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Sample records for apurinic sites design

  1. Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites

    PubMed Central

    Minko, Irina G.; Jacobs, Aaron C.; de Leon, Arnie R.; Gruppi, Francesca; Donley, Nathan; Harris, Thomas M.; Rizzo, Carmelo J.; McCullough, Amanda K.; Lloyd, R. Stephen

    2016-01-01

    Apurinic/apyrimidinic (AP) sites are constantly formed in cellular DNA due to instability of the glycosidic bond, particularly at purines and various oxidized, alkylated, or otherwise damaged nucleobases. AP sites are also generated by DNA glycosylases that initiate DNA base excision repair. These lesions represent a significant block to DNA replication and are extremely mutagenic. Some DNA glycosylases possess AP lyase activities that nick the DNA strand at the deoxyribose moiety via a β- or β,δ-elimination reaction. Various amines can incise AP sites via a similar mechanism, but this non-enzymatic cleavage typically requires high reagent concentrations. Herein, we describe a new class of small molecules that function at low micromolar concentrations as both β- and β,δ-elimination catalysts at AP sites. Structure-activity relationships have established several characteristics that appear to be necessary for the formation of an iminium ion intermediate that self-catalyzes the elimination at the deoxyribose ring. PMID:27363485

  2. Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites.

    PubMed

    Minko, Irina G; Jacobs, Aaron C; de Leon, Arnie R; Gruppi, Francesca; Donley, Nathan; Harris, Thomas M; Rizzo, Carmelo J; McCullough, Amanda K; Lloyd, R Stephen

    2016-01-01

    Apurinic/apyrimidinic (AP) sites are constantly formed in cellular DNA due to instability of the glycosidic bond, particularly at purines and various oxidized, alkylated, or otherwise damaged nucleobases. AP sites are also generated by DNA glycosylases that initiate DNA base excision repair. These lesions represent a significant block to DNA replication and are extremely mutagenic. Some DNA glycosylases possess AP lyase activities that nick the DNA strand at the deoxyribose moiety via a β- or β,δ-elimination reaction. Various amines can incise AP sites via a similar mechanism, but this non-enzymatic cleavage typically requires high reagent concentrations. Herein, we describe a new class of small molecules that function at low micromolar concentrations as both β- and β,δ-elimination catalysts at AP sites. Structure-activity relationships have established several characteristics that appear to be necessary for the formation of an iminium ion intermediate that self-catalyzes the elimination at the deoxyribose ring. PMID:27363485

  3. Efficient breakage of DNA apurinic sites by the indoleamine related 9-amino-ellipticine.

    PubMed

    Malvy, C; Prévost, P; Gansser, C; Viel, C; Paoletti, C

    1986-01-01

    The aromatic amine, 9-NH2-ellipticine, is a synthetic DNA intercalating derivative of the antitumor agent ellipticine, which breaks circular DNA containing apurinic sites. This breakage is inhibited when the apurinic (AP) sites are reduced. The concentration of 9-NH2-ellipticine required to get a significant effect (0.1 microM) is the lowest known among chemicals which induce the same breakage reaction. Comparison with the action of structurally related amines shows that the amino-indole structure is specific for AP sites. The ability of ellipticine derivatives to induce breakage in DNA containing apurinic sites is related to the nucleophile substituent in position 9. Two ellipticine derivatives with known antitumor activity, BD 40 and 9-OH-ellipticine, were able to break purified DNA at apurinic sites.

  4. AP Endonuclease 1 as a Key Enzyme in Repair of Apurinic/Apyrimidinic Sites.

    PubMed

    Dyrkheeva, N S; Lebedeva, N A; Lavrik, O I

    2016-09-01

    Human apurinic/apyrimidinic endonuclease 1 (APE1) is one of the key participants in the DNA base excision repair system. APE1 hydrolyzes DNA adjacent to the 5'-end of an apurinic/apyrimidinic (AP) site to produce a nick with a 3'-hydroxyl group and a 5'-deoxyribose phosphate moiety. APE1 exhibits 3'-phosphodiesterase, 3'-5'-exonuclease, and 3'-phosphatase activities. APE1 was also identified as a redox factor (Ref-1). In this review, data on the role of APE1 in the DNA repair process and in other metabolic processes occurring in cells are analyzed as well as the interaction of this enzyme with DNA and other proteins participating in the repair system. PMID:27682167

  5. DNA Apurinic-Apyrimidinic Site Binding And Excision By Endonuclease IV

    SciTech Connect

    Garcin, E.D.; Hosfield, D.J.; Desai, S.A.; Haas, B.J.; Bjoras, M.; Cunningham, R.P.; Tainer, J.A.

    2009-05-18

    Escherichia coli endonuclease IV is an archetype for an abasic or apurinic-apyrimidinic endonuclease superfamily crucial for DNA base excision repair. Here biochemical, mutational and crystallographic characterizations reveal a three-metal ion mechanism for damage binding and incision. The 1.10-{angstrom} resolution DNA-free and the 2.45-{angstrom} resolution DNA-substrate complex structures capture substrate stabilization by Arg37 and reveal a distorted Zn{sub 3}-ligand arrangement that reverts, after catalysis, to an ideal geometry suitable to hold rather than release cleaved DNA product. The 1.45-{angstrom} resolution DNA-product complex structure shows how Tyr72 caps the active site, tunes its dielectric environment and promotes catalysis by Glu261-activated hydroxide, bound to two Zn{sup 2+} ions throughout catalysis. These structural, mutagenesis and biochemical results suggest general requirements for abasic site removal in contrast to features specific to the distinct endonuclease IV alpha-beta triose phosphate isomerase (TIM) barrel and APE1 four-layer alpha-beta folds of the apurinic-apyrimidinic endonuclease families.

  6. Intragenic suppression of an active site mutation in the human apurinic/apyrimidinic endonuclease.

    PubMed

    Izumi, T; Malecki, J; Chaudhry, M A; Weinfeld, M; Hill, J H; Lee, J C; Mitra, S

    1999-03-19

    The apurinic/apyrimidinic endonucleases (APE) contain several highly conserved sequence motifs. The glutamic acid residue in a consensus motif, LQE96TK98 in human APE (hAPE-1), is crucial because of its role in coordinating Mg2+, an essential cofactor. Random mutagenesis of the inactive E96A mutant cDNA, followed by phenotypic screening in Escherichia coli, led to isolation of an intragenic suppressor with a second site mutation, K98R. Although the Km of the suppressor mutant was about sixfold higher than that of the wild-type enzyme, their kcat values were similar for AP endonuclease activity. These results suggest that the E96A mutation affects only the DNA-binding step, but not the catalytic step of the enzyme. The 3' DNA phosphoesterase activities of the wild-type and the suppressor mutant were also comparable. No global change of the protein conformation is induced by the single or double mutations, but a local perturbation in the structural environment of tryptophan residues may be induced by the K98R mutation. The wild-type and suppressor mutant proteins have similar Mg2+ requirement for activity. These results suggest a minor perturbation in conformation of the suppressor mutant enabling an unidentified Asp or Glu residue to substitute for Glu96 in positioning Mg2+ during catalysis. The possibility that Asp70 is such a residue, based on its observed proximity to the metal-binding site in the wild-type protein, was excluded by site-specific mutation studies. It thus appears that another acidic residue coordinates with Mg2+ in the mutant protein. These results suggest a rather flexible conformation of the region surrounding the metal binding site in hAPE-1 which is not obvious from the X-ray crystallographic structure. PMID:10074406

  7. Identification of one of the apurinic/apyrimidinic lyase active sites of topoisomerase V by structural and functional studies.

    PubMed

    Rajan, Rakhi; Prasad, Rajendra; Taneja, Bhupesh; Wilson, Samuel H; Mondragón, Alfonso

    2013-01-01

    Topoisomerase V (Topo-V) is the only member of a novel topoisomerase subtype. Topo-V is unique because it is a bifunctional enzyme carrying both topoisomerase and DNA repair lyase activities within the same protein. Previous studies had shown that the topoisomerase domain spans the N-terminus of the protein and is followed by 12 tandem helix-hairpin-helix [(HhH)(2)] domains. There are at least two DNA repair lyase active sites for apurinic/apyrimidinic (AP) site processing, one within the N-terminal region and the second within the C-terminal domain of Topo-V, but their exact locations and characteristics are unknown. In the present study, the N-terminal 78-kDa fragment of Topo-V (Topo-78), containing the topoisomerase domain and one of the lyase DNA repair domains, was characterized by structural and biochemical studies. The results show that an N-terminal 69-kDa fragment is the minimal fragment with both topoisomerase and AP lyase activities. The lyase active site of Topo-78 is at the junction of the fifth and sixth (HhH)(2) domains. From the biochemical and structural data, it appears that Lys571 is the most probable nucleophile responsible for the lyase activity. Our experiments also suggest that Topo-V most likely acts as a Class I AP endonuclease in vivo. PMID:23125368

  8. The role of Schizosaccharomyces pombe DNA repair enzymes Apn1p and Uve1p in the base excision repair of apurinic/apyrimidinic sites

    SciTech Connect

    Tanihigashi, Haruna; Yamada, Ayako; Igawa, Emi; Ikeda, Shogo . E-mail: ikeda@dbc.ous.ac.jp

    2006-09-08

    In Schizosaccharomyces pombe the repair of apurinic/apyrimidinic (AP) sites is mainly initiated by AP lyase activity of DNA glycosylase Nth1p. In contrast, the major AP endonuclease Apn2p functions by removing 3'-{alpha},{beta}-unsaturated aldehyde ends induced by Nth1p, rather than by incising the AP sites. S. pombe possesses other minor AP endonuclease activities derived from Apn1p and Uve1p. In this study, we investigated the function of these two enzymes in base excision repair (BER) for methyl methanesulfonate (MMS) damage using the nth1 and apn2 mutants. Deletion of apn1 or uve1 from nth1{delta} cells did not affect sensitivity to MMS. Exogenous expression of Apn1p failed to suppress the MMS sensitivity of nth1{delta} cells. Although Apn1p and Uve1p incised the oligonucleotide containing an AP site analogue, these enzymes could not initiate repair of the AP sites in vivo. Despite this, expression of Apn1p partially restored the MMS sensitivity of apn2{delta} cells, indicating that the enzyme functions as a 3'-phosphodiesterase to remove 3'-blocked ends. Localization of Apn1p in the nucleus and cytoplasm hints at an additional function of the enzyme other than nuclear DNA repair. Heterologous expression of Saccharomyces cerevisiae homologue of Apn1p completely restored the MMS resistance of the nth1{delta} and apn2{delta} cells. This result confirms a difference in the major pathway for processing the AP site between S. pombe and S. cerevisiae cells.

  9. Human Apurinic/Apyrimidinic Endonuclease 1

    PubMed Central

    Li, Mengxia

    2014-01-01

    Abstract Significance: Human apurinic/apyrimidinic endonuclease 1 (APE1, also known as REF-1) was isolated based on its ability to cleave at AP sites in DNA or activate the DNA binding activity of certain transcription factors. We review herein topics related to this multi-functional DNA repair and stress-response protein. Recent Advances: APE1 displays homology to Escherichia coli exonuclease III and is a member of the divalent metal-dependent α/β fold-containing phosphoesterase superfamily of enzymes. APE1 has acquired distinct active site and loop elements that dictate substrate selectivity, and a unique N-terminus which at minimum imparts nuclear targeting and interaction specificity. Additional activities ascribed to APE1 include 3′–5′ exonuclease, 3′-repair diesterase, nucleotide incision repair, damaged or site-specific RNA cleavage, and multiple transcription regulatory roles. Critical Issues: APE1 is essential for mouse embryogenesis and contributes to cell viability in a genetic background-dependent manner. Haploinsufficient APE1+/− mice exhibit reduced survival, increased cancer formation, and cellular/tissue hyper-sensitivity to oxidative stress, supporting the notion that impaired APE1 function associates with disease susceptibility. Although abnormal APE1 expression/localization has been seen in cancer and neuropathologies, and impaired-function variants have been described, a causal link between an APE1 defect and human disease remains elusive. Future Directions: Ongoing efforts aim at delineating the biological role(s) of the different APE1 activities, as well as the regulatory mechanisms for its intra-cellular distribution and participation in diverse molecular pathways. The determination of whether APE1 defects contribute to human disease, particularly pathologies that involve oxidative stress, and whether APE1 small-molecule regulators have clinical utility, is central to future investigations. Antioxid. Redox Signal. 20, 678–707

  10. SLAC site design aesthetics

    SciTech Connect

    Hall, F.F.

    1985-10-01

    Stanford Linear Accelerator Center (SLAC) is a single mission laboratory dedicated to basic research in high energy particle physics. SLAC site also houses Stanford Synchrotron Radiation Laboratory (SSRL) which is a multi-mission laboratory for research using beams of ultraviolet light and low energy photons as emitted tangentially from SLAC colliding beam facilities. This paper discusses various aspects of SLAC site design aesthetics under the following headings: (1) imposed footprint of SLAC, (2) description of selected site, (3) use of earth cover for radiation and sight screens, (4) use of landscaping for cosmetic purposes, (5) use of exterior paint colors to soften SLAC impact on neighbors, (6) relocation of SLAC main entrance, (7) relocation of SLAC collider arcs and experimental hall, (8) parking lots and storage yards, and (9) land use zoning at SLAC.

  11. Barrier Free Site Design.

    ERIC Educational Resources Information Center

    Dee, Richard K., Ed.

    The booklet provides information for the design and evaluation of a barrier free outdoor environment for handicapped individuals. Section 1 discusses the scope of the study, defines terms, cites pertinent laws and legislation, describes cost/benefit factors, and surveys population statistics. Section 2 considers recommended design details in the…

  12. Decisive role of apurinic/apyrimidinic endonuclease/Ref-1 in initiation of cell death.

    PubMed

    Cho, Kyoung Joo; Kim, Hyun Jeong; Park, Soo Chul; Kim, Hyun Woo; Kim, Gyung Whan

    2010-11-01

    The apurinic/apyrimidinic endonuclease/redox effector factor-1 (APE/Ref-1) is involved in the base excision repair of apurinic/apyrimidinic sites induced by oxidative DNA damage. APE/Ref-1 was decreased by kainic acid (KA) injury in a time-dependent manner at the level of proteins, not transcripts. We investigated whether alteration of APE/Ref-1 amounts would influence hippocampal cell fate, survival or death, after KA injury. Overexpression of APE/Ref-1 using adenovirus and restoration of APE small peptides significantly reduced KA-induced hippocampal cell death. Both silencing of APE/Ref-1 by siRNA and inhibition of endonuclease by an antibody significantly increased caspase-3 activity and apoptotic cell death triggered from the early time after exposure to KA. These findings suggest that cell death is initiated by reducing APE/Ref-1 protein and inhibiting its repair function in spite of enough protein amounts. In conclusion, APE/Ref-1 may be a regulator of cell death initiation, and APE small peptides could provide molecular mechanism-based therapies for neuroprotection in progressive excitotoxic neuronal damage.

  13. Characterization of class II apurinic/apyrimidinic endonuclease activities in the human malaria parasite, Plasmodium falciparum.

    PubMed Central

    Haltiwanger, B M; Karpinich, N O; Taraschi, T F

    2000-01-01

    We have reported that the human malaria parasite, Plasmodium falciparum, repairs apurinic/apyrimidinic (AP) sites on DNA by a long-patch base excision repair (BER) pathway. This biology is different from that in mammalian cells, which predominantly repair AP sites by a DNA-polymerase-beta-dependent, one-nucleotide patch BER pathway. As a starting point for the identification and biochemical characterization of the enzymes involved in the parasite DNA BER pathway, we chose characterization of the AP endonuclease activity in a P. falciparum cell-free lysate. Evidence is provided for the presence of class II, Mg(2+)-dependent and independent AP endonucleases in the parasite lysate. The investigation of the processing of AP sites in Plasmodium will provide new information about long-patch BER pathways; if they are different from those in the human host they might provide a new target for anti-malarial chemotherapy. PMID:10600642

  14. Instructional Design. [SITE 2002 Section].

    ERIC Educational Resources Information Center

    2002

    This document contains the following papers on instructional design from the SITE (Society for Information Technology & Teacher Education) 2002 conference: "Faculty Guidelines for the Video Development Process" (Ronald J. Abate and Kathleen Benghiat); "Evolution of an Online Graduate Course in Educational Multimedia" (Peter Albion); "PT3…

  15. Instructional Design. [SITE 2001 Section].

    ERIC Educational Resources Information Center

    Boger, Stephanie, Ed.

    This document contains the papers on instructional design from the SITE (Society for Information Technology & Teacher Education) 2001 conference. Topics covered include: an adaptive e-framework for teacher training; assessing the integration of technology into the curriculum; promoting instructional planning; learning and using World Wide Web page…

  16. Teaching Web Site Design: Science or Art?

    ERIC Educational Resources Information Center

    Taylor, Mark John; Salces, Fausto Sainz; Duffy, Sandra Patricia

    2005-01-01

    This paper discusses an approach to teaching web site design to higher education (HE) students that attempts to balance the artistic and scientific aspects of the web site design process. The design of IT systems has traditionally been viewed as a technical activity. However, unlike existing types of IT systems, an organization's web site is…

  17. Publicity through Better Web Site Design.

    ERIC Educational Resources Information Center

    Guenther, Kim

    1999-01-01

    Describes how to design Web sites that will reach the most people possible. Discusses publicity; Web search engine sites; adopting Web development standards; using metatags to effectively index a site; Web site addresses and naming conventions; writing for the Web; mass submissions; subject area knowledge; making Web rings; and additional ideas to…

  18. GEOSTATISTICAL SAMPLING DESIGNS FOR HAZARDOUS WASTE SITES

    EPA Science Inventory

    This chapter discusses field sampling design for environmental sites and hazardous waste sites with respect to random variable sampling theory, Gy's sampling theory, and geostatistical (kriging) sampling theory. The literature often presents these sampling methods as an adversari...

  19. Apurinic/apyrimidinic endonuclease 1 is the essential nuclease during immunoglobulin class switch recombination.

    PubMed

    Masani, Shahnaz; Han, Li; Yu, Kefei

    2013-04-01

    Immunoglobulin (Ig) class switch recombination (CSR) is initiated by activation-induced cytidine deaminase (AID) that catalyzes numerous DNA cytosine deaminations within switch regions. The resulting uracils are processed by uracil base excision and/or mismatch repair enzymes that ultimately generate switch region DNA double-strand breaks (DSBs). Uracil glycosylase 2 (UNG2) is required for CSR, most likely by removing uracils to generate abasic sites. Although it is presumed that the apurinic/apyrimidinic endonuclease 1 (APE1) generates DNA strand incisions (a prerequisite for CSR) at these abasic sites, a direct test of the requirement for APE1 in CSR has been difficult because of the embryonic lethality of APE1 ablation in mice. Here, we report the successful deletion of the APE1 gene in a mouse B cell line (CH12F3) capable of robust CSR in vitro. In contrast to the general assumption that APE1 is essential for cellular viability, deletion of APE1 in CH12F3 cells has no apparent effect on cell viability or growth. Moreover, CSR in APE1-null CH12F3 cells is drastically reduced, providing direct evidence for an essential role for APE1 in switch region cleavage and CSR. Finally, deletion of AP endonuclease 2 (APE2) has no effect on CSR in either APE1-proficient or -deficient cells.

  20. Suppression of oxidative phosphorylation in mouse embryonic fibroblast cells deficient in apurinic/apyrimidinic endonuclease

    PubMed Central

    Suganya, Rangaswamy; Chakraborty, Anirban; Miriyala, Sumitra; Hazra, Tapas K.; Izumi, Tadahide

    2015-01-01

    The mammalian apurinic/apyrimidinic (AP) endonuclease 1 (APE1) is an essential DNA repair/gene regulatory protein. Decrease of APE1 in cells by inducible shRNA knockdown or by conditional gene knockout caused apoptosis. Here we succeeded in establishing a unique mouse embryonic fibroblast (MEF) line expressing APE1 at a level far lower than those achieved with shRNA knockdown. The cells, named MEFla (MEFlowAPE1), were hypersensitive to methyl methanesulfonate (MMS), and showed little activity for repairing AP-sites and MMS induced DNA damage. While these results were consistent with the essential role of APE1 in repair of AP sites, the MEFla cells grew normally and the basal activation of poly(ADP-ribose) polymerases in MEFla was lower than that in the wild-type MEF (MEFwt), indicating the low DNA damage stress in MEFla under the normal growth condition. Oxidative phosphorylation activity in MEFla was lower than in MEFwt, while the glycolysis rates in MEFla were higher than in MEFwt. In addition, we observed decreased intracellular oxidative stress in MEFla. These results suggest that cells with low APE1 reversibly suppress mitochondrial respiration and thereby reduce DNA damage stress and increases the cell viability. PMID:25645679

  1. Suppression of oxidative phosphorylation in mouse embryonic fibroblast cells deficient in apurinic/apyrimidinic endonuclease.

    PubMed

    Suganya, Rangaswamy; Chakraborty, Anirban; Miriyala, Sumitra; Hazra, Tapas K; Izumi, Tadahide

    2015-03-01

    The mammalian apurinic/apyrimidinic (AP) endonuclease 1 (APE1) is an essential DNA repair/gene regulatory protein. Decrease of APE1 in cells by inducible shRNA knockdown or by conditional gene knockout caused apoptosis. Here we succeeded in establishing a unique mouse embryonic fibroblast (MEF) line expressing APE1 at a level far lower than those achieved with shRNA knockdown. The cells, named MEF(la) (MEF(lowAPE1)), were hypersensitive to methyl methanesulfonate (MMS), and showed little activity for repairing AP-sites and MMS induced DNA damage. While these results were consistent with the essential role of APE1 in repair of AP sites, the MEF(la) cells grew normally and the basal activation of poly(ADP-ribose) polymerases in MEF(la) was lower than that in the wild-type MEF (MEF(wt)), indicating the low DNA damage stress in MEF(la) under the normal growth condition. Oxidative phosphorylation activity in MEF(la) was lower than in MEF(wt), while the glycolysis rates in MEF(la) were higher than in MEF(wt). In addition, we observed decreased intracellular oxidative stress in MEF(la). These results suggest that cells with low APE1 reversibly suppress mitochondrial respiration and thereby reduce DNA damage stress and increases the cell viability.

  2. Redox regulation of apurinic/apyrimidinic endonuclease 1 activity in Long-Evans Cinnamon rats during spontaneous hepatitis.

    PubMed

    Karmahapatra, Soumendra Krishna; Saha, Tapas; Adhikari, Sanjay; Woodrick, Jordan; Roy, Rabindra

    2014-03-01

    The Long-Evans Cinnamon (LEC) rat is an animal model for Wilson's disease. This animal is genetically predisposed to copper accumulation in the liver, increased oxidative stress, accumulation of DNA damage, and the spontaneous development of hepatocellular carcinoma. Thus, this animal model is useful for studying the relationship of endogenous DNA damage to spontaneous carcinogenesis. In this study, we have investigated the apurinic/apyrimidinic endonuclease 1 (APE1)-mediated excision repair of endogenous DNA damage, apurinic/apyrimidinic (AP)-sites, which is highly mutagenic and implicated in human cancer. We found that the activity was reduced in the liver extracts from the acute hepatitis period of LEC rats as compared with extracts from the age-matched Long-Evans Agouti rats. The acute hepatitis period had also a heightened oxidative stress condition as assessed by an increase in oxidized glutathione level and loss of enzyme activity of glyceraldehyde 3-phosphate dehydrogenase, a key redox-sensitive protein in cells. Interestingly, the activity reduction was not due to changes in protein expression but apparently by reversible protein oxidation as the addition of reducing agents to extracts of the liver from acute hepatitis period reactivated APE1 activity and thus, confirmed the oxidation-mediated loss of APE1 activity under increased oxidative stress. These findings show for the first time in an animal model that the repair mechanism of AP-sites is impaired by increased oxidative stress in acute hepatitis via redox regulation which contributed to the increased accumulation of mutagenic AP-sites in liver DNA.

  3. Characterization and genetic mapping of a mutation affecting apurinic endonuclease activity in Staphylococcus aureus.

    PubMed Central

    Tam, J E; Pattee, P A

    1986-01-01

    Protoplast fusion between the Rec- mutant RN981 (L. Wyman, R. V. Goering, and R. P. Novick, Genetics 76:681-702, 1974) of Staphylococcus aureus NCTC 8325 and a Rec+ NCTC 8325 derivative yielded Rec+ recombinants that exhibited the increased sensitivity to N-methyl-N'-nitro-N-nitrosoguanidine characteristic of RN981. Transformation analyses identified a specific mutation, designated ngr-374, that was responsible not only for N-methyl-N'-nitro-N-nitrosoguanidine sensitivity, but also sensitivity to methyl methanesulfonate, ethyl methanesulfonate, nitrous acid, and UV irradiation. However, ngr-374-carrying recombinants showed no significant increase in their sensitivity to mitomycin C or 4-nitroquinoline 1-oxide and were unaffected in recombination proficiency. In vitro assays showed that ngr-374-carrying strains had lower apurinic/apyrimidinic endonuclease activities than the wild type. The chromosomal locus occupied by ngr-374 was shown to exist in the gene order omega(Chr::Tn551)40-ngr-374-thrB106. PMID:2430940

  4. GMT site: facilities and enclosure design overview

    NASA Astrophysics Data System (ADS)

    Teran, Jose; Sheehan, Michael; Neff, Daniel H.; Grigel, Eric; Adriaanse, David; Farahani, Arash

    2014-07-01

    The Giant Magellan Telescope (GMT), one of several next generation Extremely Large Telescopes (ELTs), is a 25.4 meter diameter altitude over azimuth design set to be built at the summit of Cerro Campanas at the Las Campanas Observatory in Chile. This paper provides an update and overview of the ongoing efforts for the GMT site, infrastructure, facilities and enclosure design. The paper provides insight of the proposed systems, trade studies and approach resulting in the current design solution.

