, addition of desorbing agents, and the use of pulsed electrical fields....

  16. Differential patterns of histone acetylation in inflammatory bowel diseases

    Directory of Open Access Journals (Sweden)

    Adcock Ian M

    2011-01-01

    Full Text Available Abstract Post-translational modifications of histones, particularly acetylation, are associated with the regulation of inflammatory gene expression. We used two animal models of inflammation of the bowel and biopsy samples from patients with Crohn's disease (CD to study the expression of acetylated histones (H 3 and 4 in inflamed mucosa. Acetylation of histone H4 was significantly elevated in the inflamed mucosa in the trinitrobenzene sulfonic acid model of colitis particularly on lysine residues (K 8 and 12 in contrast to non-inflamed tissue. In addition, acetylated H4 was localised to inflamed tissue and to Peyer's patches (PP in dextran sulfate sodium (DSS-treated rat models. Within the PP, H3 acetylation was detected in the mantle zone whereas H4 acetylation was seen in both the periphery and the germinal centre. Finally, acetylation of H4 was significantly upregulated in inflamed biopsies and PP from patients with CD. Enhanced acetylation of H4K5 and K16 was seen in the PP. These results demonstrate that histone acetylation is associated with inflammation and may provide a novel therapeutic target for mucosal inflammation.

  17. New histone supply regulates replication fork speed and PCNA unloading

    DEFF Research Database (Denmark)

    Mejlvang, Jakob; Feng, Yunpeng; Alabert, Constance

    2014-01-01

    Correct duplication of DNA sequence and its organization into chromatin is central to genome function and stability. However, it remains unclear how cells coordinate DNA synthesis with provision of new histones for chromatin assembly to ensure chromosomal stability. In this paper, we show that re...

  18. Hypothalamic leptin action is mediated by histone deacetylase 5

    DEFF Research Database (Denmark)

    Kabra, Dhiraj G; Pfuhlmann, Katrin; García-Cáceres, Cristina

    2016-01-01

    Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and...

  19. Cell shape regulates global histone acetylation in human mammaryepithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Le Beyec, Johanne; Xu, Ren; Lee, Sun-Young; Nelson, Celeste M.; Rizki, Aylin; Alcaraz, Jordi; Bissell, Mina J.

    2007-02-28

    Extracellular matrix (ECM) regulates cell morphology and gene expression in vivo; these relationships are maintained in three-dimensional (3D) cultures of mammary epithelial cells. In the presence of laminin-rich ECM (lrECM), mammary epithelial cells round up and undergo global histone deacetylation, a process critical for their functional differentiation. However, it remains unclear whether lrECM-dependent cell rounding and global histone deacetylation are indeed part of a common physical-biochemical pathway. Using 3D cultures as well as nonadhesive and micropatterned substrata, here we showed that the cell 'rounding' caused by lrECM was sufficient to induce deacetylation of histones H3 and H4 in the absence of biochemical cues. Microarray and confocal analysis demonstrated that this deacetylation in 3D culture is associated with a global increase in chromatin condensation and a reduction in gene expression. Whereas cells cultured on plastic substrata formed prominent stress fibers, cells grown in 3D lrECM or on micropatterns lacked these structures. Disruption of the actin cytoskeleton with cytochalasin D phenocopied the lrECM-induced cell rounding and histone deacetylation. These results reveal a novel link between ECM-controlled cell shape and chromatin structure, and suggest that this link is mediated by changes in the actin cytoskeleton.

  20. Post-Translational Modifications of Histones in Human Sperm

    Czech Academy of Sciences Publication Activity Database

    Krejčí, Jana; Stixová, Lenka; Legartová, Soňa; Kozubek, Stanislav; Lochmanová, G.; Zdráhal, Z.; Sehnalová, Petra; Dabravolski, S.; Hejatko, J.; Bártová, Eva

    2015-01-01

    Roč. 116, č. 10 (2015), s. 2195-2209 ISSN 0730-2312 R&D Projects: GA MŠk(CZ) ED1.1.00/02.0068 Institutional support: RVO:68081707 Keywords : HUMAN SPERM * HISTONES * PROTAMINE P2 Subject RIV: BO - Biophysics Impact factor: 3.446, year: 2015

  1. Effect of histone deacetylase inhibitor, trichostatin A, on cartilage ...

    African Journals Online (AJOL)

    Purpose: To evaluate the effect of histone deacetylase (HDAC) inhibitor, trichostatin A (TCA), on cartilage regeneration in a rabbit perichondrial graft model. Methods: Perichondrial grafts (20 × 20 mm2) were derived from the ears of New Zealand rabbits and transplanted onto the paravertebral muscle of the face of each ...

  2. Sepsis and ARDS: The Dark Side of Histones

    Science.gov (United States)

    Xu, Zhiheng; Huang, Yongbo; Mao, Pu; Zhang, Jianrong; Li, Yimin

    2015-01-01

    Despite advances in management over the last several decades, sepsis and acute respiratory distress syndrome (ARDS) still remain major clinical challenges and the leading causes of death for patients in intensive care units (ICUs) due to insufficient understanding of the pathophysiological mechanisms of these diseases. However, recent studies have shown that histones, also known as chromatin-basic structure proteins, could be released into the extracellular space during severe stress and physical challenges to the body (e.g., sepsis and ARDS). Due to their cytotoxic and proinflammatory effects, extracellular histones can lead to excessive and overwhelming cell damage and death, thus contributing to the pathogenesis of both sepsis and ARDS. In addition, antihistone-based treatments (e.g., neutralizing antibodies, activated protein C, and heparin) have shown protective effects and have significantly improved the outcomes of mice suffering from sepsis and ARDS. Here, we review researches related to the pathological role of histone in context of sepsis and ARDS and evaluate the potential value of histones as biomarkers and therapeutic targets of these diseases. PMID:26609197

  3. TIDAL TAILS OF MINOR MERGERS. II. COMPARING STAR FORMATION IN THE TIDAL TAILS OF NGC 2782

    Energy Technology Data Exchange (ETDEWEB)