  5. Apurinic/Apyrimidinic Endonuclease 1 Upregulation Reduces Oxidative DNA Damage and Protects Hippocampal Neurons from Ischemic Injury

    PubMed Central

    Leak, Rehana K.; Li, Peiying; Zhang, Feng; Sulaiman, Hassan H.; Weng, Zhongfang; Wang, Guohua; Stetler, R. Anne; Shi, Yejie; Cao, Guodong

    2015-01-01

    Abstract Aims: Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme that participates in base-excision repair of oxidative DNA damage and in the redox activation of transcription factors. We tested the hypothesis that APE1 upregulation protects neuronal structure and function against transient global cerebral ischemia (tGCI). Results: Upregulation of APE1 by low-dose proton irradiation (PI) or by transgene overexpression protected hippocampal CA1 neurons against tGCI-induced cell loss and reduced apurinic/apyrimidinic sites and DNA fragmentation. Conversely, APE1 knockdown attenuated the protection afforded by PI and ischemic preconditioning. APE1 overexpression inhibited the DNA damage response, as evidenced by lower phospho-histone H2A and p53-upregulated modulator of apoptosis levels. APE1 overexpression also partially rescued dendritic spines and attenuated the decrease in field excitatory postsynaptic potentials in hippocampal CA1. Presynaptic and postsynaptic markers were reduced after tGCI, and this effect was blunted in APE1 transgenics. The Morris water maze test revealed that APE1 protected against learning and memory deficits for at least 27 days post-injury. Animals expressing DNA repair-disabled mutant APE1 (D210A) exhibited more DNA damage than wild-type controls and were not protected against tGCI-induced cell loss. Innovation: This is the first study that thoroughly characterizes structural and functional protection against ischemia after APE1 upregulation by measuring synaptic markers, electrophysiological function, and long-term neurological deficits in vivo. Furthermore, disabling the DNA repair activity of APE1 was found to abrogate its protective impact. Conclusion: APE1 upregulation, either endogenously or through transgene overexpression, protects DNA, neuronal structures, synaptic function, and behavioral output from ischemic injury. Antioxid. Redox Signal. 22, 135–148. PMID:24180454

  6. Using Participatory Design to Improve Web Sites

    ERIC Educational Resources Information Center

    Nikolova-Houston, Tatiana

    2005-01-01

    In this article, the author, a doctoral candidate from the School of Information at the University of Texas-Austin, describes the experience gathered from her attempt to redesign her existing Web sites in order to supply online resources for Slavic and Byzantine studies. The use of participatory design, which involves the users in creating the…

  7. Characterization of DNA substrate specificities of apurinic/apyrimidinic endonucleases from Mycobacterium tuberculosis.

    PubMed

    Abeldenov, Sailau; Talhaoui, Ibtissam; Zharkov, Dmitry O; Ishchenko, Alexander A; Ramanculov, Erlan; Saparbaev, Murat; Khassenov, Bekbolat

    2015-09-01

    Apurinic/apyrimidinic (AP) endonucleases are key enzymes involved in the repair of abasic sites and DNA strand breaks. Pathogenic bacteria Mycobacterium tuberculosis contains two AP endonucleases: MtbXthA and MtbNfo members of the exonuclease III and endonuclease IV families, which are exemplified by Escherichia coli Xth and Nfo, respectively. It has been shown that both MtbXthA and MtbNfo contain AP endonuclease and 3'→5' exonuclease activities. However, it remains unclear whether these enzymes hold 3'-repair phosphodiesterase and nucleotide incision repair (NIR) activities. Here, we report that both mycobacterial enzymes have 3'-repair phosphodiesterase and 3'-phosphatase, and MtbNfo contains in addition a very weak NIR activity. Interestingly, depending on pH, both enzymes require different concentrations of divalent cations: 0.5mM MnCl2 at pH 7.6 and 10 mM at pH 6.5. MtbXthA requires a low ionic strength and 37 °C, while MtbNfo requires high ionic strength (200 mM KCl) and has a temperature optimum at 60 °C. Point mutation analysis showed that D180 and N182 in MtbXthA and H206 and E129 in MtbNfo are critical for enzymes activities. The steady-state kinetic parameters indicate that MtbXthA removes 3'-blocking sugar-phosphate and 3'-phosphate moieties at DNA strand breaks with an extremely high efficiency (kcat/KM=440 and 1280 μM(-1)∙min(-1), respectively), while MtbNfo exhibits much lower 3'-repair activities (kcat/KM=0.26 and 0.65 μM(-1)∙min(-1), respectively). Surprisingly, both MtbXthA and MtbNfo exhibited very weak AP site cleavage activities, with kinetic parameters 100- and 300-fold lower, respectively, as compared with the results reported previously. Expression of MtbXthA and MtbNfo reduced the sensitivity of AP endonuclease-deficient E. coli xth nfo strain to methylmethanesulfonate and H2O2 to various degrees. Taken together, these data establish the DNA substrate specificity of M. tuberculosis AP endonucleases and suggest their possible role

  8. Characterization of DNA substrate specificities of apurinic/apyrimidinic endonucleases from Mycobacterium tuberculosis.

    PubMed

    Abeldenov, Sailau; Talhaoui, Ibtissam; Zharkov, Dmitry O; Ishchenko, Alexander A; Ramanculov, Erlan; Saparbaev, Murat; Khassenov, Bekbolat

    2015-09-01

    Apurinic/apyrimidinic (AP) endonucleases are key enzymes involved in the repair of abasic sites and DNA strand breaks. Pathogenic bacteria Mycobacterium tuberculosis contains two AP endonucleases: MtbXthA and MtbNfo members of the exonuclease III and endonuclease IV families, which are exemplified by Escherichia coli Xth and Nfo, respectively. It has been shown that both MtbXthA and MtbNfo contain AP endonuclease and 3'→5' exonuclease activities. However, it remains unclear whether these enzymes hold 3'-repair phosphodiesterase and nucleotide incision repair (NIR) activities. Here, we report that both mycobacterial enzymes have 3'-repair phosphodiesterase and 3'-phosphatase, and MtbNfo contains in addition a very weak NIR activity. Interestingly, depending on pH, both enzymes require different concentrations of divalent cations: 0.5mM MnCl2 at pH 7.6 and 10 mM at pH 6.5. MtbXthA requires a low ionic strength and 37 °C, while MtbNfo requires high ionic strength (200 mM KCl) and has a temperature optimum at 60 °C. Point mutation analysis showed that D180 and N182 in MtbXthA and H206 and E129 in MtbNfo are critical for enzymes activities. The steady-state kinetic parameters indicate that MtbXthA removes 3'-blocking sugar-phosphate and 3'-phosphate moieties at DNA strand breaks with an extremely high efficiency (kcat/KM=440 and 1280 μM(-1)∙min(-1), respectively), while MtbNfo exhibits much lower 3'-repair activities (kcat/KM=0.26 and 0.65 μM(-1)∙min(-1), respectively). Surprisingly, both MtbXthA and MtbNfo exhibited very weak AP site cleavage activities, with kinetic parameters 100- and 300-fold lower, respectively, as compared with the results reported previously. Expression of MtbXthA and MtbNfo reduced the sensitivity of AP endonuclease-deficient E. coli xth nfo strain to methylmethanesulfonate and H2O2 to various degrees. Taken together, these data establish the DNA substrate specificity of M. tuberculosis AP endonucleases and suggest their possible role

  9. 10 CFR 862.7 - Designation of sites.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Federal Register of the notice designating the site. (c) Upon designation of a site, the cognizant Manager of Operations may inform the public of such designation through press release or posting of notice...

  10. Access to Space Interactive Design Web Site

    NASA Technical Reports Server (NTRS)

    Leon, John; Cutlip, William; Hametz, Mark

    2000-01-01

    The Access To Space (ATS) Group at NASA's Goddard Space Flight Center (GSFC) supports the science and technology community at GSFC by facilitating frequent and affordable opportunities for access to space. Through partnerships established with access mode suppliers, the ATS Group has developed an interactive Mission Design web site. The ATS web site provides both the information and the tools necessary to assist mission planners in selecting and planning their ride to space. This includes the evaluation of single payloads vs. ride-sharing opportunities to reduce the cost of access to space. Features of this site include the following: (1) Mission Database. Our mission database contains a listing of missions ranging from proposed missions to manifested. Missions can be entered by our user community through data input tools. Data is then accessed by users through various search engines: orbit parameters, ride-share opportunities, spacecraft parameters, other mission notes, launch vehicle, and contact information. (2) Launch Vehicle Toolboxes. The launch vehicle toolboxes provide the user a full range of information on vehicle classes and individual configurations. Topics include: general information, environments, performance, payload interface, available volume, and launch sites.

  11. 10 CFR 862.7 - Designation of sites.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Designation of sites. 862.7 Section 862.7 Energy DEPARTMENT OF ENERGY RESTRICTIONS ON AIRCRAFT LANDING AND AIR DELIVERY AT DEPARTMENT OF ENERGY NUCLEAR SITES § 862.7 Designation of sites. (a) DOE shall designate sites covered by this part as deemed necessary, consistent with the national security and...

  12. Conceptual design report for site drainage control

    SciTech Connect

    Hunter, M.R.

    1996-07-01

    The Mound Plant (Mound), located in Miamisburg, Ohio, is a Department of Energy (DOE) development and production facility performing support work for DOE`s weapons and energy-related programs. EG&G Mound Applied Technologies, Inc. (EG&G) is the Operating Contractor (OC) for this Government-Owned, Contractor-Operated (GOCO) facility. The work performed at Mound emphasizes nuclear energy and explosives technology. Mound is currently implementing an Environmental, Safety & Health (ES&H) Upgrades Program designed to protect its employees, the public, and the environment from adverse effects caused by facility activities. The first project of this multiphase program is now in the final stages of construction, and the second project is currently under design. Four additional projects, one of which is presented in this report, are in the conceptual design stage. At Mound, 22 soil zones have become contaminated with radioactive material. These zones cover approximately 20 percent of the total area of developed property at the site. During a storm event, the rainwater washes contaminated soil from these zones into the storm sewer system. These radioactive contaminants may then be discharged along with the stormwater into the Great Miami River via the Miami Erie Canal. This conceptual design report (CDR), Site Drainage Control, the fourth project in the ES&H program, describes a project that will provide improvements and much needed repairs to inadequate and deteriorating portions of the storm drainage system on the developed property. The project also will provide a stormwater retention facility capable of storing the stormwater runoff, from the developed property, resulting from a 100-year storm event. These improvements will permit the effective control and monitoring of stormwater to prevent the spread of radioactive contaminants from contaminated soil zones and will provide a means to collect and contain accidental spills of hazardous substances.

  13. Lucanthone and Its Derivative Hycanthone Inhibit Apurinic Endonuclease-1 (APE1) by Direct Protein Binding

    PubMed Central

    Naidu, Mamta D.; Agarwal, Rakhi; Pena, Louis A.; Cunha, Luis; Mezei, Mihaly; Shen, Min; Wilson, David M.; Liu, Yuan; Sanchez, Zina; Chaudhary, Pankaj; Wilson, Samuel H.; Waring, Michael J.

    2011-01-01

    Lucanthone and hycanthone are thioxanthenone DNA intercalators used in the 1980s as antitumor agents. Lucanthone is in Phase I clinical trial, whereas hycanthone was pulled out of Phase II trials. Their potential mechanism of action includes DNA intercalation, inhibition of nucleic acid biosyntheses, and inhibition of enzymes like topoisomerases and the dual function base excision repair enzyme apurinic endonuclease 1 (APE1). Lucanthone inhibits the endonuclease activity of APE1, without affecting its redox activity. Our goal was to decipher the precise mechanism of APE1 inhibition as a prerequisite towards development of improved therapeutics that can counteract higher APE1 activity often seen in tumors. The IC50 values for inhibition of APE1 incision of depurinated plasmid DNA by lucanthone and hycanthone were 5 µM and 80 nM, respectively. The KD values (affinity constants) for APE1, as determined by BIACORE binding studies, were 89 nM for lucanthone/10 nM for hycanthone. APE1 structures reveal a hydrophobic pocket where hydrophobic small molecules like thioxanthenones can bind, and our modeling studies confirmed such docking. Circular dichroism spectra uncovered change in the helical structure of APE1 in the presence of lucanthone/hycanthone, and notably, this effect was decreased (Phe266Ala or Phe266Cys or Trp280Leu) or abolished (Phe266Ala/Trp280Ala) when hydrophobic site mutants were employed. Reduced inhibition by lucanthone of the diminished endonuclease activity of hydrophobic mutant proteins (as compared to wild type APE1) supports that binding of lucanthone to the hydrophobic pocket dictates APE1 inhibition. The DNA binding capacity of APE1 was marginally inhibited by lucanthone, and not at all by hycanthone, supporting our hypothesis that thioxanthenones inhibit APE1, predominantly, by direct interaction. Finally, lucanthone-induced degradation was drastically reduced in the presence of short and long lived free radical scavengers, e.g., TRIS and DMSO

  14. Lucanthone and its derivative hycanthone inhibit apurinic endonuclease-1 (APE1) by direct protein binding

    SciTech Connect

    Naidu, M.; Naidu, M.; Agarwal, R.; Pena, L.A.; Cunha, L.; Mezei, M.; Shen, M.; Wilson, D.M.; Liu, Y.; Sanchez, Z.; Chaudhary, P.; Wilson, S.H.; Waring, M.J.

    2011-09-15

    Lucanthone and hycanthone are thioxanthenone DNA intercalators used in the 1980s as antitumor agents. Lucanthone is in Phase I clinical trial, whereas hycanthone was pulled out of Phase II trials. Their potential mechanism of action includes DNA intercalation, inhibition of nucleic acid biosyntheses, and inhibition of enzymes like topoisomerases and the dual function base excision repair enzyme apurinic endonuclease 1 (APE1). Lucanthone inhibits the endonuclease activity of APE1, without affecting its redox activity. Our goal was to decipher the precise mechanism of APE1 inhibition as a prerequisite towards development of improved therapeutics that can counteract higher APE1 activity often seen in tumors. The IC{sub 50} values for inhibition of APE1 incision of depurinated plasmid DNA by lucanthone and hycanthone were 5 {mu}M and 80 nM, respectively. The K{sub D} values (affinity constants) for APE1, as determined by BIACORE binding studies, were 89 nM for lucanthone/10 nM for hycanthone. APE1 structures reveal a hydrophobic pocket where hydrophobic small molecules like thioxanthenones can bind, and our modeling studies confirmed such docking. Circular dichroism spectra uncovered change in the helical structure of APE1 in the presence of lucanthone/hycanthone, and notably, this effect was decreased (Phe266Ala or Phe266Cys or Trp280Leu) or abolished (Phe266Ala/Trp280Ala) when hydrophobic site mutants were employed. Reduced inhibition by lucanthone of the diminished endonuclease activity of hydrophobic mutant proteins (as compared to wild type APE1) supports that binding of lucanthone to the hydrophobic pocket dictates APE1 inhibition. The DNA binding capacity of APE1 was marginally inhibited by lucanthone, and not at all by hycanthone, supporting our hypothesis that thioxanthenones inhibit APE1, predominantly, by direct interaction. Finally, lucanthone-induced degradation was drastically reduced in the presence of short and long lived free radical scavengers, e

  15. Repository surface design site layout analysis

    SciTech Connect

    Montalvo, H.R.

    1998-02-27

    The purpose of this analysis is to establish the arrangement of the Yucca Mountain Repository surface facilities and features near the North Portal. The analysis updates and expands the North Portal area site layout concept presented in the ACD, including changes to reflect the resizing of the Waste Handling Building (WHB), Waste Treatment Building (WTB), Carrier Preparation Building (CPB), and site parking areas; the addition of the Carrier Washdown Buildings (CWBs); the elimination of the Cask Maintenance Facility (CMF); and the development of a concept for site grading and flood control. The analysis also establishes the layout of the surface features (e.g., roads and utilities) that connect all the repository surface areas (North Portal Operations Area, South Portal Development Operations Area, Emplacement Shaft Surface Operations Area, and Development Shaft Surface Operations Area) and locates an area for a potential lag storage facility. Details of South Portal and shaft layouts will be covered in separate design analyses. The objective of this analysis is to provide a suitable level of design for the Viability Assessment (VA). The analysis was revised to incorporate additional material developed since the issuance of Revision 01. This material includes safeguards and security input, utility system input (size and location of fire water tanks and pump houses, potable water and sanitary sewage rates, size of wastewater evaporation pond, size and location of the utility building, size of the bulk fuel storage tank, and size and location of other exterior process equipment), main electrical substation information, redundancy of water supply and storage for the fire support system, and additional information on the storm water retention pond.

  16. Effects of mono- and divalent metal ions on DNA binding and catalysis of human apurinic/apyrimidinic endonuclease 1.

    PubMed

    Miroshnikova, Anastasia D; Kuznetsova, Alexandra A; Vorobjev, Yuri N; Kuznetsov, Nikita A; Fedorova, Olga S

    2016-05-26

    Here, we used stopped-flow fluorescence techniques to conduct a comparative kinetic analysis of the conformational transitions in human apurinic/apyrimidinic endonuclease 1 (APE1) and in DNA containing an abasic site in the course of their interaction. Effects of monovalent (K(+)) and divalent (Mg(2+), Mn(2+), Ca(2+), Zn(2+), Cu(2+), and Ni(2+)) metal ions on DNA binding and catalytic stages were studied. It was shown that the first step of substrate binding (corresponding to formation of a primary enzyme-substrate complex) does not depend on the concentration (0.05-5.0 mM) or the nature of divalent metal ions. In contrast, the initial DNA binding efficiency significantly decreased at a high concentration (5-250 mM) of monovalent K(+) ions, indicating the involvement of electrostatic interactions in this stage. It was also shown that Cu(2+) ions abrogated the DNA binding ability of APE1, possibly, due to a strong interaction with DNA bases and the sugar-phosphate backbone. In the case of Ca(2+) ions, the catalytic activity of APE1 was lost completely with retention of binding potential. Thus, the enzymatic activity of APE1 is increased in the order Zn(2+) < Ni(2+) < Mn(2+) < Mg(2+). Circular dichroism spectra and calculation of the contact area between APE1 and DNA reveal that Mg(2+) ions stabilize the protein structure and the enzyme-substrate complex. PMID:27063150

  17. Reduced Nuclease Activity of Apurinic/Apyrimidinic Endonuclease (APE1) Variants on Nucleosomes: IDENTIFICATION OF ACCESS RESIDUES.

    PubMed

    Hinz, John M; Mao, Peng; McNeill, Daniel R; Wilson, David M

    2015-08-21

    Non-coding apurinic/apyrimidinic (AP) sites are generated at high frequency in genomic DNA via spontaneous hydrolytic, damage-induced or enzyme-mediated base release. AP endonuclease 1 (APE1) is the predominant mammalian enzyme responsible for initiating removal of mutagenic and cytotoxic abasic lesions as part of the base excision repair (BER) pathway. We have examined here the ability of wild-type (WT) and a collection of variant/mutant APE1 proteins to cleave at an AP site within a nucleosome core particle. Our studies indicate that, in comparison to the WT protein and other variant/mutant enzymes, the incision activity of the tumor-associated variant R237C and the rare population variant G241R are uniquely hypersensitive to nucleosome complexes in the vicinity of the AP site. This defect appears to stem from an abnormal interaction of R237C and G241R with abasic DNA substrates, but is not simply due to a DNA binding defect, as the site-specific APE1 mutant Y128A, which displays markedly reduced AP-DNA complex stability, did not exhibit a similar hypersensitivity to nucleosome structures. Notably, this incision defect of R237C and G241R was observed on a pre-assembled DNA glycosylase·AP-DNA complex as well. Our results suggest that the BER enzyme, APE1, has acquired distinct surface residues that permit efficient processing of AP sites within the context of protein-DNA complexes independent of classic chromatin remodeling mechanisms.

  18. Molecular design of substrate binding sites

    SciTech Connect

    Shelnutt, J.A.; Hobbs, J.D.

    1991-12-31

    Computer-aided molecular design methods were used to tailor binding sites for small substrate molecules, including CO{sub 2} and methane. The goal is to design a cavity, adjacent to a catalytic metal center, into which the substrate will selectively bind through only non-bonding interactions with the groups lining the binding pocket. Porphyrins are used as a basic molecular structure, with various substituents added to construct the binding pocket. The conformations of these highly-substituted porphyrins are predicted using molecular mechanics calculations with a force field that gives accurate predictions for metalloporhyrins. Dynamics and energy-minimization calculations of substrate molecules bound to the cavity indicate high substrate binding affinity. The size, shape and charge-distribution of groups surrounding the cavity provide molecular selectivity. Specifically, calculated binding energies of methane, benzene, dichloromethane, CO{sub 2} and chloroform vary by about 10 kcal/mol for metal octaethyl-tetraphenylporphyrins (OETPPs) with chloroform, dichloromethane, and CO{sub 2} having the lowest. Significantly, a solvent molecule is found in the cavity in the X-ray structures of Co- and CuOETPP crystals obtained from dichloromethane. 5 refs., 3 figs., 3 tabs.

  19. Molecular design of substrate binding sites

    SciTech Connect

    Shelnutt, J.A.; Hobbs, J.D.

    1991-01-01

    Computer-aided molecular design methods were used to tailor binding sites for small substrate molecules, including CO{sub 2} and methane. The goal is to design a cavity, adjacent to a catalytic metal center, into which the substrate will selectively bind through only non-bonding interactions with the groups lining the binding pocket. Porphyrins are used as a basic molecular structure, with various substituents added to construct the binding pocket. The conformations of these highly-substituted porphyrins are predicted using molecular mechanics calculations with a force field that gives accurate predictions for metalloporhyrins. Dynamics and energy-minimization calculations of substrate molecules bound to the cavity indicate high substrate binding affinity. The size, shape and charge-distribution of groups surrounding the cavity provide molecular selectivity. Specifically, calculated binding energies of methane, benzene, dichloromethane, CO{sub 2} and chloroform vary by about 10 kcal/mol for metal octaethyl-tetraphenylporphyrins (OETPPs) with chloroform, dichloromethane, and CO{sub 2} having the lowest. Significantly, a solvent molecule is found in the cavity in the X-ray structures of Co- and CuOETPP crystals obtained from dichloromethane. 5 refs., 3 figs., 3 tabs.

  20. 40 CFR 228.4 - Procedures for designation of sites.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... DUMPING CRITERIA FOR THE MANAGEMENT OF DISPOSAL SITES FOR OCEAN DUMPING § 228.4 Procedures for designation... environmental studies of each site, regions adjacent to the site, and on historical knowledge of the impact of... environmental studies of each site, regions adjacent to the site, and on historical knowledge of the impact...

  1. Web Site Design Benchmarking within Industry Groups.

    ERIC Educational Resources Information Center

    Kim, Sung-Eon; Shaw, Thomas; Schneider, Helmut

    2003-01-01

    Discussion of electronic commerce focuses on Web site evaluation criteria and applies them to different industry groups in Korea. Defines six categories of Web site evaluation criteria: business function, corporate credibility, contents reliability, Web site attractiveness, systematic structure, and navigation; and discusses differences between…

  2. Principles of web site development and design: powerful educational tools.

    PubMed

    Sproat, Sara Breckenridge

    2002-01-01

    Setting up an educational Web site is easy and is a huge benefit to the nursing profession. Although Web sites may radically differ in their audiences and intent, the principles behind a great site are the same. This article provides basic information, terminology, and advice on how to create effective Web sites using concepts of Web design and Web publishing. PMID:11984259

  3. Newmark design spectra considering earthquake magnitudes and site categories

    NASA Astrophysics Data System (ADS)

    Li, Bo; Xie, Wei-Chau; Pandey, M. D.

    2016-09-01

    Newmark design spectra have been implemented in many building codes, especially in building codes for critical structures. Previous studies show that Newmark design spectra exhibit lower amplitudes at high frequencies and larger amplitudes at low frequencies in comparison with spectra developed by statistical methods. To resolve this problem, this study considers three suites of ground motions recorded at three types of sites. Using these ground motions, influences of the shear-wave velocity, earthquake magnitudes, source-to-site distances on the ratios of ground motion parameters are studied, and spectrum amplification factors are statistically calculated. Spectral bounds for combinations of three site categories and two cases of earthquake magnitudes are estimated. Site design spectrum coefficients for the three site categories considering earthquake magnitudes are established. The problems of Newmark design spectra could be resolved by using the site design spectrum coefficients to modify the spectral values of Newmark design spectra in the acceleration sensitive, velocity sensitive, and displacement sensitive regions.

  4. Subsystem design package for the on-site monitor at solar heating and cooling sites

    NASA Technical Reports Server (NTRS)

    1977-01-01

    The on-site monitor is a portable device which can be easily connected to a Site Data Acquisition Subsystem to allow readouts of realtime sensor data in voltage or engineering units at instrumented solar heating and cooling sites. The design package consists of the performance specification, performance requirements cross reference, and the acceptance test procedure.

  5. SCP (Site Characterization Plan) conceptual design criteria document

    SciTech Connect

    Naiknimbalkar, N.M.

    1985-05-01

    This SCP Conceptual Design Criteria Document was developed to guide engineering efforts for Engineering Study No. 10, the supporting document for Chapter 6 of the SCP. The document provides regulatory design guidance, design rationale derived from the Generic Requirements for a Mined Geological Disposal System document, site-specific criteria, and design assumptions. Appendices were added to provide additional information on geology and seals design.

  6. Site Characterization Plan (SCP) conceptual design criteria document

    SciTech Connect

    Naiknimbalkar, N.M.

    1986-05-19

    This SCP Conceptual Design Criteria Document was developed to guide engineering effort for Engineering Study No. 10, the supporting document for Chapter 6 of the SCP. The document provides regulatory design guidance, design rationale derived from the Generic Requirements for a Mined Geological Disposal System document, site-specific criteria, and design assumptions. Appendices were added to provide additional information on geology and seals design. 24 figs., 15 tabs.

  7. Design control for the Savannah River Site Consolidated Incineration Facility

    SciTech Connect

    Walker, R.E.; Rider, R.L. )

    1991-01-01

    The initiation, development, and control of the design for the Consolidated Incineration Facility at the US Department of Energy Savannah River Site has been, from the inception, a precisely and formally controlled process. A plan was developed and implemented to ensure output properly aligned with approved design criteria and conformed to applicable regulations throughout the design process. The key element of design control was the technical baseline which established the benchmark against which all changes to the design was evaluated. During the conceptual design phase of the project, design criteria were written to reflect the project objectives and functional requirements. Governmental regulations were reviewed to determine permitting and licensing actions required. Hazards assessments were performed to establish design classifications. The resulting design criteria, permitting requirements, and facility classifications were incorporated into the design plan which provided the basis for subsequent design activities. As the project proceeded through the various design phases, design control was maintained according to the design plan. Review of all design products was performed by the project team routinely. Formal independent design reviews were accomplished prior to releasing the design for construction. Alignment between criteria and design output was verified periodically throughout the design process. A formal design change control board was invoked to effect design changes impacting technical baselines. All changes to design initiated following issue for construction also were subject to procedural control.

  8. Design control for the Savannah River Site Consolidated Incineration Facility

    SciTech Connect

    Walker, R.E.; Rider, R.L.

    1991-12-31

    The initiation, development, and control of the design for the Consolidated Incineration Facility at the US Department of Energy Savannah River Site has been, from the inception, a precisely and formally controlled process. A plan was developed and implemented to ensure output properly aligned with approved design criteria and conformed to applicable regulations throughout the design process. The key element of design control was the technical baseline which established the benchmark against which all changes to the design was evaluated. During the conceptual design phase of the project, design criteria were written to reflect the project objectives and functional requirements. Governmental regulations were reviewed to determine permitting and licensing actions required. Hazards assessments were performed to establish design classifications. The resulting design criteria, permitting requirements, and facility classifications were incorporated into the design plan which provided the basis for subsequent design activities. As the project proceeded through the various design phases, design control was maintained according to the design plan. Review of all design products was performed by the project team routinely. Formal independent design reviews were accomplished prior to releasing the design for construction. Alignment between criteria and design output was verified periodically throughout the design process. A formal design change control board was invoked to effect design changes impacting technical baselines. All changes to design initiated following issue for construction also were subject to procedural control.

  9. HVDC power transmission electrode siting and design

    SciTech Connect

    Holt, R.J.; Dabkowski, J.; Hauth, R.L.

    1997-04-01

    This research strives to shed light on the feasibility and practicality of using deep earth electrodes to permit their use for extended periods without adverse consequences. This report begins with a review of the fundamentals associated with current conduction in earth, including the various techniques available for measuring the earth`s electrical properties. The sources of existing data are discussed and some specific data for selected regions of the U.S. and Canada are reviewed as examples. Electrode technology and design issues are reviewed and recent experience gained by New England Power and Hydro-Quebec is discussed. The issues associated with direct current flowing in underground pipelines (and other facilities) are described and the present-day mitigation measures are evaluated. Suggestions are made for further R&D in the coordination of cathodic protection systems, an area that has evolved as an empirical, trial- and-error art more than a science.

  10. Phase I privatization, site development, and roads design requirements document

    SciTech Connect

    Parazin, R.J.

    1996-09-30

    To prepare for the privatization contractor development of their assigned sites, roads and rail system must be extended from the existing area network systems. Various road and rail modification alternatives were investigated through an engineering study, @C-SD-TWR-ES- 004, with the preferred transportation corridors identified. Various Site development alternatives were also investigated, WHC-SD-TWR-ES-003. The preferred alternative, as discussed herein, will: 1. Establish boundaries and set monuments for the two PC sites. All work within each designated site will be by the PC. 2. Assure that the systems to serve each site - Roads and Rail System Modifications, Raw and Potable Water Service, Liquid Effluent Transfer Systems and Electric Power- are integrated with each other to best serve the sites. 3. Identify the corridors for Low Activity Waste (LAW) feed lines from the existing AP Tank Farm to the PC sites. Site development project will prepare these corridors for construction ofthe feed lines by the PC. Ifrequired, these corridors would include room for the optional High Level Waste (HLW) feed line. 4. Perform necessary site earthwork and grading outside of the PC sites. 1.3 DOCUMENT OVERVIEW This DRD will list the documents that will form the basis for design and construction of the roads and rail modifications and site development.

  11. Molecular Recognition of DNA Damage Sites by Apurinic/Apyrimidinic Endonucleases

    SciTech Connect

    Braun, W. A.

    2005-07-28

    The DNA repair/redox factor AP endonuclease 1 (APE1) is a multifunctional protein which is known to to be essential for DNA repair activity in human cells. Structural/functional analyses of the APE activity is thus been an important research field to assess cellular defense mechanisms against ionizing radiation.

  12. Site Analysis--Rudimentary Concept in Residential Design

    ERIC Educational Resources Information Center

    Nystrom, Dennis C.

    1969-01-01

    This article on site analysis is concerned with the external factors affecting the dwelling and surrounding area when planning a residential design. Schematic drawings as well as a list of important data to be considered when planning are included. (GR)

  13. 40 CFR 228.4 - Procedures for designation of sites.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... DUMPING CRITERIA FOR THE MANAGEMENT OF DISPOSAL SITES FOR OCEAN DUMPING § 228.4 Procedures for designation... permits. Areas where ocean dumping is permitted subject to the specific conditions of individual special... studies for the evaluation and potential selection of dumping sites will be conducted in accordance...

  14. Designing Search: Effective Search Interfaces for Academic Library Web Sites

    ERIC Educational Resources Information Center

    Teague-Rector, Susan; Ghaphery, Jimmy

    2008-01-01

    Academic libraries customize, support, and provide access to myriad information systems, each with complex graphical user interfaces. The number of possible information entry points on an academic library Web site is both daunting to the end-user and consistently challenging to library Web site designers. Faced with the challenges inherent in…

  15. Conserved structural chemistry for incision activity in structurally non-homologous apurinic/apyrimidinic endonuclease APE1 and endonuclease IV DNA repair enzymes.

    SciTech Connect

    Tsutakawa, Susan E.; Shin, David S.; Mol, Clifford D.; Izum, Tadahide; Arvai, Andrew S.; Mantha, Anil K.; Szczesny, Bartosz; Ivanov, Ivaylo N.; Hosfield, David J.; Maiti, Buddhadev; Pique, Mike E.; Frankel, Kenneth A.; Hitomi, Kenichi; Cunningham, Richard P.; Mitra, Sankar; Tainer, John A.

    2013-03-22

    Non-coding apurinic/apyrimidinic (AP) sites in DNA form spontaneously and as DNA base excision repair intermediates are the most common toxic and mutagenic in vivo DNA lesion. For repair, AP sites must be processed by 5' AP endonucleases in initial stages of base repair. Human APE1 and bacterial Nfo represent the two conserved 5' AP endonuclease families in the biosphere; they both recognize AP sites and incise the phosphodiester backbone 5' to the lesion, yet they lack similar structures and metal ion requirements. Here, we determined and analyzed crystal structures of a 2.4 ? resolution APE1-DNA product complex with Mg(2+) and a 0.92 Nfo with three metal ions. Structural and biochemical comparisons of these two evolutionarily distinct enzymes characterize key APE1 catalytic residues that are potentially functionally similar to Nfo active site components, as further tested and supported by computational analyses. We observe a magnesium-water cluster in the APE1 active site, with only Glu-96 forming the direct protein coordination to the Mg(2+). Despite differences in structure and metal requirements of APE1 and Nfo, comparison of their active site structures surprisingly reveals strong geometric conservation of the catalytic reaction, with APE1 catalytic side chains positioned analogously to Nfo metal positions, suggesting surprising functional equivalence between Nfo metal ions and APE1 residues. The finding that APE1 residues are positioned to substitute for Nfo metal ions is supported by the impact of mutations on activity. Collectively, the results illuminate the activities of residues, metal ions, and active site features for abasic site endonucleases.

  16. Directed site exploration for permeable reactive barrier design

    USGS Publications Warehouse

    Lee, J.; Graettinger, A.J.; Moylan, J.; Reeves, H.W.

    2009-01-01

    Permeable reactive barriers (PRBs) are being employed for in situ site remediation of groundwater that is typically flowing under natural gradients. Site characterization is of critical importance to the success of a PRB. A design-specific site exploration approach called quantitatively directed exploration (QDE) is presented. The QDE approach employs three spatially related matrices: (1) covariance of input parameters, (2) sensitivity of model outputs, and (3) covariance of model outputs to identify the most important location to explore based on a specific design. Sampling at the location that most reduces overall site uncertainty produces a higher probability of success of a particular design. The QDE approach is demonstrated on the Kansas City Plant, Kansas City, MO, a case study where a PRB was installed and failed. It is shown that additional quantitatively directed site exploration during the design phase could have prevented the remedial failure that was caused by missing a geologic body having high hydraulic conductivity at the south end of the barrier. The most contributing input parameter approach using head uncertainty clearly indicated where the next sampling should be made toward the high hydraulic conductivity zone. This case study demonstrates the need to include the specific design as well as site characterization uncertainty when choosing the sampling locations. ?? 2008 Elsevier B.V.

  17. Directed site exploration for permeable reactive barrier design.

    PubMed

    Lee, Jejung; Graettinger, Andrew J; Moylan, John; Reeves, Howard W

    2009-02-15

    Permeable reactive barriers (PRBs) are being employed for in situ site remediation of groundwater that is typically flowing under natural gradients. Site characterization is of critical importance to the success of a PRB. A design-specific site exploration approach called quantitatively directed exploration (QDE) is presented. The QDE approach employs three spatially related matrices: (1) covariance of input parameters, (2) sensitivity of model outputs, and (3) covariance of model outputs to identify the most important location to explore based on a specific design. Sampling at the location that most reduces overall site uncertainty produces a higher probability of success of a particular design. The QDE approach is demonstrated on the Kansas City Plant, Kansas City, MO, a case study where a PRB was installed and failed. It is shown that additional quantitatively directed site exploration during the design phase could have prevented the remedial failure that was caused by missing a geologic body having high hydraulic conductivity at the south end of the barrier. The most contributing input parameter approach using head uncertainty clearly indicated where the next sampling should be made toward the high hydraulic conductivity zone. This case study demonstrates the need to include the specific design as well as site characterization uncertainty when choosing the sampling locations. PMID:18573602

  18. Directed site exploration for permeable reactive barrier design.

    PubMed

    Lee, Jejung; Graettinger, Andrew J; Moylan, John; Reeves, Howard W

    2009-02-15

    Permeable reactive barriers (PRBs) are being employed for in situ site remediation of groundwater that is typically flowing under natural gradients. Site characterization is of critical importance to the success of a PRB. A design-specific site exploration approach called quantitatively directed exploration (QDE) is presented. The QDE approach employs three spatially related matrices: (1) covariance of input parameters, (2) sensitivity of model outputs, and (3) covariance of model outputs to identify the most important location to explore based on a specific design. Sampling at the location that most reduces overall site uncertainty produces a higher probability of success of a particular design. The QDE approach is demonstrated on the Kansas City Plant, Kansas City, MO, a case study where a PRB was installed and failed. It is shown that additional quantitatively directed site exploration during the design phase could have prevented the remedial failure that was caused by missing a geologic body having high hydraulic conductivity at the south end of the barrier. The most contributing input parameter approach using head uncertainty clearly indicated where the next sampling should be made toward the high hydraulic conductivity zone. This case study demonstrates the need to include the specific design as well as site characterization uncertainty when choosing the sampling locations.

  19. A design method for an intuitive web site

    SciTech Connect

    Quinniey, M.L.; Diegert, K.V.; Baca, B.G.; Forsythe, J.C.; Grose, E.

    1999-11-03

    The paper describes a methodology for designing a web site for human factor engineers that is applicable for designing a web site for a group of people. Many web pages on the World Wide Web are not organized in a format that allows a user to efficiently find information. Often the information and hypertext links on web pages are not organized into intuitive groups. Intuition implies that a person is able to use their knowledge of a paradigm to solve a problem. Intuitive groups are categories that allow web page users to find information by using their intuition or mental models of categories. In order to improve the human factors engineers efficiency for finding information on the World Wide Web, research was performed to develop a web site that serves as a tool for finding information effectively. The paper describes a methodology for designing a web site for a group of people who perform similar task in an organization.

  20. Umatilla Satellite and Release Sites Project : Final Conceptual Design Report.

    SciTech Connect

    Montgomery, James M.

    1992-03-01

    This report presents the results of site analysis for the Umatilla Satellite and Release Sites Project. The purpose of this project is to provide engineering services for the siting and conceptual design of satellite and release facilities for the Umatilla Basin hatchery program. The Umatilla Basin hatchery program consists of artificial production facilities for salmon and steelhead to enhance production in the Umatilla River as defined in the Umatilla master plan approved in 1989 by the Northwest Power Planning Council. Facilities identified in the master plan include adult salmon broodstock holding and spawning facilities, facilities for recovery, acclimation, and/or extended rearing of salmon juveniles, and development of river sites for release of hatchery salmon and steelhead. The historic and current distribution of fall chinook, summer chinook, and coho salmon and steelhead trout was summarized for the Umatilla River basin. Current and future production and release objectives were reviewed. Twenty seven sites were evaluated for the potential development of facilities. Engineering and environmental attributes of the sites were evaluated and compared to facility requirements for water and space. Site screening was conducted to identify the sites with the most potential for facility development. Alternative sites were selected for conceptual design of each facility type. A proposed program for adult holding facilities, final rearing/acclimation, and direct release facilities was developed.

  1. TWRS privatization Phase I site development design requirements document

    SciTech Connect

    Shord, A.L.

    1997-01-21

    The DOE-RL is pursuing a strategy of hiring private contractors for treatment of Hanford Site tank wastes. This strategy is called privatization and includes design, permitting,construction, operation, and deactivation of facilities for tank waste treatment. The TWRS Privatization Infrastructure Project consists of several sub- projects which will provide key services needed to support the privatization mission. This document identifies the design requirements for the site development sub-project, including construction, power, water, and road modifications. It will be used in development of the project`s conceptual design.

  2. Designing functional metalloproteins: from structural to catalytic metal sites.

    PubMed

    Zastrow, Melissa L; Pecoraro, Vincent L

    2013-09-01

    Metalloenzymes efficiently catalyze some of the most important and difficult reactions in nature. For many years, coordination chemists have effectively used small molecule models to understand these systems. More recently, protein design has been shown to be an effective approach for mimicking metal coordination environments. Since the first designed proteins were reported, much success has been seen for incorporating metal sites into proteins and attaining the desired coordination environment but until recently, this has been with a lack of significant catalytic activity. Now there are examples of designed metalloproteins that, although not yet reaching the activity of native enzymes, are considerably closer. In this review, we highlight work leading up to the design of a small metalloprotein containing two metal sites, one for structural stability (HgS3) and the other a separate catalytic zinc site to mimic carbonic anhydrase activity (ZnN3O). The first section will describe previous studies that allowed for a high affinity thiolate site that binds heavy metals in a way that stabilizes three-stranded coiled coils. The second section will examine ways of preparing histidine rich environments that lead to metal based hydrolytic catalysts. We will also discuss other recent examples of the design of structural metal sites and functional metalloenzymes. Our work demonstrates that attaining the proper first coordination geometry of a metal site can lead to a significant fraction of catalytic activity, apparently independent of the type of secondary structure of the surrounding protein environment. We are now in a position to begin to meet the challenge of building a metalloenzyme systematically from the bottom-up by engineering and analyzing interactions directly around the metal site and beyond.

  3. Diverse Small Molecule Inhibitors of Human Apurinic/Apyrimidinic Endonuclease APE1 Identified from a Screen of a Large Public Collection

    PubMed Central

    Dorjsuren, Dorjbal; Kim, Daemyung; Vyjayanti, Vaddadi N.; Maloney, David J.; Jadhav, Ajit; Wilson, David M.; Simeonov, Anton

    2012-01-01

    The major human apurinic/apyrimidinic endonuclease APE1 plays a pivotal role in the repair of base damage via participation in the DNA base excision repair (BER) pathway. Increased activity of APE1, often observed in tumor cells, is thought to contribute to resistance to various anticancer drugs, whereas down-regulation of APE1 sensitizes cells to DNA damaging agents. Thus, inhibiting APE1 repair endonuclease function in cancer cells is considered a promising strategy to overcome therapeutic agent resistance. Despite ongoing efforts, inhibitors of APE1 with adequate drug-like properties have yet to be discovered. Using a kinetic fluorescence assay, we conducted a fully-automated high-throughput screen (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR), as well as additional public collections, with each compound tested as a 7-concentration series in a 4 µL reaction volume. Actives identified from the screen were subjected to a panel of confirmatory and counterscreen tests. Several active molecules were identified that inhibited APE1 in two independent assay formats and exhibited potentiation of the genotoxic effect of methyl methanesulfonate with a concomitant increase in AP sites, a hallmark of intracellular APE1 inhibition; a number of these chemotypes could be good starting points for further medicinal chemistry optimization. To our knowledge, this represents the largest-scale HTS to identify inhibitors of APE1, and provides a key first step in the development of novel agents targeting BER for cancer treatment. PMID:23110144

  4. Effects of forespore-specific overexpression of apurinic/apyrimidinic endonuclease Nfo on the DNA-damage resistance properties of Bacillus subtilis spores.

    PubMed

    Barraza-Salas, Marcelo; Ibarra-Rodríguez, Juan R; Mellado, Silvia J; Salas-Pacheco, José M; Setlow, Peter; Pedraza-Reyes, Mario

    2010-01-01

    The effects of overexpression of the apurinic/apyrimidinic DNA endonuclease Nfo on wet and dry heat and UV-C (254 nm) resistance of Bacillus subtilis spores with or without alpha/beta-type small, acid-soluble spore proteins (SASP) were determined. Results revealed that overexpression of Nfo > or =50-fold in spores increased the wet heat resistance of exoA nfo B. subtilis spores (termed alpha(-)beta(-)) that lack most alpha/beta-type SASP, but had no effect on these spores' UV-C resistance. Nfo overexpression also increased these spores' dry heat resistance, and to levels slightly greater than that of wild-type spores. These results are consistent: (1) with wet and dry heat (but not UV-C) generating abasic sites in alpha(-)beta(-) spore DNA; (2) with dry heat generating some of these lesions in spores that retain alpha/beta-type SASP; and (3) indicate that Nfo can repair these abasic lesions following spore germination.

  5. The Effects of Modeled Microgravity on Nucleocytoplasmic Localization of Human Apurinic/Apyrimidinic

    NASA Technical Reports Server (NTRS)

    Gonda, Steve; Jackson, E.B.

    2004-01-01

    Exposure to space radiation and microgravity occurs to humans during space flight. In order to have accurate risk estimations, answering questions to whether increased DNA damage seen during space flight in modified by microgravity are important. Several studies have examined whether intercellular repair of radiation-induced DNA lesions are modified by microgravity. Results from these studies show no modification of the repair processes due to microgravity. However, it is known that in studies not involving radiation that microgravity interferes with normal development. Interestingly, there is no data that attempts to analyze the possible effects of microgravity on the trafficking of DNA repair proteins. In this study, we analyze the effects of modeled microgravity on nucleocytoplasmic shuttling of the human DNA repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1/Ref1) which is involved in base excision repair. We examined nuclear translocation of APE1 using enhanced green fluorescent protein (EGFP) fused to APE1 as a reporter. While APE1 under normal gravity showed normal nuclear localization, APE1 nuclear localization under modeled microgravity was decreased. These results suggest that nucleocytoplasmic translocation of APE1 is modified under modeled microgravity.

  6. 40 CFR 228.4 - Procedures for designation of sites.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    .... 228.4 Section 228.4 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) OCEAN DUMPING CRITERIA FOR THE MANAGEMENT OF DISPOSAL SITES FOR OCEAN DUMPING § 228.4 Procedures for designation... permits. Areas where ocean dumping is permitted subject to the specific conditions of individual...

  7. 40 CFR 228.4 - Procedures for designation of sites.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    .... 228.4 Section 228.4 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) OCEAN DUMPING CRITERIA FOR THE MANAGEMENT OF DISPOSAL SITES FOR OCEAN DUMPING § 228.4 Procedures for designation... permits. Areas where ocean dumping is permitted subject to the specific conditions of individual...

  8. 40 CFR 228.4 - Procedures for designation of sites.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    .... 228.4 Section 228.4 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) OCEAN DUMPING CRITERIA FOR THE MANAGEMENT OF DISPOSAL SITES FOR OCEAN DUMPING § 228.4 Procedures for designation... permits. Areas where ocean dumping is permitted subject to the specific conditions of individual...

  9. Apurinic/Apyrimidinic Endonucleases of Mycobacterium tuberculosis Protect against DNA Damage but Are Dispensable for the Growth of the Pathogen in Guinea Pigs

    PubMed Central

    Puri, Rupangi Verma; Reddy, P. Vineel; Tyagi, Anil K.

    2014-01-01

    In host cells, Mycobacterium tuberculosis encounters an array of reactive molecules capable of damaging its genome. Non-bulky DNA lesions are the most common damages produced on the exposure of the pathogen to reactive species and base excision repair (BER) pathway is involved in the repair of such damage. During BER, apurinic/apyrimidinic (AP) endonuclease enzymes repair the abasic sites that are generated after spontaneous DNA base loss or by the action of DNA glycosylases, which if left unrepaired lead to inhibition of replication and transcription. However, the role of AP endonucleases in imparting protection against DNA damage and in the growth and pathogenesis of M.tuberculosis has not yet been elucidated. To demonstrate the biological significance of these enzymes in M.tuberculosis, it would be desirable to disrupt the relevant genes and evaluate the resulting mutants for their ability to grow in the host and cause disease. In this study, we have generated M.tuberculosis mutants of the base excision repair (BER) system, disrupted in either one (MtbΔend or MtbΔxthA) or both the AP endonucleases (MtbΔendΔxthA). We demonstrate that these genes are crucial for bacteria to withstand alkylation and oxidative stress in vitro. In addition, the mutant disrupted in both the AP endonucleases (MtbΔendΔxthA) exhibited a significant reduction in its ability to survive inside human macrophages. However, infection of guinea pigs with either MtbΔend or MtbΔxthA or MtbΔendΔxthA resulted in the similar bacillary load and pathological damage in the organs as observed in the case of infection with wild-type M.tuberculosis. The implications of these observations are discussed. PMID:24800740

  10. Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation

    PubMed Central

    Onuoha, Shimobi C.; Ferrari, Mathieu; Sblattero, Daniele

    2015-01-01

    Objective Biologic drugs, such as the anti–tumor necrosis factor (anti‐TNF) antibody adalimumab, have represented a breakthrough in the treatment of rheumatoid arthritis. Yet, concerns remain over their lack of efficacy in a sizable proportion of patients and their potential for systemic side effects such as infection. Improved biologic prodrugs specifically targeted to the site of inflammation have the potential to alleviate current concerns surrounding biologic anticytokine therapies. The purpose of this study was to design, construct, and evaluate in vitro and ex vivo the targeting and antiinflammatory capacity of activatable bispecific antibodies. Methods Activatable dual variable domain (aDVD) antibodies were designed and constructed to target intercellular adhesion molecule 1 (ICAM‐1), which is up‐regulated at sites of inflammation, and anti‐TNF antibodies (adalimumab and infliximab). These bispecific molecules included an external arm that targets ICAM‐1 and an internal arm that comprises the therapeutic domain of an anti‐TNF antibody. Both arms were linked to matrix metalloproteinase (MMP)–cleavable linkers. The constructs were tested for their ability to bind and neutralize both in vitro and ex vivo targets. Results Intact aDVD constructs demonstrated significantly reduced binding and anti‐TNF activity in the prodrug formulation as compared to the parent antibodies. Human synovial fluid and physiologic concentrations of MMP enzyme were capable of cleaving the external domain of the antibody, revealing a fully active molecule. Activated antibodies retained the same binding and anti‐TNF inhibitory capacities as the parent molecules. Conclusion The design of a biologic prodrug with enhanced specificity for sites of inflammation (synovium) and reduced specificity for off‐target TNF is described. This construct has the potential to form a platform technology that is capable of enhancing the therapeutic index of drugs for the treatment of

  11. Remedial action plan and site design for stabilization of the inactive uranium mill tailings sites at Rifle, Colorado

    SciTech Connect

    Not Available

    1992-02-01

    This appendix assesses the present conditions and data gathered about the two inactive uranium mill tailings sites near Rifle, Colorado, and the designated disposal site six miles north of Rifle in the area of Estes Gulch. It consolidates available engineering, radiological, geotechnical, hydrological, meteorological, and other information pertinent to the design of the Remedial Action Plan (RAP). The data characterize conditions at the mill, tailings, and disposal site so that the Remedial Action Contractor (RAC) may complete final designs for the remedial actions.

  12. Design and implementation of the site and engineering properties database; Yucca Mountain Site Characterzation Project

    SciTech Connect

    Krebs-Jespersen, M.L.

    1992-02-01

    The Yucca Mountain Site Characterization Project (YMP) is conducting studies to determine whether the Yucca Mountain site in southern Nevada will meet regulatory criteria for a potential mined geologic disposal system for high-level radioactive waste. Data gathered as part of these studies must be compiled and tabulated in a controlled manner for use in design and performance analyses. An integrated data management system has been developed to facilitate this process; this system relies on YMP participants to share in the development of the database and to ensure the integrity of the data. The site and Engineering Properties Database (SEPDB) is unique in that, unlike most databases where one data set is stored for use by one defined user, the SEPDB stores different sets of data which must be structured so that a variety of users can be given access to the information. All individuals responsible for activities supporting the license application should, to the extent possible,work with the same data and the same assumptions. For this reason, it is important that these data sets are readily accessible, comprehensive, and current. The SEPDB contains scientific and engineering data for use in performance assessment and design activities. These data sets currently consist of geologic, hydrologic, and rock properties information from drill holes and field measurements. The users of the SEPDB include engineers and scientists from several government research laboratories (Lawrence Livermore National Laboratory, Los Alamos National Laboratory, and Sandia National Laboratories), the US Geological Survey, and several government contractors. This manuscript describes the detailed requirements, contents, design, and status of the SEPDB, the procedures for submitting data to and/or requesting data from the SEPDB, and a SEPDB data dictionary (Appendix A) for defining the present contents.

  13. Anticancer clinical utility of the apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1).

    PubMed

    Zhang, Ying; Wang, Jian

    2010-03-01

    Apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1), as a type of multifunctional protein, plays an essential role in the base excision repair (BER) pathway, which is responsible for the repair of DNA caused by oxidative and alkylation damage. As importantly, APE/Ref-1 also functions as a redox factor maintaining transcription factors in an active reduced state. APE/Ref-1 stimulates the DNA-binding activity of numerous transcription factors that are involved in cancer promotion and progression, such as AP-1 (Fos/Jun), NF-kappaB, HIF-1alpha, p53, and others. Based on the structures and functions of APE1/Ref-1, we will provide an overview of its activities and explore the budding clinical use of this protein as a target in cancer treatment, and propose that APE/Ref-1 has a great potential for application in clinical research.