    Knierman, Karen A.; Scowen, Paul; Veach, Todd; Groppi, Christopher [School of Earth and Space Exploration, Arizona State University, 550 E. Tyler Mall, Room PSF-686 (P.O. Box 871404), Tempe, AZ 85287-1404 (United States); Mullan, Brendan; Charlton, Jane [Department of Astronomy and Astrophysics, Penn State University, 525 Davey Lab, University Park, PA (United States); Konstantopoulos, Iraklis [Australian Astronomical Observatory, P.O. Box 915, North Ryde NSW 1670 (Australia); Knezek, Patricia M., E-mail: karen.knierman@asu.edu, E-mail: paul.scowen@asu.edu, E-mail: tveach@asu.edu, E-mail: cgroppi@asu.edu, E-mail: mullan@astro.psu.edu, E-mail: iraklis@aao.gov.au, E-mail: pknezek@noao.edu [WIYN Consortium, Inc., 950 N. Cherry Avenue, Tucson, AZ 85719 (United States)

    2013-09-10

    The peculiar spiral NGC 2782 is the result of a minor merger with a mass ratio {approx}4: 1 occurring {approx}200 Myr ago. This merger produced a molecular and H I-rich, optically bright eastern tail and an H I-rich, optically faint western tail. Non-detection of CO in the western tail by Braine et al. suggested that star formation had not yet begun. However, deep UBVR and H{alpha} narrowband images show evidence of recent star formation in the western tail, though it lacks massive star clusters and cluster complexes. Using Herschel PACS spectroscopy, we discover 158 {mu}m [C II] emission at the location of the three most luminous H{alpha} sources in the eastern tail, but not at the location of the even brighter H{alpha} source in the western tail. The western tail is found to have a normal star formation efficiency (SFE), but the eastern tail has a low SFE. The lack of CO and [C II] emission suggests that the western tail H II region may have a low carbon abundance and be undergoing its first star formation. The western tail is more efficient at forming stars, but lacks massive clusters. We propose that the low SFE in the eastern tail may be due to its formation as a splash region where gas heating is important even though it has sufficient molecular and neutral gas to make massive star clusters. The western tail, which has lower gas surface density and does not form high-mass star clusters, is a tidally formed region where gravitational compression likely enhances star formation.

  4. TIDAL TAILS OF MINOR MERGERS. II. COMPARING STAR FORMATION IN THE TIDAL TAILS OF NGC 2782

    International Nuclear Information System (INIS)

    Knierman, Karen A.; Scowen, Paul; Veach, Todd; Groppi, Christopher; Mullan, Brendan; Charlton, Jane; Konstantopoulos, Iraklis; Knezek, Patricia M.

    2013-01-01

    The peculiar spiral NGC 2782 is the result of a minor merger with a mass ratio ∼4: 1 occurring ∼200 Myr ago. This merger produced a molecular and H I-rich, optically bright eastern tail and an H I-rich, optically faint western tail. Non-detection of CO in the western tail by Braine et al. suggested that star formation had not yet begun. However, deep UBVR and Hα narrowband images show evidence of recent star formation in the western tail, though it lacks massive star clusters and cluster complexes. Using Herschel PACS spectroscopy, we discover 158 μm [C II] emission at the location of the three most luminous Hα sources in the eastern tail, but not at the location of the even brighter Hα source in the western tail. The western tail is found to have a normal star formation efficiency (SFE), but the eastern tail has a low SFE. The lack of CO and [C II] emission suggests that the western tail H II region may have a low carbon abundance and be undergoing its first star formation. The western tail is more efficient at forming stars, but lacks massive clusters. We propose that the low SFE in the eastern tail may be due to its formation as a splash region where gas heating is important even though it has sufficient molecular and neutral gas to make massive star clusters. The western tail, which has lower gas surface density and does not form high-mass star clusters, is a tidally formed region where gravitational compression likely enhances star formation

  5. Canadian experience with uranium tailings disposal

    International Nuclear Information System (INIS)

    Culver, K.B.

    1982-06-01

    During the first years of uranium production in Canada uranium tailings were discharged directly into valleys or lakes near the mill. Treatment with barium chloride to precipitate radium began in 1965 at the Nordic Mine at Elliot Lake, Ontario. In the mid-60s and early 70s water quality studies indicated that discharges from uranium tailings areas were causing degradation to the upper part of the Serpent River water system. Studies into acid generation, revegetation, and leaching of radium were initiated by the mining companies and resulted in the construction of treatment plants at a number of sites. Abandoned tailings sites were revegetated. At hearings into the expansion of the Elliot Lake operations the issue of tailings management was a major item for discussion. As a result federal and provincial agencies developed guidelines for the siting and development of urnaium tailings areas prior to issuing operating licences. Western Canadian uranium producers do not have the acid generation problem of the Elliot Lake operations. The Rabbit Lake mill uses settling ponds followed by filtration. High-grade tailings from Cluff Lake are sealed in concrete and buried. Uranium producers feel that the interim criteria developed by the Atomic Energy Control Board, if adopted, would have a harmful effect on the viability of the Canadian uranium industry

  6. Four tails problems for dynamical collapse theories

    Science.gov (United States)

    McQueen, Kelvin J.

    2015-02-01

    The primary quantum mechanical equation of motion entails that measurements typically do not have determinate outcomes, but result in superpositions of all possible outcomes. Dynamical collapse theories (e.g. GRW) supplement this equation with a stochastic Gaussian collapse function, intended to collapse the superposition of outcomes into one outcome. But the Gaussian collapses are imperfect in a way that leaves the superpositions intact. This is the tails problem. There are several ways of making this problem more precise. But many authors dismiss the problem without considering the more severe formulations. Here I distinguish four distinct tails problems. The first (bare tails problem) and second (structured tails problem) exist in the literature. I argue that while the first is a pseudo-problem, the second has not been adequately addressed. The third (multiverse tails problem) reformulates the second to account for recently discovered dynamical consequences of collapse. Finally the fourth (tails problem dilemma) shows that solving the third by replacing the Gaussian with a non-Gaussian collapse function introduces new conflict with relativity theory.