  14. Fractionated Radiation Exposure of Rat Spinal Cords Leads to Latent Neuro-Inflammation in Brain, Cognitive Deficits, and Alterations in Apurinic Endonuclease 1

    SciTech Connect

    Suresh Kumar, M. A.; Peluso, Michael; Chaudhary, Pankaj; Dhawan, Jasbeer; Beheshti, Afshin; Manickam, Krishnan; Thapar, Upasna; Pena, Louis; Natarajan, Mohan; Hlatky, Lynn; Demple, Bruce; Naidu, Mamta

    2015-07-24

    Ionizing radiation causes degeneration of myelin, the insulating sheaths of neuronal axons, leading to neurological impairment. As radiation research on the central nervous system has predominantly focused on neurons, with few studies addressing the role of glial cells, we have focused our present research on identifying the latent effects of single/ fractionated -low dose of low/ high energy radiation on the role of base excision repair protein Apurinic Endonuclease-1, in the rat spinal cords oligodendrocyte progenitor cells ’ differentiation. Apurinic endonuclease-1 is predominantly upregulated in response to oxidative stress by low- energy radiation, and previous studies show significant induction of Apurinic Endonucle- ase-1 in neurons and astrocytes. Our studies show for the first time, that fractionation of pro- tons cause latent damage to spinal cord architecture while fractionation of HZE (28Si) induce increase in APE1 with single dose, which then decreased with fractionation. In conclusion, the oligoden- drocyte progenitor cells differentiation was skewed with increase in immature oligodendro- cytes and astrocytes, which likely cause the observed decrease in white matter, increased neuro-inflammation, together leading to the observed significant cognitive defects

  15. Fractionated Radiation Exposure of Rat Spinal Cords Leads to Latent Neuro-Inflammation in Brain, Cognitive Deficits, and Alterations in Apurinic Endonuclease 1

    DOE PAGESBeta

    Suresh Kumar, M. A.; Peluso, Michael; Chaudhary, Pankaj; Dhawan, Jasbeer; Beheshti, Afshin; Manickam, Krishnan; Thapar, Upasna; Pena, Louis; Natarajan, Mohan; Hlatky, Lynn; et al

    2015-07-24

    Ionizing radiation causes degeneration of myelin, the insulating sheaths of neuronal axons, leading to neurological impairment. As radiation research on the central nervous system has predominantly focused on neurons, with few studies addressing the role of glial cells, we have focused our present research on identifying the latent effects of single/ fractionated -low dose of low/ high energy radiation on the role of base excision repair protein Apurinic Endonuclease-1, in the rat spinal cords oligodendrocyte progenitor cells ’ differentiation. Apurinic endonuclease-1 is predominantly upregulated in response to oxidative stress by low- energy radiation, and previous studies show significant induction ofmore » Apurinic Endonucle- ase-1 in neurons and astrocytes. Our studies show for the first time, that fractionation of pro- tons cause latent damage to spinal cord architecture while fractionation of HZE (28Si) induce increase in APE1 with single dose, which then decreased with fractionation. In conclusion, the oligoden- drocyte progenitor cells differentiation was skewed with increase in immature oligodendro- cytes and astrocytes, which likely cause the observed decrease in white matter, increased neuro-inflammation, together leading to the observed significant cognitive defects« less

  16. Success of multiple endosseous dental implant designs to second-stage surgery across study sites.

    PubMed

    Morris, H F; Manz, M C; Tarolli, J H

    1997-12-01

    A multicenter clinical study of dental implants is being conducted by the Dental Implant Clinical Research Group to investigate the influence of implant design, application, and site on clinical performance and crestal bone. This article reports on the percentage of success up to implant uncovering for different implant designs and the distribution of failures across study sites. Data from 2,847 implants placed at 32 study sites were analyzed. Percentages of success up to implant uncovering were calculated for study implants overall, by implant design, by implant design within study strata, and according to individual study sites and quartile groupings of sites based on success. Comparisons were made, with chi-square and exact tests employed where appropriate. Differences were found between the different implant designs for the study overall, and between implant designs within the different study strata. Although some implant designs were found to have generally high success across study sites, some study sites designated as having surgeons with less experience tended to have higher failure levels, and one implant design failed at higher rates in a subset of study sites. The percentage and distribution of implant failures varied across study sites and by implant design. These differences appeared to be in part related to the level of experience of the surgeons. Further investigation should focus on identification of factors that contribute to higher success in implant placement with different implant designs.

  17. Designing a Marketing Course with Field Site Visits

    ERIC Educational Resources Information Center

    Van Doren, Doris; Corrigan, Hope Bober

    2008-01-01

    A key goal of including field site visits in marketing courses is to give business students increased interaction with industry professionals and community leaders. Site visits give students a concrete idea of how different marketing disciplines work in the business world. Business students gain greater insight into a career in marketing from this…

  18. Synthesis, Biological Evaluation and Structure-Activity Relationships of a Novel Class of Apurinic/Apyrimidinic Endonuclease 1 Inhibitors

    PubMed Central

    Rai, Ganesha; Vyjayanti, Vaddadi N.; Dorjsuren, Dorjbal; Simeonov, Anton; Jadhav, Ajit; Wilson, David M.; Maloney, David J.

    2012-01-01

    APE1 is an essential protein that operates in the base excision repair (BER) pathway and is responsible for ≥95% of the total apurinic/apyrimidinic (AP) endonuclease activity in human cells. BER is a major pathway that copes with DNA damage induced by several anti-cancer agents, including ionizing radiation and temozolomide. Overexpression of APE1 and enhanced AP endonuclease activity has been linked to increased resistance of tumor cells to treatment with monofunctional alkylators, implicating inhibition of APE1 as a valid strategy for cancer therapy. We report herein the results of a focused medicinal chemistry effort around a novel APE1 inhibitor, N-(3-(benzo[d]thiazol-2-yl)-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide (3). Compound 3 and related analogs exhibit single-digit µM activity against the purified APE1 enzyme, comparable activity in HeLa whole cell extract assays, and potentiate the cytotoxicity of the alkylating agents methylmethane sulfonate and temozolomide. Moreover, this class of compounds possesses a generally favorable in vitro ADME profile, along with good exposure levels in plasma and brain following intraperitoneal dosing (30 mg/kg body weight) in mice. PMID:22455312

  19. Functional analysis of tanshinone IIA that blocks the redox function of human apurinic/apyrimidinic endonuclease 1/redox factor-1

    PubMed Central

    Sui, Jiangdong; Li, Mengxia; Qian, Chengyuan; Wang, Shufeng; Cheng, Yi; Chen, Benjamin PC; Wang, Dong

    2014-01-01

    Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein possessing both DNA repair and redox regulatory activities. It has been shown that blocking redox function leads to genotoxic, antiangiogenic, cytostatic, and proapoptotic effects in cells. Therefore, the selective inhibitors against APE1’s redox function can be served as potential pharmaceutical candidates in cancer therapeutics. In the present study, we identified the biological specificity of the Chinese herbal compound tanshinone IIA (T2A) in blocking the redox function of APE1. Using dual polarization interferometry, the direct interaction between APE1 and T2A was observed with a KD value at subnanomolar level. In addition, we showed that T2A significantly compromised the growth of human cervical cancer and colon cancer cells. Furthermore, the growth-inhibitory or proapoptotic effect of T2A was diminished in APE1 knockdown or redox-deficient cells, suggesting that the cytostatic effect of T2A might be specifically through inhibiting the redox function of APE1. Finally, T2A pretreatment enhanced the cytotoxicity of ionizing radiation or other chemotherapeutic agents in human cervical cancer and colon cancer cell lines. The data presented herein suggest T2A as a promising bioactive inhibitor of APE1 redox activity. PMID:25395832

  20. Hanford Site waste tank farm facilities design reconstitution program plan

    SciTech Connect

    Vollert, F.R.

    1994-09-06

    Throughout the commercial nuclear industry the lack of design reconstitution programs prior to the mid 1980`s has resulted in inadequate documentation to support operating facilities configuration changes or safety evaluations. As a result, many utilities have completed or have ongoing design reconstitution programs and have discovered that without sufficient pre-planning their program can be potentially very expensive and may result in end-products inconsistent with the facility needs or expectations. A design reconstitution program plan is developed here for the Hanford waste tank farms facility as a consequence of the DOE Standard on operational configuration management. This design reconstitution plan provides for the recovery or regeneration of design requirements and basis, the compilation of Design Information Summaries, and a methodology to disposition items open for regeneration that were discovered during the development of Design Information Summaries. Implementation of this plan will culminate in an end-product of about 30 Design Information Summary documents. These documents will be developed to identify tank farms facility design requirements and design bases and thereby capture the technical baselines of the facility. This plan identifies the methodology necessary to systematically recover documents that are sources of design input information, and to evaluate and disposition open items or regeneration items discovered during the development of the Design Information Summaries or during the verification and validation processes. These development activities will be governed and implemented by three procedures and a guide that are to be developed as an outgrowth of this plan.

  1. Energy conserving site design case study: Shenandoah, Georgia. Final report

    SciTech Connect

    Not Available

    1980-01-01

    The case study examines the means by which energy conservation can be achieved at an aggregate community level by using proper planning and analytical techniques for a new town, Shenandoah, Georgia, located twenty-five miles southwest of Atlanta's Hartsfield International Airport. A potentially implementable energy conservation community plan is achieved by a study team examining the land use options, siting characteristics of each building type, alternate infrastructure plans, possible decentralized energy options, and central utility schemes to determine how community energy conservation can be achieved by use of pre-construction planning. The concept for the development of mixed land uses as a passively sited, energy conserving community is based on a plan (Level 1 Plan) that uses the natural site characteristics, maximizes on passive energy siting requirement, and allows flexibility for the changing needs of the developers. The Level 2 Plan is identical with Level 1 plan plus a series of decentraized systems that have been added to the residential units: the single-family detached, the apartments, and the townhouses. Level 3 Plan is similar to the Level 1 Plan except that higher density dwellings have been moved to areas adjacent to central site. The total energy savings for each plan relative to the conventional plan are indicated. (MCW)

  2. ARAC`s site workstation final design and deployment

    SciTech Connect

    Abriam, R.O.; Moore, R.M.

    1994-08-01

    The Atmospheric Release Advisory Capability (ARAC) Center located at Lawrence Livermore National Laboratory, provides real-time estimates of the environmental consequences of accidental releases of radioactivity or other hazardous materials into the atmosphere anywhere in the world. ARAC`s expertise includes integrating a suite of local, regional and global dispersion models into a highly automated system. Since 1979, on-site computers have provided the link between DOE and DOD facilities around the U.S. and the ARAC Center. Beginning in 1993, these facilities have been replacing their personal computers with UNIX workstations running ARAC`s Site Workstation Systems (SWS) software. The SWS consists of a collection of applications that help sites prepare for and respond to incidents involving an atmospheric release. The SWS can be used either as a real-time emergency-response tool or to make historical or hypothetical assessments of releases.

  3. DNA repair and redox activities and inhibitors of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1): a comparative analysis and their scope and limitations toward anticancer drug development.

    PubMed

    Kaur, Gagandeep; Cholia, Ravi P; Mantha, Anil K; Kumar, Raj

    2014-12-26

    The apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional enzyme involved in DNA repair and activation of transcription factors through its redox function. The evolutionarily conserved C- and N-termini are involved in these functions independently. It is also reported that the activity of APE1/Ref-1 abruptly increases several-fold in various human cancers. The control over the outcomes of these two functions is emerging as a new strategy to combine enhanced DNA damage and chemotherapy in order to tackle the major hurdle of increased cancer cell growth and proliferation. Studies have targeted these two domains individually for the design and development of inhibitors for APE1/Ref-1. Here, we have made, for the first time, an attempt at a comparative analysis of APE1/Ref-1 inhibitors that target both DNA repair and redox activities simultaneously. We further discuss their scope and limitations with respect to the development of potential anticancer agents.

  4. Restructuring Web Site Design: An Alternative to WebTeams.

    ERIC Educational Resources Information Center

    Davis, Marc; Boyer, Janice

    In July 1997, the University Library at the University of Nebraska at Omaha adopted a new structural model for Web site development--the publishing metaphor. Rather than relying on an individual expert (the Webmaster) or a WebTeam comprised of a few individuals, the model permits everyone in the organization, regardless of position or Web…

  5. Optimising Web Site Designs for People with Learning Disabilities

    ERIC Educational Resources Information Center

    Williams, Peter; Hennig, Christian

    2015-01-01

    Much relevant internet-mediated information is inaccessible to people with learning disabilities because of difficulties in navigating the web. This paper reports on the methods undertaken to determine how information can be optimally presented for this cohort. Qualitative work is outlined where attributes relating to site layout affecting…

  6. Basic repository environmental assessment design basis: Deaf Smith County site

    SciTech Connect

    Not Available

    1988-03-01

    This study examines the engineering factors and costs associated with the construction, operation, and decommissioning of a high-level nuclear waste repository in salt in the Palo Duro Basin in Deaf Smith County, Texas. The study assumes a repository capacity of 36,000 metric tons of heavy metal (MTHM) of unreprocessed spent fuel and 36,000 MTHM of commercial high-level reprocessing waste, along with 7,020 canisters of defense high-level reprocessing waste and associated quantities or remote- and contact-handled transuranic waste (TRU). With the exception of TRU, all the waste forms are placed in 300- to 1000-year-life carbon-steel waste packages in a collocated waste handling and packaging facility (WHPF), which is also described. The construction, operation, and decommissioning of the proposed repository is estimated to cost approximately $4.64 billion. Costs include those for the collocate WHPF, engineering, and contingency, but exclude waste form assembly and shipment to the site and waste package fabrication and shipment to the site. These costs reflect the relative average wage rates of the region, the relatively easy access to the site, and the relatively weak nature of the salt at this site. Construction would require an estimated 7 to 7.5 years. Engineering factors and costs are not strongly influenced by environmental considerations. 62 refs., 24 figs., 20 tabs.

  7. New "persona" concept helps site designers cater to target user segments' needs.

    PubMed

    2004-09-01

    Using the relatively new "persona" design concept, Web strategists create a set of archetypical user characters, each one representing one of their site's primary audiences. Then, as their site is constructed or upgraded, they champion the personas, arguing on their behalf and forcing the design team to take each audience's needs and wants into account.

  8. Campus Demonstration Sites for Sustainable Systems and Design: Five "Creation" Stories.

    ERIC Educational Resources Information Center

    Jack, Kathy; Ihara, Dan, Ed.

    This paper provides a summary of the development and management of five campus demonstration sites designed to create harmony with natural systems and meet current student needs without compromising the needs of future generations. Information for each campus includes an overview of the site, project origins, the proposal and design process, the…

  9. Residential site design and energy conservation. Part 1: General report

    NASA Astrophysics Data System (ADS)

    1981-01-01

    The energy costs that can be saved by a subdivision design format related to energy conservation that is reasonably acceptable in marketing and aesthetic terms were determined. Six subdivision layouts were designed to densities ranging from 6.5 to 13.6 units per gross acre (1058 to 2232 units) or 16.25 to 34 units per gross hectare. Hourly radiation temperature, and wind characteristics for a year constitute the local climate data base. Six house types (from detached to apartment units) and seventeen basic house designs (mostly picked at random) were used. The method for calculating the set heat load and an analysis of the results are presented. The study shows that by way of the selection of the more energy efficient traditional house designs, orientation of buildings to maximize solar transmission, and landscaping to reduce the effect of wind, there is a possible residential space heating energy saving of up to 20% for a low density housing development.

  10. Roadmap for Integrating Sustainable Design into Site-Level Operations

    SciTech Connect

    Peterson, Keith L.; Dorsey, Judy A.

    2000-04-19

    Sustainable Design recognizes that products and processes are interdependent with the environmental, economic, and social systems surrounding them and implements measures to prevent an unsustainable compromise to these systems.

  11. Nuclear depletion of apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) is an indicator of energy disruption in neurons.

    PubMed

    Singh, Shilpee; Englander, Ella W

    2012-11-01

    Apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) is a multifunctional protein critical for cellular survival. Its involvement in adaptive survival responses includes key roles in redox sensing, transcriptional regulation, and repair of DNA damage via the base excision repair (BER) pathway. Ape1 is abundant in most cell types and central in integrating the first BER step catalyzed by different DNA glycosylases. BER is the main process for removal of oxidative DNA lesions in postmitotic brain cells, and after ischemic brain injury preservation of Ape1 coincides with neuronal survival, while its loss has been associated with neuronal death. Here, we report that in cultured primary neurons, diminution of cellular ATP by either oligomycin or H(2)O(2) is accompanied by depletion of nuclear Ape1, while other BER proteins are unaffected and retain their nuclear localization under these conditions. Importantly, while H(2)O(2) induces γH2AX phosphorylation, indicative of chromatin rearrangements in response to DNA damage, oligomycin does not. Furthermore, despite comparable diminution of ATP content, H(2)O(2) and oligomycin differentially affect critical parameters of mitochondrial respiration that ultimately determine cellular ATP content. Taken together, our findings demonstrate that in neurons, nuclear compartmentalization of Ape1 depends on ATP and loss of nuclear Ape1 reflects disruption of neuronal energy homeostasis. Energy crisis is a hallmark of stroke and other ischemic/hypoxic brain injuries. In vivo studies have shown that Ape1 deficit precedes neuronal loss in injured brain regions. Thus, our findings bring to light the possibility that energy failure-induced Ape1 depletion triggers neuronal death in ischemic brain injuries.

  12. Apurinic/apyrimidinic endonuclease/redox factor-1 (APE1/Ref-1) redox function negatively regulates NRF2.

    PubMed

    Fishel, Melissa L; Wu, Xue; Devlin, Cecilia M; Logsdon, Derek P; Jiang, Yanlin; Luo, Meihua; He, Ying; Yu, Zhangsheng; Tong, Yan; Lipking, Kelsey P; Maitra, Anirban; Rajeshkumar, N V; Scandura, Glenda; Kelley, Mark R; Ivan, Mircea

    2015-01-30

    Apurinic/apyrimidinic endonuclease/redox factor-1 (APE1/Ref-1) (henceforth referred to as Ref-1) is a multifunctional protein that in addition to its base excision DNA repair activity exerts redox control of multiple transcription factors, including nuclear factor κ-light chain enhancer of activated B cells (NF-κB), STAT3, activator protein-1 (AP-1), hypoxia-inducible factor-1 (HIF-1), and tumor protein 53 (p53). In recent years, Ref-1 has emerged as a promising therapeutic target in cancer, particularly in pancreatic ductal carcinoma. Although a significant amount of research has centered on Ref-1, no wide-ranging approach had been performed on the effects of Ref-1 inhibition and transcription factor activity perturbation. Starting with a broader approach, we identified a previously unsuspected effect on the nuclear factor erythroid-related factor 2 (NRF2), a critical regulator of cellular defenses against oxidative stress. Based on genetic and small molecule inhibitor-based methodologies, we demonstrated that repression of Ref-1 potently activates NRF2 and its downstream targets in a dose-dependent fashion, and that the redox, rather than the DNA repair function of Ref-1 is critical for this effect. Intriguingly, our results also indicate that this pathway does not involve reactive oxygen species. The link between Ref-1 and NRF2 appears to be present in all cells tested in vitro, noncancerous and cancerous, including patient-derived tumor samples. In particular, we focused on understanding the implications of the novel interaction between these two pathways in primary pancreatic ductal adenocarcinoma tumor cells and provide the first evidence that this mechanism has implications for overcoming the resistance against experimental drugs targeting Ref-1 activity, with clear translational implications.

  13. Inhibitors of the apurinic/apyrimidinic endonuclease 1 (APE1)/nucleophosmin (NPM1) interaction that display anti-tumor properties.

    PubMed

    Poletto, Mattia; Malfatti, Matilde C; Dorjsuren, Dorjbal; Scognamiglio, Pasqualina L; Marasco, Daniela; Vascotto, Carlo; Jadhav, Ajit; Maloney, David J; Wilson, David M; Simeonov, Anton; Tell, Gianluca

    2016-05-01

    The apurinic/apyrimidinic endonuclease 1 (APE1) is a protein central to the base excision DNA repair pathway and operates in the modulation of gene expression through redox-dependent and independent mechanisms. Aberrant expression and localization of APE1 in tumors are recurrent hallmarks of aggressiveness and resistance to therapy. We identified and characterized the molecular association between APE1 and nucleophosmin (NPM1), a multifunctional protein involved in the preservation of genome stability and rRNA maturation. This protein-protein interaction modulates subcellular localization and endonuclease activity of APE1. Moreover, we reported a correlation between APE1 and NPM1 expression levels in ovarian cancer, with NPM1 overexpression being a marker of poor prognosis. These observations suggest that tumors that display an augmented APE1/NPM1 association may exhibit increased aggressiveness and resistance. Therefore, targeting the APE1/NPM1 interaction might represent an innovative strategy for the development of anticancer drugs, as tumor cells relying on higher levels of APE1 and NPM1 for proliferation and survival may be more sensitive than untransformed cells. We set up a chemiluminescence-based high-throughput screening assay in order to find small molecules able to interfere with the APE1/NPM1 interaction. This screening led to the identification of a set of bioactive compounds that impair the APE1/NPM1 association in living cells. Interestingly, some of these molecules display anti-proliferative activity and sensitize cells to therapeutically relevant genotoxins. Given the prognostic significance of APE1 and NPM1, these compounds might prove effective in the treatment of tumors that show abundant levels of both proteins, such as ovarian or hepatic carcinomas.

  14. Design and preparation of a nanoprobe for imaging inflammation sites.

    PubMed

    Yoshitomi, Toru; Nagasaki, Yukio

    2012-12-01

    To image inflammation sites, we developed a novel nanoparticle, hydroxylamine-containing nanoparticle (HANP), which emits an intense electron spin resonance (ESR)-signal triggered by enzymatic oxidation reaction and pH-sensitive self-disintegration. The nanoparticle was prepared from an amphiphilic block copolymer, poly(ethylene glycol)-b-poly[4-(2,2,6,6-tetramethylpiperidine-1-hydroxyl)aminomethylstyrene] (PEG-b-PMNT-H), which spontaneously forms a core-shell type polymeric micelle (particle diameter = ca. 50 nm) in aqueous media. Because the PMNT-H segment in the block copolymer possesses amino groups in each repeating unit, the particle can be disintegrated by protonation of the amino groups in an acidic pH environment such as inflammation sites, which is confined to the hydrophobic core of HANP. Mixing HANP with horseradish peroxidase (HRP)/H(2)O(2) mixture resulted in enzymatic oxidization of the hydroxylamines in the PEG-b-PMNT-H and converted the hydroxylamine to the stable nitroxide radical form in PEG-b-poly[4-(2,2,6,6-tetramethylpiperidine-1-oxyl)aminomethylstyrene] (PEG-b-PMNT), which shows an intense ESR signal. It is interesting to note that the ESR signal increased at a greater rate under acidic conditions (pH 5.6) than that under neutral conditions (pH 7.4), although the enzymatic activity of HRP under neutral conditions is known to be much higher than that under acidic conditions. This indicates that enzymatic oxidation reaction was accelerated by synchronizing the disintegration of HANP under acidic conditions. On the basis of these results, HANP can be used as a high-performance ESR probe for imaging of inflammation sites.

  15. The Role of Identity and Culture on Web Site Design

    ERIC Educational Resources Information Center

    Eugene, Wanda; Clark, Kevin

    2009-01-01

    Purpose: The purpose of this paper is to outline an instructional design approach for further development of an African ancestry learning center in order to enhance its educational utility. This is being done in an effort to use technology in transformative ways that extends the practices and opportunities for African Americans.…

  16. HYNOL PROCESS ENGINEERING: PROCESS CONFIGURATION, SITE PLAN, AND EQUIPMENT DESIGN

    EPA Science Inventory

    The report describes the design of the hydropyrolysis reactor system of the Hynol process. (NOTE: A bench scale methanol production facility is being constructed to demonstrate the technical feasibility of producing methanol from biomass using the Hynol process. The plant is bein...

  17. Site study plan for EDBH (Engineering Design Boreholes) seismic surveys, Deaf Smith County site, Texas: Revision 1

    SciTech Connect

    Hume, H.

    1987-12-01

    This site study plan describes seismic reflection surveys to run north-south and east-west across the Deaf Smith County site, and intersecting near the Engineering Design Boreholes (EDBH). Both conventional and shallow high-resolution surveys will be run. The field program has been designed to acquire subsurface geologic and stratigraphic data to address information/data needs resulting from Federal and State regulations and Repository program requirements. The data acquired by the conventional surveys will be common-depth- point, seismic reflection data optimized for reflection events that indicate geologic structure near the repository horizon. The data will also resolve the basement structure and shallow reflection events up to about the top of the evaporite sequence. Field acquisition includes a testing phase to check/select parameters and a production phase. The field data will be subjected immediately to conventional data processing and interpretation to determine if there are any anamolous structural for stratigraphic conditions that could affect the choice of the EDBH sites. After the EDBH's have been drilled and logged, including vertical seismic profiling, the data will be reprocessed and reinterpreted for detailed structural and stratigraphic information to guide shaft development. The shallow high-resulition seismic reflection lines will be run along the same alignments, but the lines will be shorter and limited to immediate vicinity of the EDBH sites. These lines are planned to detect faults or thick channel sands that may be present at the EDBH sites. 23 refs. , 7 figs., 5 tabs.

  18. 41 CFR 102-76.20 - What issues must Federal agencies consider in providing site planning and landscape design services?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... agencies consider in providing site planning and landscape design services? 102-76.20 Section 102-76.20... What issues must Federal agencies consider in providing site planning and landscape design services? In providing site planning and design services, Federal agencies must— (a) Make the site planning and...

  19. 41 CFR 102-76.20 - What issues must Federal agencies consider in providing site planning and landscape design services?

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... agencies consider in providing site planning and landscape design services? 102-76.20 Section 102-76.20... What issues must Federal agencies consider in providing site planning and landscape design services? In providing site planning and design services, Federal agencies must— (a) Make the site planning and...

  20. Rosetta and the Design of Ligand Binding Sites.

    PubMed

    Moretti, Rocco; Bender, Brian J; Allison, Brittany; Meiler, Jens

    2016-01-01

    Proteins that bind small molecules (ligands) can be used as biosensors, signal modulators, and sequestering agents. When naturally occurring proteins for a particular target ligand are not available, artificial proteins can be computationally designed. We present a protocol based on RosettaLigand to redesign an existing protein pocket to bind a target ligand. Starting with a protein structure and the structure of the ligand, Rosetta can optimize both the placement of the ligand in the pocket and the identity and conformation of the surrounding sidechains, yielding proteins that bind the target compound.

  1. Rosetta and the Design of Ligand Binding Sites.

    PubMed

    Moretti, Rocco; Bender, Brian J; Allison, Brittany; Meiler, Jens

    2016-01-01

    Proteins that bind small molecules (ligands) can be used as biosensors, signal modulators, and sequestering agents. When naturally occurring proteins for a particular target ligand are not available, artificial proteins can be computationally designed. We present a protocol based on RosettaLigand to redesign an existing protein pocket to bind a target ligand. Starting with a protein structure and the structure of the ligand, Rosetta can optimize both the placement of the ligand in the pocket and the identity and conformation of the surrounding sidechains, yielding proteins that bind the target compound. PMID:27094285

  2. Remedial action plan and site design for stabilization of the inactive uranium mill tailings site at Tuba City, Arizona

    SciTech Connect

    Not Available

    1989-08-01

    This Remedial Action Plan (RAP) has been developed to serve a threefold purpose. It presents the series of activities which are proposed by the US Department of Energy (DOE) to accomplish long-term stabilization and control of radioactive materials at the inactive uranium processing site near Tuba City, Arizona. It provides a characterization of the present conditions of the site. It also serves to document the concurrence of the Navajo Nation, the Hopi Tribe, US Bureau of Indian Affairs (BIA), and the US Nuclear Regulatory Commission (NRC) in the remedial action. This agreement, upon execution by DOE, the Navajo Nation, and the Hopi Tribe, and concurrence by NRC, becomes Appendix B of the Cooperative Agreement. Following the introduction, contents are as follows: Section 2.0 presents the EPA standards, including a discussion of their objectives. Section 3.0 summarizes the present site characteristics and provides a definition of site-specific problems. Section 4.0 is the site design for the proposed action. Section 5.0 summarizes the plan for ensuring environmental, health, and safety protection for the surrounding community and the on-site workers. Section 6.0 presents a detailed listing of the responsibilities of the project participants. Section 7.0 describes the features of the long-term surveillance and maintenance plan. Section 8.0 presents the quality assurance aspects of the project. Section 9.0 documents the ongoing activities to keep the public informed and participating in the project.

  3. Synthesis, thermal stability and reactivity towards 9-aminoellipticine of double-stranded oligonucleotides containing a true abasic site.

    PubMed Central

    Bertrand, J R; Vasseur, J J; Rayner, B; Imbach, J L; Paoletti, J; Paoletti, C; Malvy, C

    1989-01-01

    A 13 mers abasic oligonucleotide was synthetized. It was therefore possible to compare thermal stability and reactivity of duplex oligonucleotides either with an apurinic/apyrimidinic site or without any lesion. An important decrease in the melting temperature appeared for duplexes with an abasic site. The chemical reaction of these modified oligonucleotides with the intercalating agent 9-aminoellipticine was studied by gel electrophoresis and by fluorescence. The formation of a Schiff base between 9-aminoellipticine and abasic sites was rapid and complete with duplexes at 11 degrees C. Schiff base related fluorescence and beta-elimination cleavage were more important with the apyrimidinic sites than with the apurinic ones. When compared to previous results obtained with the model d(TprpT) some unexpected behaviours appeared with longer and duplex oligonucleotides. For instance only partial beta-elimination cleavage was observed. It is likely that stacking parameters in the double helix play a great role in the studied reaction. Images PMID:2602153

  4. Title I conceptual design for Pit 6 landfill closure at Lawrence Livermore National Laboratory Site 300

    SciTech Connect

    MacDonnell, B.A.; Obenauf, K.S.

    1996-08-01

    The objective of this design project is to evaluate and prepare design and construction documents for a closure cover cap for the Pit 6 Landfill located at Lawrence Livermore National Laboratory Site 300. This submittal constitutes the Title I Design (Conceptual Design) for the closure cover of the Pit 6 Landfill. A Title I Design is generally 30 percent of the design effort. Title H Design takes the design to 100 percent complete. Comments and edits to this Title I Design will be addressed in the Title II design submittal. Contents of this report are as follows: project background; design issues and engineering approach; design drawings; calculation packages; construction specifications outline; and construction quality assurance plan outline.

  5. NGA-West 2 GMPE average site coefficients for use in earthquake-resistant design

    USGS Publications Warehouse

    Borcherdt, Roger D.

    2015-01-01

    Site coefficients corresponding to those in tables 11.4–1 and 11.4–2 of Minimum Design Loads for Buildings and Other Structures published by the American Society of Civil Engineers (Standard ASCE/SEI 7-10) are derived from four of the Next Generation Attenuation West2 (NGA-W2) Ground-Motion Prediction Equations (GMPEs). The resulting coefficients are compared with those derived by other researchers and those derived from the NGA-West1 database. The derivation of the NGA-W2 average site coefficients provides a simple procedure to update site coefficients with each update in the Maximum Considered Earthquake Response MCER maps. The simple procedure yields average site coefficients consistent with those derived for site-specific design purposes. The NGA-W2 GMPEs provide simple scale factors to reduce conservatism in current simplified design procedures.

  6. Comment and response document for the final remedial action plan and site design for stabilization of the inactive uranium mill tailings sites at Slick Rock, Colorado. Revision 2

    SciTech Connect

    1996-05-01

    This document for the final remedial action plan and site design has been prepared for US Department of Energy Environmental Restoration Division as part of the Uranium Mill Tailings Remedial Action plan. Comments and responses are included for the site design for stabilization of the inactive uranium mill tailings sites at Slick Rock, Colorado.

  7. Fracture analysis and rock quality designation estimation for the Yucca Mountain Site Characterization Project; Yucca Mountain Site Characterization Project

    SciTech Connect

    Lin, M.; Hardy, M.P.; Bauer, S.J.

    1993-02-01

    Within the Yucca Mountain Site Characterization Project, the design of drifts and ramps and evaluation of the impacts of thermomechanical loading of the host rock requires definition of the rock mass mechanical properties. Ramps and exploratory drifts will intersect both welded and nonwelded tuffs with varying abundance of fractures. The rock mass mechanical properties are dependent on the intact rock properties and the fracture joint characteristics. An understanding of the effects of fractures on the mechanical properties of the rock mass begins with a detailed description of the fracture spatial location and abundance, and includes a description of their physical characteristics. This report presents a description of the abundance, orientation, and physical characteristics of fractures and the Rock Quality Designation in the thermomechanical stratigraphic units at the Yucca Mountain site. Data was reviewed from existing sources and used to develop descriptions for each unit. The product of this report is a data set of the best available information on the fracture characteristics.

  8. Proteus and the Design of Ligand Binding Sites.

    PubMed

    Polydorides, Savvas; Michael, Eleni; Mignon, David; Druart, Karen; Archontis, Georgios; Simonson, Thomas

    2016-01-01

    This chapter describes the organization and use of Proteus, a multitool computational suite for the optimization of protein and ligand conformations and sequences, and the calculation of pK α shifts and relative binding affinities. The software offers the use of several molecular mechanics force fields and solvent models, including two generalized Born variants, and a large range of scoring functions, which can combine protein stability, ligand affinity, and ligand specificity terms, for positive and negative design. We present in detail the steps for structure preparation, system setup, construction of the interaction energy matrix, protein sequence and structure optimizations, pK α calculations, and ligand titration calculations. We discuss illustrative examples, including the chemical/structural optimization of a complex between the MHC class II protein HLA-DQ8 and the vinculin epitope, and the chemical optimization of the compstatin analog Ac-Val4Trp/His9Ala, which regulates the function of protein C3 of the complement system. PMID:27094287

  9. Impact of Binding Site Comparisons on Medicinal Chemistry and Rational Molecular Design.

    PubMed

    Ehrt, Christiane; Brinkjost, Tobias; Koch, Oliver

    2016-05-12

    Modern rational drug design not only deals with the search for ligands binding to interesting and promising validated targets but also aims to identify the function and ligands of yet uncharacterized proteins having impact on different diseases. Additionally, it contributes to the design of inhibitors with distinct selectivity patterns and the prediction of possible off-target effects. The identification of similarities between binding sites of various proteins is a useful approach to cope with those challenges. The main scope of this perspective is to describe applications of different protein binding site comparison approaches to outline their applicability and impact on molecular design. The article deals with various substantial application domains and provides some outstanding examples to show how various binding site comparison methods can be applied to promote in silico drug design workflows. In addition, we will also briefly introduce the fundamental principles of different protein binding site comparison methods.

  10. Facilitating Participation: From the EML Web Site to the Learning Network for Learning Design

    ERIC Educational Resources Information Center

    Hummel, Hans G. K.; Tattersall, Colin; Burgos, Daniel; Brouns, Francis; Kurvers, Hub; Koper, Rob

    2005-01-01

    This article investigates conditions for increasing active participation in on-line communities. As a case study, we use three generations of facilities designed to promote learning in the area of Educational Modelling Languages. Following a description of early experience with a conventional web site and with a community site offering facilities…

  11. The Path to Graduation: A Model Interactive Web Site Design Supporting Doctoral Students

    ERIC Educational Resources Information Center

    Simmons-Johnson, Nicole

    2012-01-01

    Objective. This 2-phase mixed method study assessed 2nd-year doctoral students' and dissertation students' perceptions of the current Graduate School of Education dissertation support Web site, with implications for designing a model dissertation support Web site. Methods. Phase 1 collected quantitative and qualitative data through an…

  12. The Role of Virtual Reference in Library Web Site Design: A Qualitative Source for Usage Data

    ERIC Educational Resources Information Center

    Powers, Amanda Clay; Shedd, Julie; Hill, Clay

    2011-01-01

    Gathering qualitative information about usage behavior of library Web sites is a time-consuming process requiring the active participation of patron communities. Libraries that collect virtual reference transcripts, however, hold valuable data regarding how the library Web site is used that could benefit Web designers. An analysis of virtual…

  13. A Checklist for Designing and Evaluating Physical Education Program Web Sites

    ERIC Educational Resources Information Center

    Tucker, Michael; Hill, Grant

    2009-01-01

    Creating a physical education department web site is an excellent way to promote a positive image of the program, because students and parents are able to find important information and improve the lines of communication. A well-designed physical education web site can even encourage students to increase their physical activity levels. Improved…

  14. Design Insights and Inspiration from the Tate: What Museum Web Sites Can Offer Us

    ERIC Educational Resources Information Center

    Riley-Huff, Debra A.

    2009-01-01

    There are many similarities between museums and academic libraries as public service institutions. This article is an examination of museum Web site practices and concepts that might also be transferable to academic library Web sites. It explores the digital manifestations of design and information presentation, user engagement, interactivity, and…

  15. Designing a Web Site for One Imaginary Persona that Reflect the Needs of Many

    ERIC Educational Resources Information Center

    Cunningham, Heather

    2005-01-01

    Does designing a large academic library Web site for an imaginary person seem a sensible thing to do? As a reference librarian and member of the Web team of the Gerstein Science Information Centre (Gerstein Library), that is exactly what this author set out to do in May 2005. She proposed that the best way to ensure that the Web site meets the…

  16. 10 CFR 61.51 - Disposal site design for land disposal.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 2 2012-01-01 2012-01-01 false Disposal site design for land disposal. 61.51 Section 61.51 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSING REQUIREMENTS FOR LAND DISPOSAL OF... result in erosion that will require ongoing active maintenance in the future. (6) The disposal site...

  17. Prognostic Significance of Human Apurinic/Apyrimidinic Endonuclease (APE/Ref-1) Expression in Rectal Cancer Treated With Preoperative Radiochemotherapy

    SciTech Connect

    Kim, Jun-Sang; Kim, Jin-Man; Liang, Zhe Long; Jang, Ji Young; Kim, Sup; Huh, Gil Ja; Kim, Ki-Hwan; Cho, Moon-June

    2012-01-01

    Purpose: Human apurinic endonuclease/redox factor 1 (APE/Ref-1) mediates repair of radiation-induced DNA lesions and regulates transcription via redox-based activation. We investigated the predictive and prognostic significance of APE/Ref-1 expression in pretreatment biopsy specimens in locally advanced rectal cancer (LARC) (cT3-T4 or N+). Methods and Materials: APE/Ref-1 expression was analyzed by immunohistochemistry in pretreatment biopsy specimens obtained from 83 patients with LARC. Patients received preoperative radiotherapy of 50.4 Gy in 28 fractions, combined with oral capecitabine and leucovorin chemotherapy, followed by curative surgery. The prognostic significance of various clinicopathologic characteristics, including APE/Ref-1 protein expression, was evaluated. Results: APE/Ref-1 was expressed in 97% of patient samples. Exclusive APE/Ref-1 nuclear staining was observed in 49 of 83 samples (59%), and mixed nuclear and cytoplasmic staining was observed in 31 samples (37%). APE/Ref-1 nuclear expression levels were low in 49 patients (59%) and high in 34 patients (41%). The level of APE/Ref-1 nuclear expression was not a prognostic factor for overall and disease-free survival. Cytoplasmic expression of APE/Ref-1 was a borderline-significant predictive factor for pathologic tumor response (p = 0.08) and a significant prognostic factor for disease-free survival, as shown by univariate analysis (p = 0.037). Multivariate analysis confirmed that cytoplasmic localization of APE/Ref-1 is a significant predictor of disease-free survival (hazard ratio, 0.45; p = 0.046). Conclusions: APE/Ref-1 was expressed in a majority of pretreatment biopsy specimens from patients with LARC. The level of APE/Ref-1 nuclear expression was not a significant predictive and prognostic factor; however, cytoplasmic localization of the protein was negatively associated with disease-free survival. These results indicate that cytoplasmic expression of APE/Ref-1 represents an adverse

  18. Comments and responses on the Remedial Action Plan and site design for stabilization of the Inactive Uranium Mill Tailings Site, Grand Junction, Colorado. Revision 1

    SciTech Connect

    1994-01-01

    This report contains information concerning public comments and responses on the remedial action plan and site design for stabilization of the inactive uranium mill tailings site in Grand Junction, Colorado.

  19. A usability evaluation exploring the design of American Nurses Association state web sites.

    PubMed

    Alexander, Gregory L; Wakefield, Bonnie J; Anbari, Allison B; Lyons, Vanessa; Prentice, Donna; Shepherd, Marilyn; Strecker, E Bradley; Weston, Marla J

    2014-08-01

    National leaders are calling for opportunities to facilitate the Future of Nursing. Opportunities can be encouraged through state nurses association Web sites, which are part of the American Nurses Association, that are well designed, with appropriate content, and in a language professional nurses understand. The American Nurses Association and constituent state nurses associations provide information about nursing practice, ethics, credentialing, and health on Web sites. We conducted usability evaluations to determine compliance with heuristic and ethical principles for Web site design. We purposefully sampled 27 nursing association Web sites and used 68 heuristic and ethical criteria to perform systematic usability assessments of nurse association Web sites. Web site analysis included seven double experts who were all RNs trained in usability analysis. The extent to which heuristic and ethical criteria were met ranged widely from one state that met 0% of the criteria for "help and documentation" to states that met greater than 92% of criteria for "visibility of system status" and "aesthetic and minimalist design." Suggested improvements are simple yet make an impact on a first-time visitor's impression of the Web site. For example, adding internal navigation and tracking features and providing more details about the application process through help and frequently asked question documentation would facilitate better use. Improved usability will improve effectiveness, efficiency, and consumer satisfaction with these Web sites.

  20. Remedial action plan and site design for stabilization of the inactive uranium mill tailings sites at Rifle, Colorado. Volume 2, Appendices D and E: Final report

    SciTech Connect

    Not Available

    1992-02-01

    This appendix assesses the present conditions and data gathered about the two inactive uranium mill tailings sites near Rifle, Colorado, and the designated disposal site six miles north of Rifle in the area of Estes Gulch. It consolidates available engineering, radiological, geotechnical, hydrological, meteorological, and other information pertinent to the design of the Remedial Action Plan (RAP). The data characterize conditions at the mill, tailings, and disposal site so that the Remedial Action Contractor (RAC) may complete final designs for the remedial actions.

  1. Site selection and its influence on the design of a lunar-based telescope

    NASA Astrophysics Data System (ADS)

    McCarter, James W.

    1993-09-01

    Parameter studies related to site selection for the Lunar Ultraviolet Telescope Experiment (LUTE) are presented. Sky coverage is determined for various telescope fields-of-view and site locations. Sunlight and earthshine interference on UV measurements necessitates a light shade whose shape, size, and weight is site dependent and which is constrained by volume and weight limits of the delivery launch vehicle. Operating times free from sunlight or earthshine interference were determined for a solar powered LUTE and an RTG powered LUTE. An RTG allows operation during the lunar night resulting in increased operation time. The design of the focal plane sensor depends on site latitude for a zenith-pointing LUTE or on viewing declination and the focal plane sensor requires precise alignment to properly record the curved tracks of the star images. Results indicate that the design of a lunar-based telescope is significantly influenced by the selection of the lunar site from which it will operate.

  2. 75 FR 19311 - Ocean Dumping; Guam Ocean Dredged Material Disposal Site Designation

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-14

    ... for formal designation through rulemaking published in the Federal Register (FR). Formal designation..., wetland creation, habitat restoration, landfill daily cover, and recycling into commercial products such... at the site--no dumping of toxic materials or industrial or municipal waste would be allowed....

  3. Interfacing Media: User-Centered Design for Media-Rich Web Sites.

    ERIC Educational Resources Information Center

    Horton, Sarah

    2000-01-01

    Discusses multimedia Web site design that may include images, animations, audio, and video. Highlights include interfaces that stress user-centered design; using only relevant media; placing high-demand content on secondary pages and keeping the home page simpler; providing information about the media; considering users with disabilities; and user…

  4. I've Been Framed! Designing a Library Web Site Within a Government Frame

    ERIC Educational Resources Information Center

    Houghton, Sarah

    2005-01-01

    Often, because of political reasons, a library's site must be designed within the frame of another organization's. In this article, the author, the e-services librarian for the Marin County Free Library in San Rafael, California, details her experience of designing a library website within the frame--and within the rules and limitations--of the…

  5. 10 CFR 433.6 - Sustainable principles for siting, design and construction. [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 3 2010-01-01 2010-01-01 false Sustainable principles for siting, design and construction. 433.6 Section 433.6 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY EFFICIENCY STANDARDS FOR THE DESIGN AND CONSTRUCTION OF NEW FEDERAL COMMERCIAL AND MULTI-FAMILY HIGH-RISE RESIDENTIAL...

  6. 10 CFR 433.6 - Sustainable principles for siting, design and construction. [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 3 2011-01-01 2011-01-01 false Sustainable principles for siting, design and construction. 433.6 Section 433.6 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY EFFICIENCY STANDARDS FOR THE DESIGN AND CONSTRUCTION OF NEW FEDERAL COMMERCIAL AND MULTI-FAMILY HIGH-RISE RESIDENTIAL...

  7. National Ignition Facility subsystem design requirements NIF site improvements SSDR 1.2.1

    SciTech Connect

    Kempel, P.; Hands, J.

    1996-08-19

    This Subsystem Design Requirements (SSDR) document establishes the performance, design, and verification requirements associated with the NIF Project Site at Lawrence Livermore National Laboratory (LLNL) at Livermore, California. It identifies generic design conditions for all NIF Project facilities, including siting requirements associated with natural phenomena, and contains specific requirements for furnishing site-related infrastructure utilities and services to the NIF Project conventional facilities and experimental hardware systems. Three candidate sites were identified as potential locations for the NIF Project. However, LLNL has been identified by DOE as the preferred site because of closely related laser experimentation underway at LLNL, the ability to use existing interrelated infrastructure, and other reasons. Selection of a site other than LLNL will entail the acquisition of site improvements and infrastructure additional to those described in this document. This SSDR addresses only the improvements associated with the NIF Project site located at LLNL, including new work and relocation or demolition of existing facilities that interfere with the construction of new facilities. If the Record of Decision for the PEIS on Stockpile Stewardship and Management were to select another site, this SSDR would be revised to reflect the characteristics of the selected site. Other facilities and infrastructure needed to support operation of the NIF, such as those listed below, are existing and available at the LLNL site, and are not included in this SSDR. Office Building. Target Receiving and Inspection. General Assembly Building. Electro- Mechanical Shop. Warehousing and General Storage. Shipping and Receiving. General Stores. Medical Facilities. Cafeteria services. Service Station and Garage. Fire Station. Security and Badging Services.

  8. Study of seismic design bases and site conditions for nuclear power plants

    SciTech Connect

    Not Available

    1980-04-01

    This report presents the results of an investigation of four topics pertinent to the seismic design of nuclear power plants: Design accelerations by regions of the continental United States; review and compilation of design-basis seismic levels and soil conditions for existing nuclear power plants; regional distribution of shear wave velocity of foundation materials at nuclear power plant sites; and technical review of surface-founded seismic analysis versus embedded approaches.

  9. 41 CFR 102-76.20 - What issues must Federal agencies consider in providing site planning and landscape design services?

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... agencies consider in providing site planning and landscape design services? 102-76.20 Section 102-76.20...) FEDERAL MANAGEMENT REGULATION REAL PROPERTY 76-DESIGN AND CONSTRUCTION Design and Construction § 102-76.20 What issues must Federal agencies consider in providing site planning and landscape design services?...

  10. 41 CFR 102-76.20 - What issues must Federal agencies consider in providing site planning and landscape design services?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... agencies consider in providing site planning and landscape design services? 102-76.20 Section 102-76.20...) FEDERAL MANAGEMENT REGULATION REAL PROPERTY 76-DESIGN AND CONSTRUCTION Design and Construction § 102-76.20 What issues must Federal agencies consider in providing site planning and landscape design services?...

  11. 41 CFR 102-76.20 - What issues must Federal agencies consider in providing site planning and landscape design services?

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... agencies consider in providing site planning and landscape design services? 102-76.20 Section 102-76.20...) FEDERAL MANAGEMENT REGULATION REAL PROPERTY 76-DESIGN AND CONSTRUCTION Design and Construction § 102-76.20 What issues must Federal agencies consider in providing site planning and landscape design services?...

  12. Remedial action plan and site design for stabilization of the inactive Uranium Mill Tailings Site at Lowman, Idaho

    SciTech Connect

    Not Available

    1991-09-01

    The DOE proposes to achieve compliance with the proposed EPA groundwater protection standards (Subparts A and B of 40 CFR 192) by meeting the EPA maximum concentration limits (MCLs) or background concentrations for designated hazardous constituents in groundwater in the uppermost aquifer (alluvium/weathered granodiorite) at the point of compliance (POC) at the Lowman disposal site near Lowman, Idaho. The proposed remedial action in conjunction with existing hydrogeological conditions at the Lowman site will ensure sufficient protection of human health and the environment. The DOE has concluded that the EPA groundwater protection standards will be met at the POC because, with the exception of antimony, none of the hazardous constituents that exceed laboratory method detection limits within the radioactive sand pore fluids were above the proposed concentration limits. The DOE has demonstrated that antimony will meet the proposed concentration limits at the POC through attenuation in subsoils beneath the disposal cell and by dilution in groundwater underflow. The Lowman processing site is in compliance with Subpart B of 40 CFR 192 because statistical analyses of groundwater samples indicate no groundwater contamination.

  13. Drift design methodology and preliminary application for the Yucca Mountain Site Characterization Project; Yucca Mountain Site Characterization Project

    SciTech Connect

    Hardy, M.P.; Bauer, S.J.

    1991-12-01

    Excavation stability in an underground nuclear waste repository is required during construction, emplacement, retrieval (if required), and closure phases to ensure worker health and safety, and to prevent development of potential pathways for radionuclide migration in the post-closure period. Stable excavations are developed by appropriate excavation procedures, design of the room shape, design and installation of rock support reinforcement systems, and implementation of appropriate monitoring and maintenance programs. In addition to the loads imposed by the in situ stress field, the repository drifts will be impacted by thermal loads developed after waste emplacement and, periodically, by seismic loads from naturally occurring earthquakes and underground nuclear events. A priori evaluation of stability is required for design of the ground support system, to confirm that the thermal loads are reasonable, and to support the license application process. In this report, a design methodology for assessing drift stability is presented. This is based on site conditions, together with empirical and analytical methods. Analytical numerical methods are emphasized at this time because empirical data are unavailable for excavations in welded tuff either at elevated temperatures or under seismic loads. The analytical methodology incorporates analysis of rock masses that are systematically jointed, randomly jointed, and sparsely jointed. In situ thermal and seismic loads are considered. Methods of evaluating the analytical results and estimating ground support requirements for all the full range of expected ground conditions are outlines. The results of a preliminary application of the methodology using the limited available data are presented. 26 figs., 55 tabs.

  14. Aerosol measurements at the Southern Great Plains Site: Design and surface installation

    SciTech Connect

    Leifer, R.; Knuth, R.H.; Guggenheim, S.F.; Albert, B.

    1996-04-01

    To impropve the predictive capabilities of the Atmospheric Radiation Measurements (ARM) program radiation models, measurements of awserosol size distributions, condensation particle concentrations, aerosol scattering coefficients at a number of wavelenghts, and the aerosol absorption coefficients are needed at the Southern Great Plains (SGP) site. Alos, continuous measurements of ozone concnetrations are needed for model validation. The environmental Measuremenr Laboratory (EMK) has the responsibility to establish the surface aerosol measurements program at the SGP site. EML has designed a special sampling manifold.

  15. Are Biophilic-Designed Site Office Buildings Linked to Health Benefits and High Performing Occupants?

    PubMed Central

    Gray, Tonia; Birrell, Carol

    2014-01-01

    This paper discusses the first phase of a longitudinal study underway in Australia to ascertain the broad health benefits of specific types of biophilic design for workers in a building site office. A bespoke site design was formulated to include open plan workspace, natural lighting, ventilation, significant plants, prospect and views, recycled materials and use of non-synthetic materials. Initial data in the first three months was gathered from a series of demographic questions and from interviews and observations of site workers. Preliminary data indicates a strong positive effect from incorporating aspects of biophilic design to boost productivity, ameliorate stress, enhance well-being, foster a collaborative work environment and promote workplace satisfaction, thus contributing towards a high performance workspace. The longitudinal study spanning over two years will track human-plant interactions in a biophilic influenced space, whilst also assessing the concomitant cognitive, social, psychological and physical health benefits for workers. PMID:25431874

  16. Are biophilic-designed site office buildings linked to health benefits and high performing occupants?

    PubMed

    Gray, Tonia; Birrell, Carol

    2014-12-01

    This paper discusses the first phase of a longitudinal study underway in Australia to ascertain the broad health benefits of specific types of biophilic design for workers in a building site office. A bespoke site design was formulated to include open plan workspace, natural lighting, ventilation, significant plants, prospect and views, recycled materials and use of non-synthetic materials. Initial data in the first three months was gathered from a series of demographic questions and from interviews and observations of site workers. Preliminary data indicates a strong positive effect from incorporating aspects of biophilic design to boost productivity, ameliorate stress, enhance well-being, foster a collaborative work environment and promote workplace satisfaction, thus contributing towards a high performance workspace. The longitudinal study spanning over two years will track human-plant interactions in a biophilic influenced space, whilst also assessing the concomitant cognitive, social, psychological and physical health benefits for workers.

  17. System design package for solar heating and cooling site data acquisition subsystem

    NASA Technical Reports Server (NTRS)

    1978-01-01

    The Site Data Acquisition Subsystem (SDAS) designed to collect data from sensors located on residential or commercial buildings using a solar heating and/or cooling system is described. It takes the data obtained from sensors located on the solar system, processes the data into suitable format, stores the data for a period of time, and provides the capability for either telephone retrieval by the central data processing system or manual retrieval of the data for transfer to a central site. The SDAS is also designed so that it will not degrade the operation of the solar heating/cooling system which it is monitoring.