  7. Consistency based correlations for tailings consolidation

    Energy Technology Data Exchange (ETDEWEB)

    Azam, S.; Paul, A.C. [Regina Univ., Regina, SK (Canada). Environmental Systems Engineering

    2010-07-01

    The extraction of oil, uranium, metals and mineral resources from the earth generates significant amounts of tailings slurry. The tailings are contained in a disposal area with perimeter dykes constructed from the coarser fraction of the slurry. There are many unique challenges pertaining to the management of the containment facilities for several decades beyond mine closure that are a result of the slow settling rates of the fines and the high standing toxic waters. Many tailings dam failures in different parts of the world have been reported to result in significant contaminant releases causing public concern over the conventional practice of tailings disposal. Therefore, in order to reduce and minimize the environmental footprint, the fluid tailings need to undergo efficient consolidation. This paper presented an investigation into the consolidation behaviour of tailings in conjunction with soil consistency that captured physicochemical interactions. The paper discussed the large strain consolidation behaviour (volume compressibility and hydraulic conductivity) of six fine-grained soil slurries based on published data. The paper provided background information on the study and presented the research methodology. The geotechnical index properties of the selected materials were also presented. The large strain consolidation, volume compressibility correlations, and hydraulic conductivity correlations were provided. It was concluded that the normalized void ratio best described volume compressibility whereas liquidity index best explained the hydraulic conductivity. 17 refs., 3 tabs., 4 figs.

  8. Attitudes of Dutch Pig Farmers Towards Tail Biting and Tail Docking

    OpenAIRE

    Bracke, M.B.M.; Lauwere, de, C.C.; Wind, S.M.M.; Zonderland, J.J.

    2013-01-01

    The Dutch policy objective of a fully sustainable livestock sector without mutilations by 2023 is not compatible with the routine practice of tail docking to minimize the risk of tail biting. To examine farmer attitudes towards docking, a telephone survey was conducted among 487 conventional and 33 organic Dutch pig farmers. “Biting” (of tails, ears, or limbs) was identified by the farmers as a main welfare problem in pig farming. About half of the farmers reported to have no tail biting prob...

  9. Analysis of Myc-induced histone modifications on target chromatin.

    Directory of Open Access Journals (Sweden)

    Francesca Martinato

    Full Text Available The c-myc proto-oncogene is induced by mitogens and is a central regulator of cell growth and differentiation. The c-myc product, Myc, is a transcription factor that binds a multitude of genomic sites, estimated to be over 10-15% of all promoter regions. Target promoters generally pre-exist in an active or poised chromatin state that is further modified by Myc, contributing to fine transcriptional regulation (activation or repression of the afferent gene. Among other mechanisms, Myc recruits histone acetyl-transferases to target chromatin and locally promotes hyper-acetylation of multiple lysines on histones H3 and H4, although the identity and combination of the modified lysines is unknown. Whether Myc dynamically regulates other histone modifications (or marks at its binding sites also remains to be addressed. Here, we used quantitative chromatin immunoprecipitation (qChIP to profile a total of 24 lysine-acetylation and -methylation marks modulated by Myc at target promoters in a human B-cell line with a regulatable c-myc transgene. Myc binding promoted acetylation of multiple lysines, primarily of H3K9, H3K14, H3K18, H4K5 and H4K12, but significantly also of H4K8, H4K91 and H2AK5. Dimethylation of H3K79 was also selectively induced at target promoters. A majority of target promoters showed co-induction of multiple marks - in various combinations - correlating with recruitment of the two HATs tested (Tip60 and HBO1, incorporation of the histone variant H2A.Z and transcriptional activation. Based on this and previous findings, we surmise that Myc recruits the Tip60/p400 complex to achieve a coordinated histone acetylation/exchange reaction at activated promoters. Our data are also consistent with the additive and redundant role of multiple acetylation events in transcriptional activation.

  10. The relationship between DNA synthesis and incorporation of (14C) lysine into different histone fractions in Ehrlich ascites tumour cells

    International Nuclear Information System (INIS)

    Malec, J.; Kornacka, L.; Wojnarowska, M.; Moscicka, M.

    1974-01-01

    The effect of inhibition of DNA synthesis by hydroxyurea on ( 14 C) lysine incorporation into the main four histone fractions in Ehrlich ascites tumor cells, was examined in vitro. The radioactivity of lysine-rich histones, especially of histone f1, was preferentially decreased. The smallest decrease was observed for histone f3. The incorporation into other cellular proteins was but slightly affected. (author)

  11. Substrate- and Cofactor-independent Inhibition of Histone Demethylase KDM4C

    DEFF Research Database (Denmark)

    Leurs, Ulrike; Lohse, Brian; Rand, Kasper Dyrberg

    2014-01-01

    Inhibition of histone demethylases has within recent years advanced into a new strategy for treating cancer and other diseases. Targeting specific histone demethylases can be challenging as the active sites of KDM1A-B and KDM-4A-D histone demethylases, respectively, are highly conserved. Most...... inhibitors developed up-to-date target either the cofactor- or substrate-binding sites of these enzymes, resulting in a lack of selectivity and off-target effects. This study describes the discovery of the first peptide-based inhibitors of KDM4 histone demethylases that do not share the histone peptide...... sequence, or inhibit through substrate competition. Through screening of DNA-encoded peptide libraries against KDM1 and -4 histone demethylases by phage display, two cyclic peptides targeting the histone demethylase KDM4C were identified and developed as inhibitors by amino acid replacement, truncation...

  12. Dewatering Behaviour of Fine Oil Sands Tailings : An Experimental Study

    NARCIS (Netherlands)

    Yao, Y.

    2016-01-01

    Oil sands tailings are a warm aqueous suspension of sand, silt, clay, residual bitumen and naphtha. The tailings are hydraulically transported and stored in tailing ponds where they segregate, with the sand settling from suspension forming beaches and the remaining tailings flowing to the middle of

  13. Activity, tail loss, growth and survivorship of male Psammodromus algirus

    OpenAIRE

    Salvador Milla, Alfredo; Veiga, José Pablo

    2005-01-01

    Males with autotomized tail were sighted more often and moved longer distances than males with complete tail. There were no significant differences in survival between the two groups. The increase of snout-vent lenght at emergence the following year was significantly lower for males with autotomized tail than for males with complete tail.

  14. Limits theorems for tail processes with applications tointermediate quantile estimation

    NARCIS (Netherlands)

    Einmahl, J.H.J.