  18. Design and implementation of an identification system in construction site safety for proactive accident prevention.

    PubMed

    Yang, Huanjia; Chew, David A S; Wu, Weiwei; Zhou, Zhipeng; Li, Qiming

    2012-09-01

    Identifying accident precursors using real-time identity information has great potential to improve safety performance in construction industry, which is still suffering from day to day records of accident fatality and injury. Based on the requirements analysis for identifying precursor and the discussion of enabling technology solutions for acquiring and sharing real-time automatic identification information on construction site, this paper proposes an identification system design for proactive accident prevention to improve construction site safety. Firstly, a case study is conducted to analyze the automatic identification requirements for identifying accident precursors in construction site. Results show that it mainly consists of three aspects, namely access control, training and inspection information and operation authority. The system is then designed to fulfill these requirements based on ZigBee enabled wireless sensor network (WSN), radio frequency identification (RFID) technology and an integrated ZigBee RFID sensor network structure. At the same time, an information database is also designed and implemented, which includes 15 tables, 54 queries and several reports and forms. In the end, a demonstration system based on the proposed system design is developed as a proof of concept prototype. The contributions of this study include the requirement analysis and technical design of a real-time identity information tracking solution for proactive accident prevention on construction sites. The technical solution proposed in this paper has a significant importance in improving safety performance on construction sites. Moreover, this study can serve as a reference design for future system integrations where more functions, such as environment monitoring and location tracking, can be added. PMID:22664682

  19. Design and implementation of an identification system in construction site safety for proactive accident prevention.

    PubMed

    Yang, Huanjia; Chew, David A S; Wu, Weiwei; Zhou, Zhipeng; Li, Qiming

    2012-09-01

    Identifying accident precursors using real-time identity information has great potential to improve safety performance in construction industry, which is still suffering from day to day records of accident fatality and injury. Based on the requirements analysis for identifying precursor and the discussion of enabling technology solutions for acquiring and sharing real-time automatic identification information on construction site, this paper proposes an identification system design for proactive accident prevention to improve construction site safety. Firstly, a case study is conducted to analyze the automatic identification requirements for identifying accident precursors in construction site. Results show that it mainly consists of three aspects, namely access control, training and inspection information and operation authority. The system is then designed to fulfill these requirements based on ZigBee enabled wireless sensor network (WSN), radio frequency identification (RFID) technology and an integrated ZigBee RFID sensor network structure. At the same time, an information database is also designed and implemented, which includes 15 tables, 54 queries and several reports and forms. In the end, a demonstration system based on the proposed system design is developed as a proof of concept prototype. The contributions of this study include the requirement analysis and technical design of a real-time identity information tracking solution for proactive accident prevention on construction sites. The technical solution proposed in this paper has a significant importance in improving safety performance on construction sites. Moreover, this study can serve as a reference design for future system integrations where more functions, such as environment monitoring and location tracking, can be added.

  20. Anatomy of protein pockets and cavities: measurement of binding site geometry and implications for ligand design.

    PubMed Central

    Liang, J.; Edelsbrunner, H.; Woodward, C.

    1998-01-01

    Identification and size characterization of surface pockets and occluded cavities are initial steps in protein structure-based ligand design. A new program, CAST, for automatically locating and measuring protein pockets and cavities, is based on precise computational geometry methods, including alpha shape and discrete flow theory. CAST identifies and measures pockets and pocket mouth openings, as well as cavities. The program specifies the atoms lining pockets, pocket openings, and buried cavities; the volume and area of pockets and cavities; and the area and circumference of mouth openings. CAST analysis of over 100 proteins has been carried out; proteins examined include a set of 51 monomeric enzyme-ligand structures, several elastase-inhibitor complexes, the FK506 binding protein, 30 HIV-1 protease-inhibitor complexes, and a number of small and large protein inhibitors. Medium-sized globular proteins typically have 10-20 pockets/cavities. Most often, binding sites are pockets with 1-2 mouth openings; much less frequently they are cavities. Ligand binding pockets vary widely in size, most within the range 10(2)-10(3)A3. Statistical analysis reveals that the number of pockets and cavities is correlated with protein size, but there is no correlation between the size of the protein and the size of binding sites. Most frequently, the largest pocket/cavity is the active site, but there are a number of instructive exceptions. Ligand volume and binding site volume are somewhat correlated when binding site volume is < or =700 A3, but the ligand seldom occupies the entire site. Auxiliary pockets near the active site have been suggested as additional binding surface for designed ligands (Mattos C et al., 1994, Nat Struct Biol 1:55-58). Analysis of elastase-inhibitor complexes suggests that CAST can identify ancillary pockets suitable for recruitment in ligand design strategies. Analysis of the FK506 binding protein, and of compounds developed in SAR by NMR (Shuker SB et

  1. Perceptions of Web Site Design Characteristics: A Malaysian/Australian Comparison.

    ERIC Educational Resources Information Center

    Fink, Dieter; Laupase, Ricky

    2000-01-01

    Compares the perceptions of Malaysians and Australians for four Web site design characteristics--atmospherics, news stories, signs, and products and services--as part of the integrated Internet marketing model. Hypothesizes that the predominant culture is not generalized to another culture, discusses validity and reliability, and suggest further…

  2. 10 CFR 433.6 - Sustainable principles for siting, design and construction. [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 3 2012-01-01 2012-01-01 false Sustainable principles for siting, design and construction. 433.6 Section 433.6 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY EFFICIENCY STANDARDS FOR NEW FEDERAL COMMERCIAL AND MULTI-FAMILY HIGH-RISE RESIDENTIAL BUILDINGS § 433.6 Sustainable...

  3. 10 CFR 435.6 - Sustainable principles for siting, design and construction. [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 3 2014-01-01 2014-01-01 false Sustainable principles for siting, design and construction. 435.6 Section 435.6 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY EFFICIENCY STANDARDS FOR NEW FEDERAL LOW-RISE RESIDENTIAL BUILDINGS Mandatory Energy Efficiency Standards for Federal...

  4. 10 CFR 435.6 - Sustainable principles for siting, design and construction. [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 3 2013-01-01 2013-01-01 false Sustainable principles for siting, design and construction. 435.6 Section 435.6 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY EFFICIENCY STANDARDS FOR NEW FEDERAL LOW-RISE RESIDENTIAL BUILDINGS Mandatory Energy Efficiency Standards for Federal...

  5. 10 CFR 433.6 - Sustainable principles for siting, design and construction. [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 3 2014-01-01 2014-01-01 false Sustainable principles for siting, design and construction. 433.6 Section 433.6 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY EFFICIENCY STANDARDS FOR NEW FEDERAL COMMERCIAL AND MULTI-FAMILY HIGH-RISE RESIDENTIAL BUILDINGS § 433.6 Sustainable...

  6. 10 CFR 433.6 - Sustainable principles for siting, design and construction. [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 3 2013-01-01 2013-01-01 false Sustainable principles for siting, design and construction. 433.6 Section 433.6 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY EFFICIENCY STANDARDS FOR NEW FEDERAL COMMERCIAL AND MULTI-FAMILY HIGH-RISE RESIDENTIAL BUILDINGS § 433.6 Sustainable...

  7. 10 CFR 435.6 - Sustainable principles for siting, design and construction. [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 3 2012-01-01 2012-01-01 false Sustainable principles for siting, design and construction. 435.6 Section 435.6 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY EFFICIENCY STANDARDS FOR NEW FEDERAL LOW-RISE RESIDENTIAL BUILDINGS Mandatory Energy Efficiency Standards for Federal...

  8. 7 CFR Exhibit B to Subpart C of... - Site Development Design Requirements

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Catch Basins 1. Openings 2. Access G. Drywells V. Water Supply Systems A. Individual Water Systems 1. General 2. Well Location 3. Well Construction 4. Pumps and Equipment 5. Storage Tanks B. Community Water... drainage of surface water away from buildings and adjacent sites. Grading design shall conform with...

  9. 7 CFR Exhibit B to Subpart C of... - Site Development Design Requirements

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... Catch Basins 1. Openings 2. Access G. Drywells V. Water Supply Systems A. Individual Water Systems 1. General 2. Well Location 3. Well Construction 4. Pumps and Equipment 5. Storage Tanks B. Community Water... drainage of surface water away from buildings and adjacent sites. Grading design shall conform with...

  10. Understanding and Designing for Interactional Privacy Needs within Social Networking Sites

    ERIC Educational Resources Information Center

    Wisniewski, Pamela J.

    2012-01-01

    "Interpersonal boundary regulation" is a way to optimize social interactions when sharing and connecting through Social Networking Sites (SNSs). The theoretical foundation of much of my research comes from Altman's work on privacy management in the physical world. Altman believed that "we should attempt to design responsive…

  11. 75 FR 54497 - Ocean Dumping; Guam Ocean Dredged Material Disposal Site Designation

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-08

    ... Register (FR). Historically, dredged material generated around Guam by the Navy and the Port Authority of... will, wherever feasible, designate ocean dumping sites beyond the edge of the continental shelf and... continental land mass and does not have a continental shelf. In the ] absence of a shelf break,...

  12. 10 CFR 435.6 - Sustainable principles for siting, design and construction. [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 3 2011-01-01 2011-01-01 false Sustainable principles for siting, design and construction. 435.6 Section 435.6 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY EFFICIENCY STANDARDS FOR NEW FEDERAL LOW-RISE RESIDENTIAL BUILDINGS Mandatory Energy Efficiency Standards for Federal...

  13. 10 CFR 435.6 - Sustainable principles for siting, design and construction. [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 3 2010-01-01 2010-01-01 false Sustainable principles for siting, design and construction. 435.6 Section 435.6 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY EFFICIENCY STANDARDS FOR NEW FEDERAL LOW-RISE RESIDENTIAL BUILDINGS Mandatory Energy Efficiency Standards for Federal...

  14. Design, synthesis, and characterization of nucleosomes containing site-specific DNA damage.

    PubMed

    Taylor, John-Stephen

    2015-12-01

    How DNA damaged is formed, recognized, and repaired in chromatin is an area of intense study. To better understand the structure activity relationships of damaged chromatin, mono and dinucleosomes containing site-specific damage have been prepared and studied. This review will focus on the design, synthesis, and characterization of model systems of damaged chromatin for structural, physical, and enzymatic studies.

  15. 10 CFR 61.51 - Disposal site design for land disposal.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ....51 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSING REQUIREMENTS FOR LAND DISPOSAL OF RADIOACTIVE WASTE Technical Requirements for Land Disposal Facilities § 61.51 Disposal site design for land... contact of standing water with waste during disposal, and the contact of percolating or standing...

  16. 10 CFR 61.51 - Disposal site design for land disposal.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ....51 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSING REQUIREMENTS FOR LAND DISPOSAL OF RADIOACTIVE WASTE Technical Requirements for Land Disposal Facilities § 61.51 Disposal site design for land... contact of standing water with waste during disposal, and the contact of percolating or standing...

  17. 10 CFR 61.51 - Disposal site design for land disposal.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ....51 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSING REQUIREMENTS FOR LAND DISPOSAL OF RADIOACTIVE WASTE Technical Requirements for Land Disposal Facilities § 61.51 Disposal site design for land... contact of standing water with waste during disposal, and the contact of percolating or standing...

  18. 10 CFR 61.51 - Disposal site design for land disposal.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ....51 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSING REQUIREMENTS FOR LAND DISPOSAL OF RADIOACTIVE WASTE Technical Requirements for Land Disposal Facilities § 61.51 Disposal site design for land... contact of standing water with waste during disposal, and the contact of percolating or standing...

  19. Leveraging user search behavior to design personalized browsing interfaces for healthcare Web sites.

    PubMed

    Mahoui, Malika; Jones, Josette; Zollinger, Derek; Andersen, Kanitha; Coates, Heather

    2008-11-06

    Understanding and leveraging user search behavior is increasingly becoming a key component towards improving web sites functionality for the health care consumer and provider. In this study we propose to leverage user search behavior to design user-tailored browsing interfaces to better support locating information in healthcare websites at the point-of-need.

  20. Conceptual design report, TWRS Privatization Phase I, site development and roads, subproject W-505

    SciTech Connect

    Singh, G.

    1997-06-05

    This document includes Conceptual Design Report (CDR) for the site development, construction of new roads and improvements at existing road intersections, habitat mitigation, roadway lighting, and construction power needed for the construction of two Private Contractor (PC) Facilities. Approximately 50 hectare (124 acres) land parcel, east of the Grout Facility, is planned for the PC facilities.

  1. Design superiority of palindromic DNA sites for site-specific recognition of proteins: tests using protein stitchery.

    PubMed Central

    Park, C; Campbell, J L; Goddard, W A

    1993-01-01

    Using protein stitchery with appropriate attachment of cysteines linking to either C or N termini of the basic region of the v-Jun leucine zipper gene-regulatory protein, we constructed three dimers--pCC, pCN, and pNN. All three bind specifically to the appropriately rearranged DNA recognition sites for v-Jun: ATGAcgTCAT, ATGAcgATGA, and TCATcgTCAT, respectively (Kd, approximately 4 nM at 4 degrees C). Results of DNase I footprinting provide strong support for bent recognition helices in leucine zipper protein-DNA complexes. Comparison of the results for pCC and pNN with those for pCN shows the design superiority of palindromic sequences for protein recognition. Images Fig. 1 Fig. 2 Fig. 3 PMID:8506333

  2. Geohydrologic aspects for siting and design of low-level radioactive-waste disposal

    USGS Publications Warehouse

    Bedinger, M.S.

    1989-01-01

    The objective for siting and design of low-level radioactive-waste repository sites is to isolate the waste from the biosphere until the waste no longer poses an unacceptable hazard as a result of radioactive decay. Low-level radioactive waste commonly is isolated at shallow depths with various engineered features to stabilize the waste and to reduce its dissolution and transport by ground water. The unsaturated zone generally is preferred for isolating the waste. Low-level radioactive waste may need to be isolated for 300 to 500 years. Maintenance and monitoring of the repository site are required by Federal regulations for only the first 100 years. Therefore, geohydrology of the repository site needs to provide natural isolation of the waste for the hazardous period following maintenance of the site. Engineering design of the repository needs to be compatible with the natural geohydrologic conditions at the site. Studies at existing commercial and Federal waste-disposal sites provide information on the problems encountered and the basis for establishing siting guidelines for improved isolation of radioactive waste, engineering design of repository structures, and surveillance needs to assess the effectiveness of the repositories and to provide early warning of problems that may require remedial action. Climate directly affects the hydrology of a site and probably is the most important single factor that affects the suitability of a site for shallow-land burial of low-level radioactive waste. Humid and subhumid regions are not well suited for shallow isolation of low-level radioactive waste in the unsaturated zone; arid regions with zero to small infiltration from precipitation, great depths to the water table, and long flow paths to natural discharge areas are naturally well suited to isolation of the waste. The unsaturated zone is preferred for isolation of low-level radioactive waste. The guiding rationale is to minimize contact of water with the waste and to

  3. Docking-based Design of Galantamine Derivatives with Dual-site Binding to Acetylcholinesterase.

    PubMed

    Stavrakov, Georgi; Philipova, Irena; Zheleva, Dimitrina; Atanasova, Mariyana; Konstantinov, Spiro; Doytchinova, Irini

    2016-07-01

    The enzyme acetylcholinesterase is a key target in the treatment of Alzheimer's disease because of its ability to hydrolyze acetylcholine via the catalytic binding site and to accelerate the aggregation of amyloid-β peptide via the peripheral anionic site (PAS). Using docking-based predictions, in the present study we design 20 novel galantamine derivatives with alkylamide spacers of different length ending with aromatic fragments. The galantamine moiety blocks the catalytic site, while the terminal aromatic fragments bind in PAS. The best predicted compounds are synthesized and tested for acetylcholinesterase inhibitory activity. The experimental results confirm the predictions and show that the heptylamide spacer is of optimal length to bridge the galantamine moiety bound in the catalytic site and the aromatic fragments interacting with PAS. Among the tested terminal aromatic fragments, the phenethyl substituent is the most suitable for binding in PAS. PMID:27492242

  4. Remedial action plan and site design for stabilization of the inactive uranium mill tailings site at Lowman, Idaho: Attachment 2, Geology report

    SciTech Connect

    Not Available

    1991-09-01

    Detailed investigations of geologic, geomorphic, and seismic conditions at the Lowman site in central Idaho were conducted by the Technical Assistance Contractor. The purpose of these investigations was basic site characterization and the identification of potential geologic hazards that could affect long-term site stability. Subsequent engineering studies (e.g., analyses of the hydrologic regime and liquefaction potential) use this data . The geomorphic analysis is employed in the design of effective erosion protection. Studies of the regional and local seismotectonic setting, which included a detailed search for possible capable faults within a 65-km (40-mile) radius of the site, provided the basis for estimating seismic design parameters.

  5. Remedial action plan and site design for stabilization of the inactive uranium mill tailings site at Lowman, Idaho: Attachment 2, Geology report. Final report

    SciTech Connect

    Not Available

    1991-09-01

    Detailed investigations of geologic, geomorphic, and seismic conditions at the Lowman site in central Idaho were conducted by the Technical Assistance Contractor. The purpose of these investigations was basic site characterization and the identification of potential geologic hazards that could affect long-term site stability. Subsequent engineering studies (e.g., analyses of the hydrologic regime and liquefaction potential) use this data . The geomorphic analysis is employed in the design of effective erosion protection. Studies of the regional and local seismotectonic setting, which included a detailed search for possible capable faults within a 65-km (40-mile) radius of the site, provided the basis for estimating seismic design parameters.

  6. Rational design of allosteric-inhibition sites in classical protein tyrosine phosphatases

    PubMed Central

    Chio, Cynthia M.; Yu, Xiaoling; Bishop, Anthony C.

    2015-01-01

    Protein tyrosine phosphatases (PTPs), which catalyze the dephosphorylation of phosphotyrosine in protein substrates, are critical regulators of metazoan cell signaling and have emerged as potential drug targets for a range of human diseases. Strategies for chemically targeting the function of individual PTPs selectively could serve to elucidate the signaling roles of these enzymes and would potentially expedite validation of the therapeutic promise of PTP inhibitors. Here we report a novel strategy for the design of non-natural allosteric-inhibition sites in PTPs; these sites, which can be introduced into target PTPs through protein engineering, serve to sensitize target PTPs to potent and selective inhibition by a biarsenical small molecule. Building on the recent discovery of a naturally occurring cryptic allosteric site in wild-type Src-homology-2 domain containing PTP (Shp2) that can be targeted by biarsenical compounds, we hypothesized that Shp2’s unusual sensitivity to biarsenicals could be strengthened through rational design and that the Shp2-specific site could serve as a blueprint for the introduction of non-natural inhibitor sensitivity in other PTPs. Indeed, we show here that the strategic introduction of a cysteine residue at a position removed from the Shp2 active site can serve to increase the potency and selectivity of the interaction between Shp2’s allosteric site and the biarsenical inhibitor. Moreover, we find that “Shp2-like” allosteric sites can be installed de novo in PTP enzymes that do not possess naturally occurring sensitivity to biarsenical compounds. Using primary-sequence alignments to guide our enzyme engineering, we have successfully introduced allosteric-inhibition sites in four classical PTPs—PTP1B, PTPH-1, FAP-1, and HePTP—from four different PTP subfamilies, suggesting that our sensitization approach can likely be applied widely across the classical PTP family to generate biarsenical-responsive PTPs. PMID:25828055

  7. Remedial action plan and site conceptual design for stabilization of the inactive uranium mill tailings sites at Rifle, Colorado. Appendix D, Final report

    SciTech Connect

    1992-02-01

    This appendix assesses the present conditions and data gathered about the two designated inactive uranium mill tailings sites near Rifle, Colorado, and the proposed disposal site six miles north of Rifle in the area of Estes Gulch. It consolidates available engineering, radiological, geotechnical, hydrological, meteorological, and other information pertinent to the design of the Remedial Action Plan (RAP). The data characterize conditions at the mill, tailings, and disposal site so that the Remedial Action Contractor (RAC) may complete final designs for the remedial actions.

  8. Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design.

    PubMed

    Tan, Yaw Sing; Reeks, Judith; Brown, Christopher J; Thean, Dawn; Ferrer Gago, Fernando Jose; Yuen, Tsz Ying; Goh, Eunice Tze Leng; Lee, Xue Er Cheryl; Jennings, Claire E; Joseph, Thomas L; Lakshminarayanan, Rajamani; Lane, David P; Noble, Martin E M; Verma, Chandra S

    2016-09-01

    Protein flexibility poses a major challenge in binding site identification. Several computational pocket detection methods that utilize small-molecule probes in molecular dynamics (MD) simulations have been developed to address this issue. Although they have proven hugely successful at reproducing experimental structural data, their ability to predict new binding sites that are yet to be identified and characterized has not been demonstrated. Here, we report the use of benzenes as probe molecules in ligand-mapping MD (LMMD) simulations to predict the existence of two novel binding sites on the surface of the oncoprotein MDM2. One of them was serendipitously confirmed by biophysical assays and X-ray crystallography to be important for the binding of a new family of hydrocarbon stapled peptides that were specifically designed to target the other putative site. These results highlight the predictive power of LMMD and suggest that predictions derived from LMMD simulations can serve as a reliable basis for the identification of novel ligand binding sites in structure-based drug design. PMID:27532490

  9. Conceptual Design Report: Nevada Test Site Mixed Waste Disposal Facility Project

    SciTech Connect

    NSTec Environmental Management

    2009-01-31

    Environmental cleanup of contaminated nuclear weapons manufacturing and test sites generates radioactive waste that must be disposed. Site cleanup activities throughout the U.S. Department of Energy (DOE) complex are projected to continue through 2050. Some of this waste is mixed waste (MW), containing both hazardous and radioactive components. In addition, there is a need for MW disposal from other mission activities. The Waste Management Programmatic Environmental Impact Statement Record of Decision designates the Nevada Test Site (NTS) as a regional MW disposal site. The NTS has a facility that is permitted to dispose of onsite- and offsite-generated MW until November 30, 2010. There is not a DOE waste management facility that is currently permitted to dispose of offsite-generated MW after 2010, jeopardizing the DOE environmental cleanup mission and other MW-generating mission-related activities. A mission needs document (CD-0) has been prepared for a newly permitted MW disposal facility at the NTS that would provide the needed capability to support DOE's environmental cleanup mission and other MW-generating mission-related activities. This report presents a conceptual engineering design for a MW facility that is fully compliant with Resource Conservation and Recovery Act (RCRA) and DOE O 435.1, 'Radioactive Waste Management'. The facility, which will be located within the Area 5 Radioactive Waste Management Site (RWMS) at the NTS, will provide an approximately 20,000-cubic yard waste disposal capacity. The facility will be licensed by the Nevada Division of Environmental Protection (NDEP).

  10. Designing a web site for high school geoscience teaching in Iceland

    NASA Astrophysics Data System (ADS)

    Douglas, George R.

    1998-08-01

    The need to construct an earth science teaching site on the web prompted a survey of existing sites which, in spite of containing much of value, revealed many weaknesses in basic design, particularly as regards the organisation of links to information resources. Few web sites take into consideration the particular pedagogic needs of the high school science student and there has, as yet, been little serious attempt to exploit and organise the more outstanding advantages offered by the internet to science teaching, such as accessing real-time data. A web site has been constructed which, through basic design, enables students to access relevant information resources over a wide range of subjects and topics easily and rapidly, while at the same time performing an instructional role in how to handle both on-line and off-line resources. Key elements in the design are selection and monitoring by the teacher, task oriented pages and the use of the Dewey decimal classification system. The intention is to increase gradually the extent to which most teaching tasks are carried out via the web pages, in the belief that they can become an efficient central point for all the earth science curriculum.

  11. Custom-Designed Molecular Scissors for Site-Specific Manipulation of the Plant and Mammalian Genomes

    NASA Astrophysics Data System (ADS)

    Kandavelou, Karthikeyan; Chandrasegaran, Srinivasan

    Zinc finger nucleases (ZFNs) are custom-designed molecular scissors, engineered to cut at specific DNA sequences. ZFNs combine the zinc finger proteins (ZFPs) with the nonspecific cleavage domain of the FokI restriction enzyme. The DNA-binding specificity of ZFNs can be easily altered experimentally. This easy manipulation of the ZFN recognition specificity enables one to deliver a targeted double-strand break (DSB) to a genome. The targeted DSB stimulates local gene targeting by several orders of magnitude at that specific cut site via homologous recombination (HR). Thus, ZFNs have become an important experimental tool to make site-specific and permanent alterations to genomes of not only plants and mammals but also of many other organisms. Engineering of custom ZFNs involves many steps. The first step is to identify a ZFN site at or near the chosen chromosomal target within the genome to which ZFNs will bind and cut. The second step is to design and/or select various ZFP combinations that will bind to the chosen target site with high specificity and affinity. The DNA coding sequence for the designed ZFPs are then assembled by polymerase chain reaction (PCR) using oligonucleotides. The third step is to fuse the ZFP constructs to the FokI cleavage domain. The ZFNs are then expressed as proteins by using the rabbit reticulocyte in vitro transcription/translation system and the protein products assayed for their DNA cleavage specificity.

  12. Custom-Designed Molecular Scissors for Site-Specific Manipulation of the Plant and Mammalian Genomes

    PubMed Central

    Kandavelou, Karthikeyan; Chandrasegaran, Srinivasan

    2010-01-01

    Summary Zinc finger nucleases (ZFNs) are custom-designed molecular scissors, engineered to cut at specific DNA sequences. ZFNs combine the zinc finger proteins (ZFPs) with the nonspecific cleavage domain of the FokI restriction enzyme. The DNA-binding specificity of ZFNs can be easily altered experimentally. This easy manipulation of the ZFN recognition specificity enables one to deliver a targeted double-strand break (DSB) to a genome. The targeted DSB stimulates local gene targeting by several orders of magnitude at that specific cut site via homologous recombination (HR). Thus, ZFNs have become an important experimental tool to make site-specific and permanent alterations to genomes of not only plants and mammals but also of many other organisms. Engineering of custom ZFNs involves many steps. The first step is to identify a ZFN site at or near the chosen chromosomal target within the genome to which ZFNs will bind and cut. The second step is to design and/or select various ZFP combinations that will bind to the chosen target site with high specificity and affinity. The DNA coding sequence for the designed ZFPs are then assembled by polymerase chain reaction (PCR) using oligonucleotides. The third step is to fuse the ZFP constructs to the FokI cleavage domain. The ZFNs are then expressed as proteins by using the rabbit reticulocyte in vitro transcription/translation system and the protein products assayed for their DNA cleavage specificity. PMID:19488728

  13. Design and performance of an automatic regenerating adsorption aerosol dryer for continuous operation at monitoring sites

    NASA Astrophysics Data System (ADS)

    Tuch, T. M.; Haudek, A.; Müller, T.; Nowak, A.; Wex, H.; Wiedensohler, A.

    2009-04-01

    Sizes of aerosol particles depend on the relative humidity of their carrier gas. Most monitoring networks require therefore that the aerosol is dried to a relative humidity below 50% RH to ensure comparability of measurements at different sites. Commercially available aerosol dryers are often not suitable for this purpose at remote monitoring sites. Adsorption dryers need to be regenerated frequently and maintenance-free single column Nafion dryers are not designed for high aerosol flow rates. We therefore developed an automatic regenerating adsorption aerosol dryer with a design flow rate of 1 m3/h. Particle transmission efficiency of this dryer has been determined during a 3 weeks experiment. The lower 50% cut-off was found to be below 3 nm at the design flow rate of the instrument. Measured transmission efficiencies are in good agreement with theoretical calculations. One drier has been successfully deployed in the Amazonas river basin. From this monitoring site, we present data from the first 6 months of measurements (February 2008-August 2008). Apart from one unscheduled service, this dryer did not require any maintenance during this time period. The average relative humidity of the dried aerosol was 27.1+/-7.5% RH compared to an average ambient relative humidity of nearly 80% and temperatures around 30°C. This initial deployment demonstrated that these dryers are well suitable for continuous operation at remote monitoring sites under adverse ambient conditions.

  14. Remedial action and site design for stabilization of the inactive uranium mill tailings sites at Slick Rock, Colorado. Attachment 2, Geology report: Appendix B, Preliminary final

    SciTech Connect

    Not Available

    1994-03-01

    Detailed investigations of geologic, geomorphic, and seismic conditions at the Burro Canyon site were conducted by the US Department of Energy (DOE) as a disposal site for the tailings at two processing sites near the Slick Rock, Colorado, post office. The purposes of these studies are basic site characterization and identification of potential geologic hazards that could affect long-term site stability. Subsequent engineering studies (e.g., analyses of hydrologic and liquefaction hazards) used the data developed in these studies. The geomorphic analysis was employed in the design of effective erosion protection. Studies of the regional and local seismotectonic setting, which included a detailed search for possible capable faults within a 65-km radius of the site, provided the basis for seismic design parameters.

  15. Remedial Action Plan and site design for stabilization of the inactive uranium mill tailings site at Mexican Hat, Utah: Appendix D. Final report

    SciTech Connect

    1988-07-01

    This appendix is an assessment of the present conditions of the inactive uranium mill site near Mexican Hat, Utah. It consolidates available engineering, radiological, geotechnical, hydrological, meteorological, and other information pertinent to the design of the Remedial Action Plan. Plan is to characterize the conditions at the mill and tailings site so that the Remedial Action Contractor may complete final designs of the remedial action.

  16. ONWI (Office of Nuclear Waste Isolation) 30% design review findings report for Exploratory Shaft Facility, Deaf Smith site

    SciTech Connect

    Not Available

    1987-05-08

    This document describes a review of the standards for the design of the high-level radioactive waste facility at the Deaf Smith, Texas site. It includes public comments and the official responses to the designs produced to date. (TEM)

  17. Region and site specific design guidelines for the northeastern Venezuela development

    SciTech Connect

    Gajardo, E.; Paga, M.; Sully, J.P.

    1996-12-31

    Several site specific studies were performed for the northeastern Venezuelan offshore development in order to determine the environmental parameters for the engineering design. The geotechnical parameters were obtained from the analysis of the soil borings, in situ tests and the high resolution seismic surveys. An evaluation of the seismic hazard was done, based on a detailed neotectonic study, the compilation of historical and instrumental seismological information, and an attenuation relationship developed for the studied area. Seismic response analyses were performed using the seismic parameters and dynamic characteristics obtained form the soil borings and in situ tests of shear waves. The met-ocean design loads of the local conditions were obtained from mathematical modeling based on in situ and regional measurements. This study defines the platforms design conditions based on a probabilistic reliability approach and it has been used, among others, as a basis for the earthquake design guidelines proposed by the International Standards Organization. A sensitivity analysis was performed starting from the uncertainties of all the input parameters, in order to obtain the best estimate average design spectrum and associated coefficient of variability. The specific approach was to maintain the same safety index adopted by API RP2A code, with a bias modification factor that relates the site nominal spectra with the spectral acceleration that would be used in order to satisfy the API requirements. The results of this approach make possible the use of site specific detailed environmental data and the proven standard procedures established on the API RP2 codes, with significant cost reduction in terms of both platform and foundation design. The considerable amount of tectonic, seismological, and geotechnical information was the principal factor allowing the above methodology.

  18. Guide to radiological accident considerations for siting and design of DOE nonreactor nuclear facilities

    SciTech Connect

    Elder, J.C.; Graf, J.M.; Dewart, J.M.; Buhl, T.E.; Wenzel, W.J.; Walker, L.J.; Stoker, A.K.

    1986-01-01

    This guide was prepared to provide the experienced safety analyst with accident analysis guidance in greater detail than is possible in Department of Energy (DOE) Orders. The guide addresses analysis of postulated serious accidents considered in the siting and selection of major design features of DOE nuclear facilities. Its scope has been limited to radiological accidents at nonreactor nuclear facilities. The analysis steps addressed in the guide lead to evaluation of radiological dose to exposed persons for comparison with siting guideline doses. Other possible consequences considered are environmental contamination, population dose, and public health effects. Choices of models and parameters leading to estimation of source terms, release fractions, reduction and removal factors, dispersion and dose factors are discussed. Although requirements for risk analysis have not been established, risk estimates are finding increased use in siting of major nuclear facilities, and are discussed in the guide. 3 figs., 9 tabs.

  19. The design of a Phase I non site-specific Centralized Interim Storage Facility

    SciTech Connect

    Stringer, J.; Kane, D.

    1997-10-28

    The Department of Energy (DOE), Office of Civilian Radioactive Waste Management (OCRWM) recently completed a Topical Safety Analysis Report (TSAR) for a Phase 1 non site specific Centralized Interim Storage Facility (CISF). The TSAR will be used in licensing the CISF when and if a site is designated. The combined Phase 1 and Phase 2 CISF will provide federal storage capability for 40,000 metric tons of uranium (MTU) Spent Nuclear Fuel (SNF) under the oversight of the DOE. The Phase 1 TSAR was submitted to the NRC on May 1, 1997 and is currently under review having been docketed on June 10, 1997. This paper generally describes the Phase 1 CISF design and its operations as presented in the CISF TSAR.

  20. Functional mimicry of a discontinuous antigenic site by a designed synthetic peptide.

    PubMed

    Villén, Judit; Borràs, Eva; Schaaper, Wim M M; Meloen, Rob H; Dávila, Mercedes; Domingo, Esteban; Giralt, Ernest; Andreu, David

    2002-03-01

    Functional reproduction of the discontinuous antigenic site D of foot-and-mouth disease virus (FMDV) has been achieved by means of synthetic peptide constructions that integrate each of the three protein loops that define the antigenic site into a single molecule. The site D mimics were designed on the basis of the X-ray structure of FMDV type C-S8c1 with the aid of molecular dynamics, so that the five residues assumed to be involved in antigenic recognition are located on the same face of the molecule, exposed to solvent and defining a set of native-like distances and angles. The designed site D mimics are disulfide-linked heterodimers that consist of a larger unit containing VP2(71-84), followed by a polyproline module and by VP3(52-62), and a smaller unit corresponding to VP1(188-194) (VP=viral protein). Guinea pig antisera to the peptides recognized the viral particle and competed with site D-specific monoclonal antibodies, while inoculation with a simple (not covalently joined to one another) admixture of the three VP1-VP3 sequences yielded no detectable virus-specific serum conversion. Similar results have been reproduced in two bovines. Antisera to the peptides also moderately neutralize FMDV in cell cultures and partially protect guinea pigs against challenge with the virus. These results demonstrate functional mimicry of the discontinuous site D by the peptides, which are therefore obvious candidates for a multicomponent, peptide-based vaccine against FMDV. PMID:11921395

  1. Molecular dynamics explorations of active site structure in designed and evolved enzymes.

    PubMed

    Osuna, Sílvia; Jiménez-Osés, Gonzalo; Noey, Elizabeth L; Houk, K N

    2015-04-21

    This Account describes the use of molecular dynamics (MD) simulations to reveal how mutations alter the structure and organization of enzyme active sites. As proposed by Pauling about 70 years ago and elaborated by many others since then, biocatalysis is efficient when functional groups in the active site of an enzyme are in optimal positions for transition state stabilization. Changes in mechanism and covalent interactions are often critical parts of enzyme catalysis. We describe our explorations of the dynamical preorganization of active sites using MD, studying the fluctuations between active and inactive conformations normally concealed to static crystallography. MD shows how the various arrangements of active site residues influence the free energy of the transition state and relates the populations of the catalytic conformational ensemble to the enzyme activity. This Account is organized around three case studies from our laboratory. We first describe the importance of dynamics in evaluating a series of computationally designed and experimentally evolved enzymes for the Kemp elimination, a popular subject in the enzyme design field. We find that the dynamics of the active site is influenced not only by the original sequence design and subsequent mutations but also by the nature of the ligand present in the active site. In the second example, we show how microsecond MD has been used to uncover the role of remote mutations in the active site dynamics and catalysis of a transesterase, LovD. This enzyme was evolved by Tang at UCLA and Codexis, Inc., and is a useful commercial catalyst for the production of the drug simvastatin. X-ray analysis of inactive and active mutants did not reveal differences in the active sites, but relatively long time scale MD in solution showed that the active site of the wild-type enzyme preorganizes only upon binding of the acyl carrier protein (ACP) that delivers the natural acyl group to the active site. In the absence of bound ACP

  2. Remedial action plan and site design for stabilization of the inactive uranium mill tailings sites at Slick Rock, Colorado. Remedial action selection report, Appendix B

    SciTech Connect

    Not Available

    1993-07-01

    The Slick Rock uranium mill tailings sites are located near the small town of Slick Rock, in San Miguel County, Colorado. There are two designated UMTRA sites at Slick Rock, the Union Carbide (UC) site and the North Continent (NC) site. Both sites are adjacent to the Dolores River. The UC site is approximately 1 mile (mi) [2 kilometers (km)] downstream of the NC site. Contaminated materials cover an estimated 55 acres (ac) [22 hectares (ha)] at the UC site and 12 ac (4.9 ha) at the NC site. The sites contain former mill building concrete foundations, tailings piles, demolition debris, and areas contaminated by windblown and waterborne radioactive materials. The total estimated volume of contaminated materials is approximately 620, 000 cubic yards (yd{sup 3}) [470,000 cubic meters (m{sup 3})]. In addition to the contamination at the two processing site areas, four vicinity properties were contaminated. Contamination associated with the UC and NC sites has leached into groundwater.

  3. Metal-binding sites are designed to achieve optimal mechanical and signaling properties.

    PubMed

    Dutta, Anindita; Bahar, Ivet

    2010-09-01

    Many proteins require bound metals to achieve their function. We take advantage of increasing structural data on metal-binding proteins to elucidate three properties: the involvement of metal-binding sites in the global dynamics of the protein, predicted by elastic network models, their exposure/burial to solvent, and their signal-processing properties indicated by Markovian stochastics analysis. Systematic analysis of a data set of 145 structures reveals that the residues that coordinate metal ions enjoy remarkably efficient and precise signal transduction properties. These properties are rationalized in terms of their physical properties: participation in hinge sites that control the softest modes collectively accessible to the protein and occupancy of central positions minimally exposed to solvent. Our observations suggest that metal-binding sites may have been evolutionary selected to achieve optimum allosteric communication. They also provide insights into basic principles for designing metal-binding sites, which are verified to be met by recently designed de novo metal-binding proteins.

  4. A sensitivity analysis of hazardous waste disposal site climatic and soil design parameters using HELP3

    SciTech Connect

    Adelman, D.D.; Stansbury, J.

    1997-12-31

    The Resource Conservation and Recovery Act (RCRA) Subtitle C, Comprehensive Environmental Response, Compensation, And Liability Act (CERCLA), and subsequent amendments have formed a comprehensive framework to deal with hazardous wastes on the national level. Key to this waste management is guidance on design (e.g., cover and bottom leachate control systems) of hazardous waste landfills. The objective of this research was to investigate the sensitivity of leachate volume at hazardous waste disposal sites to climatic, soil cover, and vegetative cover (Leaf Area Index) conditions. The computer model HELP3 which has the capability to simulate double bottom liner systems as called for in hazardous waste disposal sites was used in the analysis. HELP3 was used to model 54 combinations of climatic conditions, disposal site soil surface curve numbers, and leaf area index values to investigate how sensitive disposal site leachate volume was to these three variables. Results showed that leachate volume from the bottom double liner system was not sensitive to these parameters. However, the cover liner system leachate volume was quite sensitive to climatic conditions and less sensitive to Leaf Area Index and curve number values. Since humid locations had considerably more cover liner system leachate volume than and locations, different design standards may be appropriate for humid conditions than for and conditions.

  5. Department of Energy seismic siting and design decisions: Consistent use of probabilistic seismic hazard analysis

    SciTech Connect

    Kimball, J.K.; Chander, H.

    1997-02-01

    The Department of Energy (DOE) requires that all nuclear or non-nuclear facilities shall be designed, constructed and operated so that the public, the workers, and the environment are protected from the adverse impacts of Natural Phenomena Hazards including earthquakes. The design and evaluation of DOE facilities to accommodate earthquakes shall be based on an assessment of the likelihood of future earthquakes occurrences commensurate with a graded approach which depends on the potential risk posed by the DOE facility. DOE has developed Standards for site characterization and hazards assessments to ensure that a consistent use of probabilistic seismic hazard is implemented at each DOE site. The criteria included in the DOE Standards are described, and compared to those criteria being promoted by the staff of the Nuclear Regulatory Commission (NRC) for commercial nuclear reactors. In addition to a general description of the DOE requirements and criteria, the most recent probabilistic seismic hazard results for a number of DOE sites are presented. Based on the work completed to develop the probabilistic seismic hazard results, a summary of important application issues are described with recommendations for future improvements in the development and use of probabilistic seismic hazard criteria for design of DOE facilities.

  6. Design and implementation of a computer based site operations log for the ARM Program

    SciTech Connect

    Tichler, J.L.; Bernstein, H.J.; Bobrowski, S.F.; Melton, R.B.; Campbell, A.P.; Edwards, D.M.; Kanciruk, P.; Singley, P.T.

    1992-12-31

    The Atmospheric Radiation Measurement (ARM) Program is a Department of Energy (DOE) research effort to reduce the uncertainties found in general circulation and other models due to the effects of clouds and solar radiation. ARM will provide an experimental testbed for the study of important atmospheric effects, particularly cloud and radiative processes, and testing of parameterizations of the processes for use in atmospheric models. The design of the testbed known as the Clouds and Radiation Testbed (CART), calls for five, long-term field data collection sites. The first site, located in the Southern Great Plains (SGP) in Lamont, OK began operation in the spring of 1992. The CART Data Environment (CDE) is the element of the testbed which acquires the basic observations from the instruments and processes them to meet the ARM requirements. A formal design was used to develop a description of the logical requirements for the CDE. This paper discusses the design and prototype implementation of a part of the CDE known as the site operations log, which records metadata defining the environment within which the data produced by the instruments is collected.

  7. A matching algorithm for catalytic residue site selection in computational enzyme design.

    PubMed

    Lei, Yulin; Luo, Wenjia; Zhu, Yushan

    2011-09-01

    A loop closure-based sequential algorithm, PRODA_MATCH, was developed to match catalytic residues onto a scaffold for enzyme design in silico. The computational complexity of this algorithm is polynomial with respect to the number of active sites, the number of catalytic residues, and the maximal iteration number of cyclic coordinate descent steps. This matching algorithm is independent of a rotamer library that enables the catalytic residue to take any required conformation during the reaction coordinate. The catalytic geometric parameters defined between functional groups of transition state (TS) and the catalytic residues are continuously optimized to identify the accurate position of the TS. Pseudo-spheres are introduced for surrounding residues, which make the algorithm take binding into account as early as during the matching process. Recapitulation of native catalytic residue sites was used as a benchmark to evaluate the novel algorithm. The calculation results for the test set show that the native catalytic residue sites were successfully identified and ranked within the top 10 designs for 7 of the 10 chemical reactions. This indicates that the matching algorithm has the potential to be used for designing industrial enzymes for desired reactions.

  8. 75 FR 27783 - Decision To Evaluate a Petition To Designate a Class of Employees From the Mound Site in...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-18

    ... HUMAN SERVICES Decision To Evaluate a Petition To Designate a Class of Employees From the Mound Site in... employees from the Mound site in Miamisburg, Ohio, to be included in the Special Exposure Cohort under the...: Facility: Mound site. Location: Miamisburg, Ohio. Job Titles and/or Job Duties: All employees of...

  9. Colonization of UK coastal realignment sites by mosquitoes: implications for design, management, and public health.

    PubMed

    Medlock, J M; Vaux, A G C

    2013-06-01

    Coastal realignment is now widely instituted in the UK as part of local flood risk management plans to compensate for the loss of European protected habitat and to mitigate the effects of sea-level rise and coastal squeeze. Coastal aquatic habitats have long been known to provide suitable habitats for brackish-water mosquitoes and historically, coastal marshes were considered to support anopheline mosquito populations that were responsible for local malaria transmission. This study surveyed the eight largest managed realignment (MRA) sites in England (Essex and the Humber) for mosquito habitats. The apparent absence of anopheline mosquitoes exploiting aquatic habitats at all of these sites suggests that the risk of malaria associated with MRA sites is currently negligible. However, three of the eight sites supported populations of two nuisance and potential arboviral vector species, Aedes detritus and Aedes caspius. The aquatic habitats that supported mosquitoes resulted from a) specific design aspects of the new sea wall (ballast to mitigate wave action and constructed saline borrow ditches) that could be designed out or managed or b) isolated pools created through silt accretion or expansion of flooded zones to neighbouring pasture. The public health risks and recommendations for management are discussed in this report. This report highlights the need for pro-active public health impact assessments prior to MRA development in consultation with the Health Protection Agency, as well as the need for a case-by-case approach to design and management to mitigate mosquito or mosquito-borne disease issues now and in the future.

  10. Preclosure performance assessment review of the draft site characterization plan conceptual design report: Technical report

    SciTech Connect

    Waite, D.A.; Gupta, R.; Ludwig, S.B.; Maheras, S.J.; Mayberry, J.J.; Plummer, A.M.; Tarapore, P.S.

    1987-12-01

    This report presents the preclosure performance assessment review (PAR) of the Site Characterization Plan Conceptual Design Report (SCP-CDR). The PAR was performed on the design presented in the SCP-CDR working draft, Revision 1, released in October 1986. After review this working draft became the ''Site Characterization Plan Conceptual Design Report'', Revision 1. There are two distinct objectives of the PAR: (1) to analyze the design presented in the SCP-CDR in terms of offsite and occupational radiological safety, and (2) to test safety assessment methods and tools. This report addresses only the first of the PAR objectives. The PAR analysis consists of assessments of offsite and occupational doses resulting from routine and abnormal repository events. The scope of the analysis is restricted to preclosure operations at the repository. This report addresses (1) the description of repository facilities and operations, (2) the development of radioactive material inventories and radiation dose rates, (3) the development of radioactive material release scenarios and source terms, and (4) the assessment of offsite and occupational radiation dose equivalents. This report contains a summary of the analyses in the above four areas, and analysis details are documented. The results of the assessments are compared with regulatory requirements to determine how the repository performs relative to the requirements. The analyses indicate that the offsite and occupational impacts comply with regulatory requirements. However, based on this preliminary analysis of the draft design document, the occupational impacts exceed the SCP-CDR design objective of 1 rem/year in some areas. 59 refs., 12 figs., 127 tabs.

  11. The Design, Synthesis, and Characterization of Open Sites on Metal Clusters

    NASA Astrophysics Data System (ADS)

    Nigra, Michael Mark

    Coordinatively unsaturated corner and edge atoms have been hypothesized to have the highest activity of sites responsible for many catalytic reactions on a metal surface. Recent studies have validated this hypothesis in varied reaction systems. However, quantification of different types of coordinatively unsaturated sites, and elucidation of their individual catalytic rates has remained a largely unresolved challenge when understanding catalysis on metal surfaces. Yet such structure-function knowledge would be invaluable to the design of more active and selective metal-surface catalysts in the future. I investigated the catalytic contributions of undercoordinated sites such as corner and edge atoms are investigated in a model reaction system using organic ligands bound to the gold nanoparticle surface. The catalyst consisted of 4 nm gold nanoparticles on a metal oxide support, using resazurin to resorufin as a model reaction system. My results demonstrate that in this system, corner atom sites are the most undercoordinated sites, and are over an order of magnitude more active when compared to undercoordinated edge atom sites, while terrace sites remain catalytically inactive for the reduction reaction of resazurin to resorufin. Catalytic activity has been also demonstrated for calixarene-bound gold nanoparticles using the reduction of 4-nitrophenol. With the 4-nitrophenol reduction reaction, a comparative study was undertaken to compare calixarene phosphine and calixarene thiol bound 4 nm gold particles. The results of the study suggested that a leached site was responsible for catalysis and not sites on the original gold nanoparticles. Future experiments with calixarene bound gold clusters could investigate ligand effects in reactions where the active site is not a leached or aggregated gold species, possibly in oxidation reactions, where electron-rich gold is hypothesized to be a good catalyst. The results that emphasize the enhanced catalytic activity of

  12. Apurinic/apyrimidinic endonuclease 1 induced upregulation of fibroblast growth factor 2 and its receptor 3 induces angiogenesis in human osteosarcoma cells.

    PubMed

    Ren, Tao; Qing, Yi; Dai, Nan; Li, Mengxia; Qian, Chengyuan; Yang, Yuxin; Cheng, Yi; Li, Zheng; Zhang, Shiheng; Zhong, Zhaoyang; Wang, Dong

    2014-02-01

    Tumor angiogenesis contributes to inferior prognosis in osteosarcoma. Apurinic/apyrimidinic endonuclease 1 (APE1) and fibroblast growth factor 2 (FGF2) and its receptor 3 (FGFR3) signaling pathway plays an important role in the angiogenic process. In this study we observed that high expression of APE1, FGF2 and FGFR3, and microvessel density are positively correlated with poor prognosis of osteosarcoma patients. Furthermore, the Cox model showed that the tumor size, FGF2 and its receptor 3 (FGFR3), and microvessel density were adverse prognostic factors. Based on our clinical data, and the fact that APE1 is involved in tumor angiogenesis, we hypothesize that it is very likely that APE1 may indirectly promote angiogenesis by upregulating fibroblast FGF2 and FGFR3. Our preliminary data show small interfering RNA-mediated silence of APE1 experiments, which further supports this hypothesis. APE1-small interfering RNA significantly inhibited tumor angiogenesis by downregulating in vitro expression of FGF2 and FGFR3 in human umbilical vein endothelial cells in Matrigel tube formation assay, and further inhibited tumor growth in vivo in a mouse xenograft model. Thus, the proposed APE1-FGF2 and FGFR3 pathway may provide a novel mechanism for regulation of FGF2 and FGFR3 by APE1 in tumor angiogenesis. PMID:24329908

  13. Informatics in radiology (infoRAD): HTML and Web site design for the radiologist: a primer.

    PubMed

    Ryan, Anthony G; Louis, Luck J; Yee, William C

    2005-01-01

    A Web site has enormous potential as a medium for the radiologist to store, present, and share information in the form of text, images, and video clips. With a modest amount of tutoring and effort, designing a site can be as painless as preparing a Microsoft PowerPoint presentation. The site can then be used as a hub for the development of further offshoots (eg, Web-based tutorials, storage for a teaching library, publication of information about one's practice, and information gathering from a wide variety of sources). By learning the basics of hypertext markup language (HTML), the reader will be able to produce a simple and effective Web page that permits display of text, images, and multimedia files. The process of constructing a Web page can be divided into five steps: (a) creating a basic template with formatted text, (b) adding color, (c) importing images and multimedia files, (d) creating hyperlinks, and (e) uploading one's page to the Internet. This Web page may be used as the basis for a Web-based tutorial comprising text documents and image files already in one's possession. Finally, there are many commercially available packages for Web page design that require no knowledge of HTML.

  14. 2009 Melbourne metropolitan sewerage strategy: a portfolio of decentralised and on-site concept designs.

    PubMed

    Brown, V; Jackson, D W; Khalifé, M

    2010-01-01

    The bulk and retail water companies of the greater Melbourne area are developing the 2009 Metropolitan Sewerage Strategy to provide sustainable sewerage services to 2060. The objective of the strategy is to establish long term principles and near term actions to produce a robust sewage management system for Melbourne. Melbourne's existing sewerage system is largely centralised and discharges to two major treatment plants. Several small satellite treatment plants service local urban areas generally more distant from the centralised system. Decentralised and on-site wastewater systems are options for future sewage management and could play a role in local recycling. A portfolio of 18 on-site and decentralised concept designs was developed, applicable to the full range of urban development types in Melbourne. The concepts can be used in evaluation of metropolitan system configurations as part of future integrated water cycle planning. The options included secondary and tertiary treatment systems incorporating re-use of water for non potable uses, urine separation, black and greywater separation and composting toilets. On-site and cluster treatment systems were analysed. Each option is described by its indicative capital and operating costs, energy use and water and nutrient balances. This paper summarises and compares the portfolio mix of decentralized and on-site options in Melbourne's context.

  15. Final report on the radiological surveys of designated DX firing sites at Los Alamos National Laboratory

    SciTech Connect

    1996-09-09

    CHEMRAD was contracted by Los Alamos National Laboratory to perform USRADS{reg_sign} (UltraSonic Ranging And Data System) radiation scanning surveys at designated DX Sites at the Los Alamos National Laboratory. The primary purpose of these scanning surveys was to identify the presence of Depleted Uranium (D-38) resulting from activities at the DX Firing Sites. This effort was conducted to update the most recent surveys of these areas. This current effort was initiated with site orientation on August 12, 1996. Surveys were completed in the field on September 4, 1996. This Executive Summary briefly presents the major findings of this work. The detail survey results are presented in the balance of this report and are organized by Technical Area and Site number in section 2. This organization is not in chronological order. USRADS and the related survey methods are described in section 3. Quality Control issues are addressed in section 4. Surveys were conducted with an array of radiation detectors either mounted on a backpack frame for man-carried use (Manual mode) or on a tricycle cart (RadCart mode). The array included radiation detectors for gamma and beta surface near surface contamination as well as dose rate at 1 meter above grade. The radiation detectors were interfaced directly to an USRADS 2100 Data Pack.

  16. 2009 Melbourne metropolitan sewerage strategy: a portfolio of decentralised and on-site concept designs.