    1992-01-01

    A description of the weak and strong limiting behaviour of weighted uniform tail empirical and tail quantile processes is given. The results for the tail quantile process are applied to obtain weak and strong functional limit theorems for a weighted non-uniform tail-quantile-type process based on a

  15. Influence of hydrology on heavy metal speciation and mobility in a Pb-Zn mine tailing

    International Nuclear Information System (INIS)

    Kovacs, Elza; Dubbin, William E.; Tamas, Janos

    2006-01-01

    Among the inorganic toxicants of greatest concern in mine tailings, Pb, Zn, Cu, Cd and As figure prominently due to their abundance and potential toxicity. Here we report on their biolability and solid-phase speciation in two sediment cores subject to variable hydrological regimes at an abandoned pyritic mine tailing. The oxic conditions of well-drained sediments induced pyrite oxidation and the subsequent liberation of H + , SO 4 2- and considerable quantities of Fe(III), which precipitated as goethite. Solubility of Pb, Zn, Cu and Cd was closely coupled to pH and goethite presence. Metal lability was particularly low in zones of neutralization, formed by the accumulation of calcite, first carried then deposited by percolating waters in both saturated and unsaturated cores. We conclude that differential hydrology induces variable heavy metal speciation and biolability in Pb-Zn mine tailings, and suggest that site-specific risk assessments must account for past and present hydrological regimes. - Variable hydrology influences heavy metal speciation and mobility, and the formation of neutralization zones, in a Pb-Zn mine tailing

  16. Engineering assessment of inactive uranium mill tailings: Lakeview site, Lakeview, Oregon

    International Nuclear Information System (INIS)

    1981-10-01

    This assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The three alternative actions presented in this engineering assessment include millsite decontamination with the addition of 3 m of stabilization cover material (Option I) and removal of the tailings to remote disposal sites and decontamination of the tailings site (Options II and III). Cost estimates range from about $6,000,000 for stabilization in-place, to about $7,500,000 for disposal at a distance of about 10 miles. Three alternatives for reprocessing the Lakeview tailings were examined: heap leaching, treatment at an existing mill, and reprocessing at a new conventional mill. The cost of the uranium recovered would be over $450/lb of U 3 O 8 and hence reprocessing is not economical

  17. Engineering assessment of inactive uranium mill tailings: Lakeview site, Lakeview, Oregon

    Energy Technology Data Exchange (ETDEWEB)

    None

    1981-10-01

    This assessment has included the preparation of topographic maps, the performance of core drillings and radiometric measurements sufficient to determine areas and volumes of tailings and radiation exposures of individuals and nearby populations, the investigations of site hydrology and meteorology, and the evaluation and costing of alternative corrective actions. Radon gas constitutes the most significant environmental impact, although windblown tailings and external gamma radiation also are factors. The three alternative actions presented in this engineering assessment include millsite decontamination with the addition of 3 m of stabilization cover material (Option I) and removal of the tailings to remote disposal sites and decontamination of the tailings site (Options II and III). Cost estimates range from about $6,000,000 for stabilization in-place, to about $7,500,000 for disposal at a distance of about 10 miles. Three alternatives for reprocessing the Lakeview tailings were examined: heap leaching, treatment at an existing mill, and reprocessing at a new conventional mill. The cost of the uranium recovered would be over $450/lb of U/sub 3/O/sub 8/ and hence reprocessing is not economical.

  18. Observations of thermal and suprathermal tail ions from WIND

    Science.gov (United States)

    Randol, B. M.; Christian, E. R.; Wilson, L. B., III

    2016-12-01

    The velocity distribution function (VDF) of solar wind protons (as well as other ion populations) is comprised of a thermal Maxwellian core and an accelerated suprathermal tail, beginning at around 1 keV in the frame co-moving with solar wind bulk velocity. The form of the suprathermal tail is a power law in phase space density, f, vs. speed, v, such that f / vγ, where γ is the power law index. This commonly observed index is of particular interest because no traditional theory predicts its existence. We need more data in order to test these theories. The general shape is of interest because it is kappa-like. We show combined observations from three different instruments on the WIND spacecraft: 3DP/PLSP, STICS, and 3DP/SST/Open. These data stretch from 102 to 107 eV in energy, encompassing both the thermal and suprathermal proton populations. We show further evidence for this kappa-like distribution and report on our progress on fitting of empirical functions to these data.

  19. Diagnostic analysis of electrodialysis in mine tailing materials

    DEFF Research Database (Denmark)

    Hansen, Henrik K.; Ribeiro, Alexandra B.; Mateus, Eduardo

    2007-01-01

    Removal of heavy metals from mine tailings and soil contaminated by copper mining activities was studied under batch electrodialytic conditions. Two types of mine tailings were treated: (i) freshly produced tailings coming directly from the flotation process, and (ii) tailings deposited...... in a tailings pond, for approximately 20 years. The main contaminant was copper-found in concentration around 800-1800 ppm. The fractionation of copper and other characteristics of the tailings differ for the two tailings, indicating natural oxidation reactions in the old deposited ones. Electrodialytical...

  20. Histones induce phosphatidylserine exposure and a procoagulant phenotype in human red blood cells.

    Science.gov (United States)

    Semeraro, F; Ammollo, C T; Esmon, N L; Esmon, C T

    2014-10-01

    Extracellular histones exert part of their prothrombotic activity through the stimulation of blood cells. Besides platelets, histones can bind to red blood cells (RBCs), which are important contributors to thrombogenesis, but little is known about the functional consequences of this interaction. To evaluate the effect of histones on the procoagulant potential of human RBCs with particular regard to the expression of surface phosphatidylserine (PS). PS exposure on human RBCs treated with a natural mixture of histones or recombinant individual histones was evaluated with fluorescein isothiocyanate-annexin-V binding and measured with flow cytometry. Calcium influx in RBCs loaded with the calcium-sensitive fluorophore Fluo-4 AM was assessed with flow cytometry. The procoagulant potential of histone-treated RBCs was evaluated with a purified prothrombinase assay and a one-stage plasma recalcification clotting test. Natural histones induced PS exposure on RBCs in a dose-dependent manner, and neutralization or cleavage of histones by heparin or activated protein C, respectively, abolished PS externalization. H4 was mainly responsible for the stimulating activity of histones, whereas the other subtypes were almost ineffective. Similarly, natural histones and H4 induced influx of calcium into RBCs, whereas the other individual histones did not. Histone-induced exposure of PS on RBCs translated into increased prothrombinase complex-mediated prothrombin activation and accelerated fibrin formation in plasma. Histones induce RBCs to express a procoagulant phenotype through the externalization of PS. This finding provides new insights into the prothrombotic activity of extracellular histones. © 2014 International Society on Thrombosis and Haemostasis.

  1. Extracellular histone H1 is neurotoxic and drives a pro-inflammatory response in microglia [v1; ref status: indexed, http://f1000r.es/18z

    Directory of Open Access Journals (Sweden)

    Jonathan D Gilthorpe

    2013-07-01

    Full Text Available In neurodegenerative conditions and following brain trauma it is not understood why neurons die while astrocytes and microglia survive and adopt pro-inflammatory phenotypes. We show here that the damaged adult brain releases diffusible factors that can kill cortical neurons and we have identified histone H1 as a major extracellular candidate that causes neurotoxicity and activation of the innate immune system. Extracellular core histones H2A, H2B H3 and H4 were not neurotoxic. Innate immunity in the central nervous system is mediated through microglial cells and we show here for the first time that histone H1 promotes their survival, up-regulates MHC class II antigen expression and is a powerful microglial chemoattractant. We propose that when the central nervous system is degenerating, histone H1 drives a positive feedback loop that drives further degeneration and activation of immune defences which can themselves be damaging. We suggest that histone H1 acts as an antimicrobial peptide and kills neurons through mitochondrial damage and apoptosis.

  2. Electro-remediation of copper mine tailings. Comparing copper removal efficiencies for two tailings of different age

    DEFF Research Database (Denmark)

    Hansen, Henrik K.; Lamas, Victor; Gutierrez, Claudia

    2013-01-01

    This work compares and evaluates the copper removal efficiency when applying electric fields to two mine tailings originating from the same mine but of different age. Eight experiments were carried out - four on tailings deposited more than 20 years ago (old tailings) and four on tailings deposit...

  3. Food resources, distribution and seasonal variations in ranging in lion-tailed macaques, Macaca silenus in the Western Ghats, India.

    Science.gov (United States)

    Erinjery, Joseph J; Kavana, T S; Singh, Mewa

    2015-01-01

    The distribution and availability of food was examined to see how it influenced ranging patterns and sleeping site selection in a group of lion-tailed macaques. The home range and core area were 130.48 ha (95% kernel) and 26.68 ha (50% kernel) respectively. The lion-tailed macaques had a longer day range, had a greater number of sleeping sites and used more core areas in the summer as compared to the monsoon and the post-monsoon seasons. The ranging patterns and sleeping site use were influenced by the major food resources used in a particular season. The ranging was mainly influenced by Artocarpus heterophyllus in monsoon, Cullenia exarillata and Toona ciliata in post- monsoon, and Artocarpus heterophyllus and Ficus amplissima in summer. The distribution of these four plant species is, therefore, critical to ranging, and thus to conservation of the lion-tailed macaque.

  4. A new procedure for deep sea mining tailings disposal

    OpenAIRE

    Ma, W.; Schott, D.L.; Lodewijks, G.

    2017-01-01

    Deep sea mining tailings disposal is a new environmental challenge related to water pollution, mineral crust waste handling, and ocean biology. The objective of this paper is to propose a new tailings disposal procedure for the deep sea mining industry. Through comparisons of the tailings disposal methods which exist in on-land mining and the coastal mining fields, a new tailings disposal procedure, i.e., the submarine–backfill–dam–reuse (SBDR) tailings disposal procedure, is proposed. It com...

  5. No need to be HAMLET or BAMLET to interact with histones: binding of monomeric alpha-lactalbumin to histones and basic poly-amino acids.

    Science.gov (United States)

    Permyakov, Serge E; Pershikova, Irina V; Khokhlova, Tatyana I; Uversky, Vladimir N; Permyakov, Eugene A

    2004-05-18

    The ability of a specific complex of human alpha-lactalbumin with oleic acid (HAMLET) to induce cell death with selectivity for tumor and undifferentiated cells was shown recently to be mediated by interaction of HAMLET with histone proteins irreversibly disrupting chromatin structure [Duringer, C., et al. (2003) J. Biol. Chem. 278, 42131-42135]. Here we show that monomeric alpha-lactalbumin (alpha-LA) in the absence of fatty acids is also able to bind efficiently to the primary target of HAMLET, histone HIII, regardless of Ca(2+) content. Thus, the modification of alpha-LA by oleic acid is not required for binding to histones. We suggest that interaction of negatively charged alpha-LA with the basic histone stabilizes apo-alpha-LA and destabilizes the Ca(2+)-bound protein due to compensation for excess negative charge of alpha-LA's Ca(2+)-binding loop by positively charged residues of the histone. Spectrofluorimetric curves of titration of alpha-LA by histone H3 were well approximated by a scheme of cooperative binding of four alpha-LA molecules per molecule of histone, with an equilibrium dissociation constant of 1.0 microM. Such a stoichiometry of binding implies that the binding process is not site-specific with respect to histone and likely is driven by just electrostatic interactions. Co-incubation of positively charged poly-amino acids (poly-Lys and poly-Arg) with alpha-LA resulted in effects which were similar to those caused by histone HIII, confirming the electrostatic nature of the alpha-LA-histone interaction. In all cases that were studied, the binding was accompanied by aggregation. The data indicate that alpha-lactalbumin can be used as a basis for the design of antitumor agents, acting through disorganization of chromatin structure due to interaction between alpha-LA and histone proteins.

  6. Regulation of human histone gene expression: transcriptional and posttranscriptional control in the coupling of histone messenger RNA stability with DNA replication

    International Nuclear Information System (INIS)

    Baumbach, L.L.; Stein, G.S.; Stein, J.L.

    1987-01-01

    The extent to which transcriptional and posttranscriptional regulation contributes to the coupling of histone gene expression and DNA replication was examined during the cell cycle in synchronized HeLa S3 cells. Rates of transcription were determined in vitro in isolated nuclei. A 3-5-fold increase in cell cycle dependent histone gene transcription was observed in early S phase, prior to the peak of DNA synthesis. This result is consistent with a previous determination of histone mRNA synthesis in intact cells. The transcription of these genes did not change appreciably after inhibition of DNA replication by hydroxyurea treatment, although Northern blot analysis indicated that cellular levels of histone mRNA decreased rapidly in the presence of the drug. Total cellular levels of histone mRNA closely parallel the rate of DNA synthesis as a function of cell cycle progression, reaching a maximal 20-fold increase as compared with non S phase levels. This DNA synthesis dependent accumulation of histone mRNA occurs predominantly in the cytoplasm and appears to be mediated primarily by control of histone mRNA stability. Changes in nuclear histone mRNA levels were less pronounced. These combined observations suggest that both transcriptional regulation and posttranscriptional regulation contribute toward control of the cell cycle dependent accumulation of histone mRNA during S phase, while the stability of histone mRNA throughout S phase and the selective turnover of histone mRNAs, either at the natural termination of S phase or following inhibition of DNA synthesis, are posttranscriptionally regulated

  7. Effects of tail docking and docking length on neuroanatomical changes in healed tail tips of pigs

    DEFF Research Database (Denmark)

    Herskin, M S; Thodberg, K; Jensen, Henrik Elvang

    2015-01-01

    % (n=19); or leaving 25% (n=11) of the tail length on the pigs. The piglets were docked between day 2 and 4 after birth using a gas-heated apparatus, and were kept under conventional conditions until slaughter at 22 weeks of age, where tails were removed and examined macroscopically and histologically...

  8. Tail Asymptotics for the Sum of two Heavy-tailed Dependent Risks

    DEFF Research Database (Denmark)

    Albrecher, H.; Asmussen, Søren

    Let X1,X2 denote positive exchangable heavy-tailed random variables with continuous marginal distribution function F. The asymptotic behavior of the tail of X1 + X2 is studied in a general copula framework and some bounds and extremal properties are provided. For more specific assumptions on F...

  9. Tailings neutralization and other alternatives for immobilizing toxic materials in tailings. Final report

    International Nuclear Information System (INIS)

    Opitz, B.E.; Sherwood, D.R.; Dodson, M.E.; Serne, R.J.

    1985-09-01

    This document, ''Tailing Neutralization and Other Alternatives for Immobilizing Toxic Materials in Tailings,'' is the final report in a series of six. It summarizes research completed since the beginning of the project. Three subtasks are included: Subtask A - Neutralization Methods Selection; Subtask B - Laboratory Analysis; and Subtask C - Field Testing. Subtask A reviews treatment processes from other industries to evaluate whether current waste technology from other fields is applicable to the uranium industry. This task also identifies several reagents that were tested for their effectiveness in treating acidic tailings and tailings solution in order to immobilize the contaminants associated with the acid waste. Subtask B describes the laboratory batch and column treatment studies performed on solid waste tailings and tailings solutions over the course of the project. The evaluation of several reagents identified in Subtask A was based on three criteria: (1) treated effluent water quality; (2) neutralized sludge handling and hydraulic properties; and (3) reagent costs and acid neutralizing efficiency. Subtask C presents a field demonstration plan that will evaluate the effectiveness, costs, and benefits of neutralizing acidic uranium mill tailings solution to reduce the potential leaching of toxic trace metals, radionuclides, and macro ions from a tailings impoundment. Details of the related research can be found in the documents listed in the ''Previous Documents in Series.'' 43 refs., 9 figs., 46 tabs

  10. Attitudes of Dutch Pig Farmers Towards Tail Biting and Tail Docking

    NARCIS (Netherlands)

    Bracke, M.B.M.; Lauwere, de C.C.; Wind, S.M.M.; Zonderland, J.J.

    2013-01-01

    The Dutch policy objective of a fully sustainable livestock sector without mutilations by 2023 is not compatible with the routine practice of tail docking to minimize the risk of tail biting. To examine farmer attitudes towards docking, a telephone survey was conducted among 487 conventional and 33

  11. The histone deacetylase inhibitor Trichostatin A modulates CD4+ T cell responses

    Directory of Open Access Journals (Sweden)

    Moreira José

    2003-11-01

    Full Text Available Abstract Background Histone deacetylase inhibitors (HDACIs induce hyperacetylation of core histones modulating chromatin structure and affecting gene expression. These compounds are also able to induce growth arrest, cell differentiation, and apoptotic cell death of tumor cells in vitro as well as in vivo. Even though several genes modulated by HDAC inhibition have been identified, those genes clearly responsible for the biological effects of these drugs have remained elusive. We investigated the pharmacological effect of the HDACI and potential anti-cancer agent Trichostatin A (TSA on primary T cells. Methods To ascertain the effect of TSA on resting and activated T cells we used a model system where an enriched cell population consisting of primary T-cells was stimulated in vitro with immobilized anti-CD3/anti-CD28 antibodies whilst exposed to pharmacological concentrations of Trichostatin A. Results We found that this drug causes a rapid decline in cytokine expression, accumulation of cells in the G1 phase of the cell cycle, and induces apoptotic cell death. The mitochondrial respiratory chain (MRC plays a critical role in the apoptotic response to TSA, as dissipation of mitochondrial membrane potential and reactive oxygen species (ROS scavengers block TSA-induced T-cell death. Treatment of T cells with TSA results in the altered expression of a subset of genes involved in T cell responses, as assessed by microarray gene expression profiling. We also observed up- as well as down-regulation of various costimulatory/adhesion molecules, such as CD28 and CD154, important for T-cell function. Conclusions Taken together, our findings indicate that HDAC inhibitors have an immunomodulatory potential that may contribute to the potency and specificity of these antineoplastic compounds and might be useful in the treatment of autoimmune disorders.

  12. Role of histone deacetylases(HDACs) in progression and reversal of liver fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xing; Wu, Xiao-Qin; Xu, Tao; Li, Xiao-Feng; Yang, Yang; Li, Wan-Xia; Huang, Cheng; Meng, Xiao-Ming; Li, Jun, E-mail: lijun@ahmu.edu.cn

    2016-09-01

    Liver fibrosis refers to a reversible wound healing process response to chronic liver injuries. Activation of hepatic stellate cells (HSCs) is closely correlated with the development of liver fibrosis. Histone deacetylases(HDACs) determine the acetylation levels of core histones to modulate expression of genes. To demonstrate the link between HDACs and liver fibrosis, CCl4-induced mouse liver fibrosis model and its spontaneous reversal model were established. Results of the current study demonstrated that deregulation of liver HDACs may involved in the development of liver fibrosis. Among 11 HDACs tested in our study (Class I, II, and IV HDACs), expression of HDAC2 was maximally increased in CCl4-induced fibrotic livers but decreased after spontaneous recovery. Moreover, expression of HDAC2 was elevated in human liver fibrotic tissues. In this regard, the potential role of HDAC2 in liver fibrosis was further evaluated. Our results showed that administration of HSC-T6 cells with transforming growth factor-beta1 (TGF-β1) resulted in an increase of HDAC2 protein expression in dose- and time-dependent manners. Moreover, HDAC2 deficiency inhibited HSC-T6 cell proliferation and activation induced by TGF-β1. More importantly, the present study showed HDAC2 may regulate HSCs activation by suppressing expression of Smad7, which is a negative modulator in HSCs activation and liver fibrosis. Collectively, these observations revealed that HDAC2 may play a pivotal role in HSCs activation and liver fibrosis while deregulation of HDACs may serve as a novel mechanism underlying liver fibrosis. - Highlights: • This is the first report to systematically examine expressions of HDACs during liver fibrosis and fibrosis reversal. • Aberrant expression of HDAC2 contributes to the development of liver fibrosis. • Provided important foundation for further liver fibrosis conversion studies.

  13. Blast densification trials for oilsands tailings

    Energy Technology Data Exchange (ETDEWEB)

    Port, A. [Klohn Crippen Berger Ltd., Vancouver, BC (Canada); Martens, S. [Klohn Crippen Berger Ltd., Calgary, AB (Canada); Eaton, T. [Shell Canada Ltd., Calgary, AB (Canada)

    2010-07-01

    The Shell Canada Muskeg River Mine External Tailings Facility (ETF) is an upstream constructed tailings facility located near Fort McMurray, Alberta. Raises have incrementally stepped out over the beach since construction of the starter dam and deposition within standing water has left some parts of the beach in a loose state. In order to assess the effectiveness of blast densification, a blast densification trial program that was conducted in 2006 at the ETF. The primary purpose of the test program was to determine the effectiveness of blast densification in tailings containing layers and zones of bitumen. The paper described the site characterization and explosive compaction trial program, with particular reference to test layout; drilling methodology; and blasting and timing sequence. The paper also described the instrumentation, including the seismographs; high pressure electric piezometers; low pressure electric piezometers; vibrating wire piezometers; inclinometers; settlement gauges; and surveys. Trial observations and post-trial observations were also presented. It was concluded that controlled blasting techniques could be used to safely induce liquefaction in localized areas within the tailings deposit, with a resulting increase in the tailings density. 5 refs., 1 tab., 14 figs.

  14. Reclamation plans at uranium mill tailings sites

    International Nuclear Information System (INIS)

    Abt, S.R.; Nelson, J.D.

    1990-01-01

    Long-term stability of waste impoundments is of concern because of the long time periods over which various types of waste may remain active. Over the past decade much technology has been developed specifically for reclamation of uranium mill tailings impoundments. Aspects of this technology will be discussed here and is presented as also being directly applicable to reclamation of industrial waste impoundments in general. The paper discusses Title I and Title II sites which represent two different generations in uranium tailings impoundment construction. The comparison between the two represent differences in philosophies as well as in impoundment type. Reclamation of uranium mill tailings impoundments in the U.S. is controlled by Federal legislation, which has set forth the regulatory framework for reclamation plan approval. Title I requirements govern government owned inactive sites and Title II requirements govern active tailings impoundments or those operated by private industries. While the Title I and Title II designation may result in a slightly different regulatory process, reclamation of uranium tailings sites has the same. Differences between Title I and Title II reclamation plans to achieve surface stability relate primarily to the embankment and surface covers. The differences in the cover designs result from site-specific conditions, rather than from differences in engineering approaches or the regulatory process. This paper discusses the site-specific conditions that affect the selection of cover designs, and provides a comparative example to illustrate the effect of this condition

  15. Assessment of the underground disposal of tailings

    Energy Technology Data Exchange (ETDEWEB)

    Hutt, N M [Morwijk Enterprises Ltd., (Canada); Morin, K A [Normar Enterprises, (Canada)

    1995-06-01

    The Atomic Energy Control Board (AECB) of Canada is facing the issue of long-term disposal of uranium tailings. One option that has not been examined in sufficient detail for the AECB is the retrieval of tailings from surface impoundments and subsequent placement of those tailings in underground workings of mines. This report is structured like a catalogue of facts and information, with each paragraph presenting some concept, concern, theory, or case study involving the retrieval or placement of tailings. All relevant information, findings, interpretations, conclusions, and recommendations gathered during the course of this study are included. The Table of Contents illustrates the striking number of relevant topics and acts like a flowchart or checklist to ensure that an underground-disposal submission by a mining company has addressed relevant topics. This report explains in detail the implications of disturbing surface-impounded tailings for the purpose of placing only some of the volume underground. The cumulative environmental, safety, and monetary liabilities of such a partial scheme can be discouraging in some cases. (author). 244 refs., 47 tabs., 17 figs.

  16. Grouting of uranium mill tailings piles

    International Nuclear Information System (INIS)

    Boegly, W.J. Jr.; Tamura, T.; Williams, J.D.

    1984-03-01

    A program of remedial action was initiated for a number of inactive uranium mill tailings piles. These piles result from mining and processing of uranium ores to meet the nation's defense and nuclear power needs and represent a potential hazard to health and the environment. Possible remedial actions include the application of covers to reduce radon emissions and airborne transport of the tailings, liners to prevent groundwater contamination by leachates from the piles, physical or chemical stabilization of the tailings, or moving the piles to remote locations. Conventional installation of liners would require excavation of the piles to emplace the liner; however, utilization of grouting techniques, such as those used in civil engineering to stabilize soils, might be a potential method of producing a liner without excavation. Laboratory studies on groutability of uranium mill tailings were conducted using samples from three abandoned piles and employing a number of particulate and chemical grouts. These studies indicate that it is possible to alter the permeability of the tailings from ambient values of 10 -3 cm/s to values approaching 10 -7 cm/s using silicate grouts and to 10 -8 cm/s using acrylamide and acrylate grouts. An evaluation of grouting techniques, equipment required, and costs associated with grouting were also conducted and are presented. 10 references, 1 table

  17. Remote sensing to monitor uranium tailing sites

    International Nuclear Information System (INIS)

    1992-02-01

    This report concerns the feasibility of using remotely-sensed data for long-term monitoring of uranium tailings. Decommissioning of uranium mine tailings sites may require long-term monitoring to confirm that no unanticipated release of contaminants occurs. Traditional ground-based monitoring of specific criteria of concern would be a significant expense depending on the nature and frequency of the monitoring. The objective of this study was to evaluate whether available remote-sensing data and techniques were applicable to the long-term monitoring of tailings sites. This objective was met by evaluating to what extent the data and techniques could be used to identify and discriminate information useful for monitoring tailings sites. The cost associated with obtaining and interpreting this information was also evaluated. Satellite and aircraft remote-sensing-based activities were evaluated. A monitoring programme based on annual coverage of Landsat Thematic Mapper data is recommended. Immediately prior to and for several years after decommissioning of the tailings sites, airborne multispectral and thermal infrared surveys combined with field verification data are required in order to establish a baseline for the long-term satellite-based monitoring programme. More frequent airborne surveys may be required if rapidly changing phenomena require monitoring. The use of a geographic information system is recommended for the effective storage and manipulation of data accumulated over a number of years

  18. Assessment of the underground disposal of tailings

    International Nuclear Information System (INIS)

    Hutt, N.M.; Morin, K.A.

    1995-06-01

    The Atomic Energy Control Board (AECB) of Canada is facing the issue of long-term disposal of uranium tailings. One option that has not been examined in sufficient detail for the AECB is the retrieval of tailings from surface impoundments and subsequent placement of those tailings in underground workings of mines. This report is structured like a catalogue of facts and information, with each paragraph presenting some concept, concern, theory, or case study involving the retrieval or placement of tailings. All relevant information, findings, interpretations, conclusions, and recommendations gathered during the course of this study are included. The Table of Contents illustrates the striking number of relevant topics and acts like a flowchart or checklist to ensure that an underground-disposal submission by a mining company has addressed relevant topics. This report explains in detail the implications of disturbing surface-impounded tailings for the purpose of placing only some of the volume underground. The cumulative environmental, safety, and monetary liabilities of such a partial scheme can be discouraging in some cases. (author). 244 refs., 47 tabs., 17 figs

  19. Genome-wide analysis of regions similar to promoters of histone genes

    KAUST Repository

    Chowdhary, Rajesh

    2010-05-28

    Background: The purpose of this study is to: i) develop a computational model of promoters of human histone-encoding genes (shortly histone genes), an important class of genes that participate in various critical cellular processes, ii) use the model so developed to identify regions across the human genome that have similar structure as promoters of histone genes; such regions could represent potential genomic regulatory regions, e.g. promoters, of genes that may be coregulated with histone genes, and iii/ identify in this way genes that have high likelihood of being coregulated with the histone genes.Results: We successfully developed a histone promoter model using a comprehensive collection of histone genes. Based on leave-one-out cross-validation test, the model produced good prediction accuracy (94.1% sensitivity, 92.6% specificity, and 92.8% positive predictive value). We used this model to predict across the genome a number of genes that shared similar promoter structures with the histone gene promoters. We thus hypothesize that these predicted genes could be coregulated with histone genes. This hypothesis matches well with the available gene expression, gene ontology, and pathways data. Jointly with promoters of the above-mentioned genes, we found a large number of intergenic regions with similar structure as histone promoters.Conclusions: This study represents one of the most comprehensive computational analyses conducted thus far on a genome-wide scale of promoters of human histone genes. Our analysis suggests a number of other human genes that share a high similarity of promoter structure with the histone genes and thus are highly likely to be coregulated, and consequently coexpressed, with the histone genes. We also found that there are a large number of intergenic regions across the genome with their structures similar to promoters of histone genes. These regions may be promoters of yet unidentified genes, or may represent remote control regions that

  20. Growth-Phase-Specific Modulation of Cell Morphology and Gene Expression by an Archaeal Histone Protein.

    Science.gov (United States)

    Dulmage, Keely A; Todor, Horia; Schmid, Amy K

    2015-09-08

    In all three domains of life, organisms use nonspecific DNA-binding proteins to compact and organize the genome as well as to regulate transcription on a global scale. Histone is the primary eukaryotic nucleoprotein, and its evolutionary roots can be traced to the archaea. However, not all archaea use this protein as the primary DNA-packaging component, raising questions regarding the role of histones in archaeal chromatin function. Here, quantitative phenotyping, transcriptomic, and proteomic assays were performed on deletion and overexpression mutants of the sole histone protein of the hypersaline-adapted haloarchaeal model organism Halobacterium salinarum. This protein is highly conserved among all sequenced haloarchaeal species and maintains hallmark residues required for eukaryotic histone functions. Surprisingly, despite this conservation at the sequence level, unlike in other archaea or eukaryotes, H. salinarum histone is required to regulate cell shape but is not necessary for survival. Genome-wide expression changes in histone deletion strains were global, significant but subtle in terms of fold change, bidirectional, and growth phase dependent. Mass spectrometric proteomic identification of proteins from chromatin enrichments yielded levels of histone and putative nucleoid-associated proteins similar to those of transcription factors, consistent with an open and transcriptionally active genome. Taken together, these data suggest that histone in H. salinarum plays a minor role in DNA compaction but important roles in growth-phase-dependent gene expression and regulation of cell shape. Histone function in haloarchaea more closely resembles a regulator of gene expression than a chromatin-organizing protein like canonical eukaryotic histone. Histones comprise the major protein component of eukaryotic chromatin and are required for both genome packaging and global regulation of expression. The current paradigm maintains that archaea whose genes encode