    PubMed

    Brown, V; Jackson, D W; Khalifé, M

    2010-01-01

    The bulk and retail water companies of the greater Melbourne area are developing the 2009 Metropolitan Sewerage Strategy to provide sustainable sewerage services to 2060. The objective of the strategy is to establish long term principles and near term actions to produce a robust sewage management system for Melbourne. Melbourne's existing sewerage system is largely centralised and discharges to two major treatment plants. Several small satellite treatment plants service local urban areas generally more distant from the centralised system. Decentralised and on-site wastewater systems are options for future sewage management and could play a role in local recycling. A portfolio of 18 on-site and decentralised concept designs was developed, applicable to the full range of urban development types in Melbourne. The concepts can be used in evaluation of metropolitan system configurations as part of future integrated water cycle planning. The options included secondary and tertiary treatment systems incorporating re-use of water for non potable uses, urine separation, black and greywater separation and composting toilets. On-site and cluster treatment systems were analysed. Each option is described by its indicative capital and operating costs, energy use and water and nutrient balances. This paper summarises and compares the portfolio mix of decentralized and on-site options in Melbourne's context. PMID:20705997

  17. Design, Synthesis, and Biological Evaluation of Stable Colchicine Binding Site Tubulin Inhibitors as Potential Anticancer Agents

    PubMed Central

    2015-01-01

    To block the metabolically labile sites of novel tubulin inhibitors targeting the colchicine binding site based on SMART, ABI, and PAT templates, we have designed, synthesized, and biologically tested three focused sets of new derivatives with modifications at the carbonyl linker, the para-position in the C ring of SMART template, and modification of A ring of the PAT template. Structure–activity relationships of these compounds led to the identification of new benzimidazole and imidazo[4,5-c]pyridine-fused ring templates, represented by compounds 4 and 7, respectively, which showed enhanced antitumor activity and substantially improved the metabolic stability in liver microsomes compared to SMART. MOM group replaced TMP C ring and generated a potent analogue 15, which showed comparable potency to the parent SMART compound. Further modification of PAT template yielded another potent analogue 33 with 5-indolyl substituent at A ring. PMID:25122533

  18. Technology development for the design of shallow land burial facilities at arid sites

    SciTech Connect

    Nyhan, J.W.; Abeele, W.V.; Cokal, E.J.; Perkins, B.A.; Lane, L.J.

    1984-01-01

    The field research program involving technology development for arid shallow land burial (SLB) sites is described. Field tests of biointrusion barriers at waste disposal sites and in experimental plots at Los Alamos are reported. Results of completed and on-going experiments with migration barriers for water and contaminant movement are presented. An envelope wick experiment for subsurface water management is described, and preliminary field data are reported. An integrated field experiment was designed to test individual SLB component tests related to erosion control, biobarriers, and subsurface capillary and migration barriers, and the progress made in emplacing the experiment is presented. Efforts to utilize the field data collected to validate hydrologic models (TRACR3D) important to waste management strategies are also presented. 11 references, 14 figures, 1 table.

  19. Autonomous Underwater Vehicle Survey Design for Monitoring Carbon Capture and Storage Sites

    NASA Astrophysics Data System (ADS)

    Bull, J. M.; Cevatoglu, M.; Connelly, D.; Wright, I. C.; McPhail, S.; Shitashima, K.

    2013-12-01

    Long-term monitoring of sub-seabed Carbon Capture and Storage (CCS) sites will require systems that are flexible, independent, and have long-endurance. In this presentation we will discuss the utility of autonomous underwater vehicles equipped with different sensor packages in monitoring storage sites. We will present data collected using Autosub AUV, as part of the ECO2 project, from the Sleipner area of the North Sea. The Autosub AUV was equipped with sidescan sonar, an EM2000 multibeam systems, a Chirp sub-bottom profiler, and a variety of chemical sensors. Our presentation will focus on survey design, and the simultaneous use of multiple sensor packages in environmental monitoring on the continental shelf.

  20. Development of technology for the design of shallow land burial facilities at arid sites

    NASA Astrophysics Data System (ADS)

    Nyhan, J. W.; Abeele, W. V.; Drennon, B. J.; Herrera, W. J.; Lopez, E. A.; Langhorst, G. J.; Stallings, E. A.; Walker, R. D.; Martinez, J. L.

    The Los Alamos field research program involving technology development for arid shallow land burial (SLB) sites is described. Field data are presented for an integrated field experiment, which was designed to test individual SLB component experiments related to erosion control, biobarriers, and subsurface capillary and migration barriers. Field tests of biointrusion barriers at waste disposal sites and in experimental plots are reported. The results of a joint DOE/NRC experiment to evaluate leaching and transport of sorbing (Cs, Sr, Li) and nonsorbing (I, Br) solutes in sandy silt backfill are presented for steady-state and unsteady-state flow conditions. A capillary barrier experiment performed in a large caisson (3-m diameter, 6.1 m deep) is described and a year's worth of field data is presented.

  1. Early Site Permit Demonstration Program: Guidelines for determining design basis ground motions. Volume 2, Appendices

    SciTech Connect

    Not Available

    1993-03-18

    This report develops and applies a methodology for estimating strong earthquake ground motion. The motivation was to develop a much needed tool for use in developing the seismic requirements for structural designs. An earthquake`s ground motion is a function of the earthquake`s magnitude, and the physical properties of the earth through which the seismic waves travel from the earthquake fault to the site of interest. The emphasis of this study is on ground motion estimation in Eastern North America (east of the Rocky Mountains), with particular emphasis on the Eastern United States and southeastern Canada. Eastern North America is a stable continental region, having sparse earthquake activity with rare occurrences of large earthquakes. While large earthquakes are of interest for assessing seismic hazard, little data exists from the region to empirically quantify their effects. The focus of the report is on the attributes of ground motion in Eastern North America that are of interest for the design of facilities such as nuclear power plants. This document, Volume II, contains Appendices 2, 3, 5, 6, and 7 covering the following topics: Eastern North American Empirical Ground Motion Data; Examination of Variance of Seismographic Network Data; Soil Amplification and Vertical-to-Horizontal Ratios from Analysis of Strong Motion Data From Active Tectonic Regions; Revision and Calibration of Ou and Herrmann Method; Generalized Ray Procedure for Modeling Ground Motion Attenuation; Crustal Models for Velocity Regionalization; Depth Distribution Models; Development of Generic Site Effects Model; Validation and Comparison of One-Dimensional Site Response Methodologies; Plots of Amplification Factors; Assessment of Coupling Between Vertical & Horizontal Motions in Nonlinear Site Response Analysis; and Modeling of Dynamic Soil Properties.

  2. Postclosure performance assessment of the SCP (Site Characterization Plan) conceptual design for horizontal emplacement: Revision 1

    SciTech Connect

    Not Available

    1987-08-01

    This report is a preliminary postclosure performance assessment of the repository design specified in the Site Characterization Plan Conceptual Design Report (SCP-CDR) for horizontal emplacement of high-level nuclear waste. At the time that these analyses were done, horizontal emplacement was the preferred orientation for the waste packages but vertical emplacement is now the reference design. This assessment consists of (1) a review of the regulatory requirements and strategy to demonstrate compliance with these requirements, (2) an analysis of the performance of the total repository system, (3) an analysis of the thermomechanical behavior of the repository, (4) an analysis of brine mobility in the repository, (5) an analysis of the waste package performance, (6) an analysis of the performance of seals, and (7) comments on the sensitivity of the various performance measures to uncertainties in the data and models. These are preliminary analyses and, in most cases, involve bounding calculations of the repository behavior. They have several purposes including (1) assessing how well this conceptual design ''measures up'' against requirements, (2) gaining experience in implementing the performance assessment strategy and tools and thereby learning where improvements are needed, (3) helping to identify needed data, and (4) helping to indicate required design modifications. 26 refs., 40 figs., 20 tabs.

  3. Evolution of web site design: implications for medical education on the Internet.

    PubMed

    Chu, L F; Chan, B K

    1998-09-01

    Since its inception, the world wide web (WWW) has possessed the potential for becoming a 'watershed' medium for conveying complex, structured information across vast temporal and geographical barriers. In 1995, the MedWorld project (http:(/)/medworld.stanford.edu) was created at the Stanford University School of Medicine in an effort to innovate and explore the design process of creating WWW applications specifically for medical education. Until recently, the evolution of WWW applications has been mainly driven by technological advances in client-server technology, enabling or translating traditional modes of collaborative medical education (e.g. voice, presence, print, motion) into WWW devices and applications. Many of these applications, while technologically advanced, lack focused development of interface and interactivity design, which may enhance learning experiences. WWW applications which incorporate design innovation in parity with advances in client-server technology have been termed, 'third generation' web sites and have the potential to improve the quality of WWW applications designed for medical education. This work describes how the MedWorld project has created a 'third generation' WWW application by utilizing innovation in information, interface and interactivity design to create innovative WWW technology for the medical education arena.

  4. Investigation into the optimal hydrologic design of porous concrete sites using mathematical modeling

    NASA Astrophysics Data System (ADS)

    Syrrakou, C.; Fitch, J.; Eliassen, T.; Ahearn, W.; Pinder, G. F.

    2011-12-01

    Increase in the amount of paved areas as a result of urbanization in modern societies has lead to the need of stormwater best management practices (BMPs). In that direction, porous pavement has been used successfully in regions of warm climate and application in regions of colder climate is an object of ongoing research with encouraging results to date. The significant cost and effort that accompanies the maintenance of porous pavement facilities calls for a design tool that can be used prior construction to facilitate the design process and also post production to evaluate the site's overall performance. Such a tool is a mathematical model which takes into account the different physical processes that can occur in a porous concrete system including recharge from rainfall, runoff from surrounding conventionally paved areas, vertical flow, storage and finally infiltration into the subsurface. In this research a three-dimensional saturated-unsaturated flow and transport model is modified to account for flow through the porous concrete slab and also evaporation. Runoff is accounted by means of a two-dimensional surface flow model which calculates the infiltration into the perimeter porous concrete area. The mathematical model is used to simulate a porous concrete site which operates as a public parking lot facility in Randolph, Vermont. The subgrade soil in the area of interest consists mainly of dense till deposits typically found in New England. Such deposits can result in small infiltration rates. The specific site is unique not only in terms of the underlying geology but also the heavy instrumentation not usually observed in similar sites. The instrumentation includes a number of groundwater wells which are being monitored continuously through a pressure transducer system, temperature probes installed inside the porous concrete and a detailed underdrain system located in the porous concrete's sub-base accumulating infiltrated water. Laboratory research is also

  5. Uncertainty based optimal monitoring network design for a chlorinated hydrocarbon contaminated site.

    PubMed

    Chadalavada, Sreenivasulu; Datta, Bithin; Naidu, Ravi

    2011-02-01

    An application of a newly developed optimal monitoring network for the delineation of contaminants in groundwater is demonstrated in this study. Designing a monitoring network in an optimal manner helps to delineate the contaminant plume with a minimum number of monitoring wells at optimal locations at a contaminated site. The basic principle used in this study is that the wells are installed where the measurement uncertainties are minimum at the potential monitoring locations. The development of the optimal monitoring network is based on the utilization of contaminant concentration data from an existing initial arbitrary monitoring network. The concentrations at the locations that were not sampled in the study area are estimated using geostatistical tools. The uncertainty in estimating the contaminant concentrations at such locations is used as design criteria for the optimal monitoring network. The uncertainty in the study area was quantified by using the concentration estimation variances at all the potential monitoring locations. The objective function for the monitoring network design minimizes the spatial concentration estimation variances at all potential monitoring well locations where a monitoring well is not to be installed as per the design criteria. In the proposed methodology, the optimal monitoring network is designed for the current management period and the contaminant concentration data estimated at the potential observation locations are then used as the input to the network design model. The optimal monitoring network is designed for the consideration of two different cases by assuming different initial arbitrary existing data. Three different scenarios depending on the limit of the maximum number of monitoring wells that can be allowed at any period are considered for each case. In order to estimate the efficiency of the developed optimal monitoring networks, mass estimation errors are compared for all the three different scenarios of the two

  6. Modifications to the remedial action plan and site design for stabilization of the inactive Uranium Mill Tailings Site at Green River, Utah

    SciTech Connect

    Not Available

    1994-09-01

    Modifications to the water resources protection strategy detailed in the remedial action plan for the Green River, Utah, disposal site are presented. The modifications are based on new information, including ground water quality data collected after remedial action was completed and on a revised assessment of disposal cell design features, surface conditions, and site hydrogeology. The modifications will result in compliance with the U.S. EPA proposed ground water standards (52 FR 36000 (1987)).

  7. Binding site elucidation and structure guided design of macrocyclic IL-17A antagonists

    PubMed Central

    Liu, Shenping; Dakin, Leslie A.; Xing, Li; Withka, Jane M.; Sahasrabudhe, Parag V.; Li, Wei; Banker, Mary Ellen; Balbo, Paul; Shanker, Suman; Chrunyk, Boris A.; Guo, Zuojun; Chen, Jinshan M.; Young, Jennifer A.; Bai, Guoyun; Starr, Jeremy T.; Wright, Stephen W.; Bussenius, Joerg; Tan, Sheng; Gopalsamy, Ariamala; Lefker, Bruce A.; Vincent, Fabien; Jones, Lyn H.; Xu, Hua; Hoth, Lise R.; Geoghegan, Kieran F.; Qiu, Xiayang; Bunnage, Mark E.; Thorarensen, Atli

    2016-01-01

    Interleukin-17A (IL-17A) is a principal driver of multiple inflammatory and immune disorders. Antibodies that neutralize IL-17A or its receptor (IL-17RA) deliver efficacy in autoimmune diseases, but no small-molecule IL-17A antagonists have yet progressed into clinical trials. Investigation of a series of linear peptide ligands to IL-17A and characterization of their binding site has enabled the design of novel macrocyclic ligands that are themselves potent IL-17A antagonists. PMID:27527709

  8. Advanced Imaging for Glaucoma Study: Design, Baseline Characteristics, and Inter-Site Comparison

    PubMed Central

    Le, Phuc V.; Zhang, Xinbo; Francis, Brian A.; Varma, Rohit; Greenfield, David S.; Schuman, Joel S.; Loewen, Nils; Huang, David

    2014-01-01

    Purpose To report the baseline characteristics of the participants in the Advanced Imaging for Glaucoma Study. To compare the participating sites for variations among subjects and the performance of imaging instruments. Design Multi-center longitudinal observational cohort study Methods A total of 788 participants (1,329 eyes) were enrolled from three academic referral centers. There were 145 participants (289 eyes) in the normal group, 394 participants (663 eyes) in the glaucoma suspect/preperimetric glaucoma group, and 249 participants (377 eyes) in the perimetric glaucoma group. Participants underwent a full clinical exam, standard automated perimetry, and imaging with time-domain and Fourier-domain optical coherence tomography (OCT), scanning laser polarimetry, and confocal scanning laser ophthalmoscopy. Main Outcome Measures The baseline average, population standard deviation, and repeatability of imaging-derived anatomic variables were reported for each technology and center. Results Compared to the normal participants, glaucoma suspect/preperimetric glaucoma and perimetric glaucoma groups had significantly reduced anatomic measurements. Repeatability of nerve fiber layer thickness was best for Fourier-domain OCT (overall coefficient of variation < 2%), followed by time-domain OCT (coefficient of variation 2-2.9%), scanning laser polarimetry (coefficient of variation 2.6-4.5%), and confocal scanning laser ophthalmoscopy rim area (coefficient of variation 4.2-7.6%). A mixed-effects model showed that the differences between sites was less than 25 percent of the variation within groups and less than the differences between the normal and glaucoma suspect/preperimetric glaucoma group. Conclusions Site-to-site variation was smaller than both the variation within groups and the changes due to glaucoma. Therefore pooling of participants between sites is appropriate. PMID:25447111

  9. Remedial action plan and site design for stabilization of the inactive uranium mill tailings sites at Rifle, Colorado

    SciTech Connect

    Not Available

    1990-02-01

    This volume contains appendices D6 through D8 containing laboratory test data: from MK-F investigation, 1987, Old Rifle and New Rifle sites; on bentonite amended radon barrier material; and from MK-F investigation, 1987, riprap tests.

  10. Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site.

    PubMed

    Kanekiyo, Masaru; Bu, Wei; Joyce, M Gordon; Meng, Geng; Whittle, James R R; Baxa, Ulrich; Yamamoto, Takuya; Narpala, Sandeep; Todd, John-Paul; Rao, Srinivas S; McDermott, Adrian B; Koup, Richard A; Rossmann, Michael G; Mascola, John R; Graham, Barney S; Cohen, Jeffrey I; Nabel, Gary J

    2015-08-27

    Epstein-Barr virus (EBV) represents a major global health problem. Though it is associated with infectious mononucleosis and ∼200,000 cancers annually worldwide, a vaccine is not available. The major target of immunity is EBV glycoprotein 350/220 (gp350) that mediates attachment to B cells through complement receptor 2 (CR2/CD21). Here, we created self-assembling nanoparticles that displayed different domains of gp350 in a symmetric array. By focusing presentation of the CR2-binding domain on nanoparticles, potent neutralizing antibodies were elicited in mice and non-human primates. The structurally designed nanoparticle vaccine increased neutralization 10- to 100-fold compared to soluble gp350 by targeting a functionally conserved site of vulnerability, improving vaccine-induced protection in a mouse model. This rational approach to EBV vaccine design elicited potent neutralizing antibody responses by arrayed presentation of a conserved viral entry domain, a strategy that can be applied to other viruses.

  11. ZrO2 -Based Alternatives to Conventional Propane Dehydrogenation Catalysts: Active Sites, Design, and Performance.

    PubMed

    Otroshchenko, Tatyana; Sokolov, Sergey; Stoyanova, Mariana; Kondratenko, Vita A; Rodemerck, Uwe; Linke, David; Kondratenko, Evgenii V

    2015-12-21

    Non-oxidative dehydrogenation of propane to propene is an established large-scale process that, however, faces challenges, particularly in catalyst development; these are the toxicity of chromium compounds, high cost of platinum, and catalyst durability. Herein, we describe the design of unconventional catalysts based on bulk materials with a certain defect structure, for example, ZrO2 promoted with other metal oxides. Comprehensive characterization supports the hypothesis that coordinatively unsaturated Zr cations are the active sites for propane dehydrogenation. Their concentration can be adjusted by varying the kind of ZrO2 promoter and/or supporting tiny amounts of hydrogenation-active metal. Accordingly designed Cu(0.05 wt %)/ZrO2 -La2 O3 showed industrially relevant activity and durability over ca. 240 h on stream in a series of 60 dehydrogenation and oxidative regeneration cycles between 550 and 625 °C. PMID:26566072

  12. Computational design of a red fluorophore ligase for site-specific protein labeling in living cells

    DOE PAGESBeta

    Liu, Daniel S.; Nivon, Lucas G.; Richter, Florian; Goldman, Peter J.; Deerinck, Thomas J.; Yao, Jennifer Z.; Richardson, Douglas; Phipps, William S.; Ye, Anne Z.; Ellisman, Mark H.; et al

    2014-10-13

    In this study, chemical fluorophores offer tremendous size and photophysical advantages over fluorescent proteins but are much more challenging to target to specific cellular proteins. Here, we used Rosetta-based computation to design a fluorophore ligase that accepts the red dye resorufin, starting from Escherichia coli lipoic acid ligase. X-ray crystallography showed that the design closely matched the experimental structure. Resorufin ligase catalyzed the site-specific and covalent attachment of resorufin to various cellular proteins genetically fused to a 13-aa recognition peptide in multiple mammalian cell lines and in primary cultured neurons. We used resorufin ligase to perform superresolution imaging of themore » intermediate filament protein vimentin by stimulated emission depletion and electron microscopies. This work illustrates the power of Rosetta for major redesign of enzyme specificity and introduces a tool for minimally invasive, highly specific imaging of cellular proteins by both conventional and superresolution microscopies.« less

  13. Computational design of a red fluorophore ligase for site-specific protein labeling in living cells

    SciTech Connect

    Liu, Daniel S.; Nivon, Lucas G.; Richter, Florian; Goldman, Peter J.; Deerinck, Thomas J.; Yao, Jennifer Z.; Richardson, Douglas; Phipps, William S.; Ye, Anne Z.; Ellisman, Mark H.; Drennan, Catherine L.; Baker, David; Ting, Alice Y.

    2014-10-13

    In this study, chemical fluorophores offer tremendous size and photophysical advantages over fluorescent proteins but are much more challenging to target to specific cellular proteins. Here, we used Rosetta-based computation to design a fluorophore ligase that accepts the red dye resorufin, starting from Escherichia coli lipoic acid ligase. X-ray crystallography showed that the design closely matched the experimental structure. Resorufin ligase catalyzed the site-specific and covalent attachment of resorufin to various cellular proteins genetically fused to a 13-aa recognition peptide in multiple mammalian cell lines and in primary cultured neurons. We used resorufin ligase to perform superresolution imaging of the intermediate filament protein vimentin by stimulated emission depletion and electron microscopies. This work illustrates the power of Rosetta for major redesign of enzyme specificity and introduces a tool for minimally invasive, highly specific imaging of cellular proteins by both conventional and superresolution microscopies.

  14. Computational design of a red fluorophore ligase for site-specific protein labeling in living cells

    PubMed Central

    Liu, Daniel S.; Nivón, Lucas G.; Richter, Florian; Goldman, Peter J.; Deerinck, Thomas J.; Yao, Jennifer Z.; Richardson, Douglas; Phipps, William S.; Ye, Anne Z.; Ellisman, Mark H.; Drennan, Catherine L.; Baker, David; Ting, Alice Y.

    2014-01-01

    Chemical fluorophores offer tremendous size and photophysical advantages over fluorescent proteins but are much more challenging to target to specific cellular proteins. Here, we used Rosetta-based computation to design a fluorophore ligase that accepts the red dye resorufin, starting from Escherichia coli lipoic acid ligase. X-ray crystallography showed that the design closely matched the experimental structure. Resorufin ligase catalyzed the site-specific and covalent attachment of resorufin to various cellular proteins genetically fused to a 13-aa recognition peptide in multiple mammalian cell lines and in primary cultured neurons. We used resorufin ligase to perform superresolution imaging of the intermediate filament protein vimentin by stimulated emission depletion and electron microscopies. This work illustrates the power of Rosetta for major redesign of enzyme specificity and introduces a tool for minimally invasive, highly specific imaging of cellular proteins by both conventional and superresolution microscopies. PMID:25313043

  15. Remedial Action Plan and site design for stabilization of the inactive uranium mill tailings site at Durango, Colorado: Attachment 2, Geology report. Revised final report

    SciTech Connect

    Not Available

    1991-12-01

    Detailed investigations of geologic, geomorphic, and seismic conditions at the Bodo Canyon disposal site were conducted. The purpose of these investigations was basic site characterization and identification of potential geologic hazards that could affect long-term site stability. Subsequent engineering studies, such as analyses of hydrologic and liquefaction hazards, used the data developed in these studies. The geomorphic analysis was employed in the design of effective erosion protection. Studies of the regional and local seismotectonic setting, which included a detailed search for possible capable faults within a 65 kilometer radius of the site, provided the basis for seismic design parameters. The scope of work performed included the following: Compilation and analysis of previous published and unpublished geologic literature and maps; Review of historical and instrumental earthquake data; Review of site-specific subsurface geologic data, including lithologic and geophysical logs of exploratory boreholes advanced in the site area; Photogeologic interpretations of existing conventional aerial photographs; and, Ground reconnaissance and mapping of the site region.

  16. Remedial Action Plan and site design for stabilization of the inactive uranium mill tailings site at Gunnison, Colorado. Attachment 2, Geology report: Final report

    SciTech Connect

    Not Available

    1992-10-01

    Detailed investigations of geologic, geomorphic, and seismic conditions at the Landfill disposal site were conducted. The purpose of these studies was basic site characterization and identification of potential geologic hazards that could affect long-term site stability. Subsequent engineering studies, such as analyses of hydrologic and liquefaction hazards, used the data developed in these studies. The geomorphic analysis was employed in the design of effective erosion protection. Studies of the regional and local seismotectonic setting, which included a detailed search for possible capable faults within a 65-kilometer (km) (40-mile) radius of the site, provided the basis for seismic design parameters. The scope of work performed included the following: Compilation and analysis of previous published and unpublished geologic literature and maps. Review of historical and instrumental earthquake data. Review of site-specific subsurface geologic data, including lithologic and geophysical logs of exploratory boreholes advanced in the site area. Photogeologic interpretations of existing conventional aerial photographs. Ground reconnaissance and mapping of the site region.

  17. Design of Hanford Site 4th Generation Multi Function Corrosion Monitoring System

    SciTech Connect

    NORMAN, E.C.

    2000-08-30

    This document describes the design of the fourth-generation corrosion monitoring system scheduled to be installed in DST 241-AN-104 early in fiscal year 2001. A fourth-generation multi-function corrosion monitoring system has been designed for installation into a DST in the 241-AN farm at the Hanford Site in FY 2001. Improvements and upgrades from the third-generation system (installed in 241-AN-105) that have been incorporated into the fourth-generation system include: Addition of a built-in water lance to assist installation of probe into tanks with a hard crust layer at the surface of the waste; and Improvement of the electrode mounting apparatus used to attach the corrosion monitoring electrodes to the stainless steel probe body (new design simplifies probe assembly/wiring). These new features improve on the third-generation design and yield a system that is easier to fabricate and install, provides for a better understanding of the relationship between corrosion and other tank operating parameters, and optimizes the use of the riser that houses the probe in the tank.

  18. Health Literacy Online: A Guide to Writing and Designing Easy-to-Use Health Web Sites.

    PubMed

    Hou, Su-I

    2012-09-01

    Health Literacy Online: A Guide to Writing and Designing Easy-to-Use Health Web Sites is a practical and well-written resource for public health and health communication professionals and web designers. This guide builds on the principles of web usability and adds to existing best practices by providing research-based strategies for writing and designing health websites especially for users with limited literacy and health literacy skills. This guide synthesizes years of lessons learned from Office of Disease Prevention and Health Promotion's original research with hundreds of web users, experience with revising the healthfinder.gov, as well as strategies supported by the Research-Based Web Design and Usability Guidelines (Usability.gov). In the United States, roughly one third of adults have limited literacy skills, yet far more (as many as 90%) have limited health literacy skills, meaning they have trouble understanding complex health information. This how-to guide is timely and developed with the aim of creating easy-to-use health websites to reach as many web users as possible, especially those with limited literacy and health literacy skills. PMID:22763891

  19. Structure-guided inhibitor design for human FAAH by interspecies active site conversion

    SciTech Connect

    Mileni, Mauro; Johnson, Douglas S.; Wang, Zhigang; Everdeen, Daniel S.; Liimatta, Marya; Pabst, Brandon; Bhattacharya, Keshab; Nugent, Richard A.; Kamtekar, Satwik; Cravatt, Benjamin F.; Ahn, Kay; Stevens, Raymond C.

    2008-11-24

    The integral membrane enzyme fatty acid amide hydrolase (FAAH) hydrolyzes the endocannabinoid anandamide and related amidated signaling lipids. Genetic or pharmacological inactivation of FAAH produces analgesic, anxiolytic, and antiinflammatory phenotypes but not the undesirable side effects of direct cannabinoid receptor agonists, indicating that FAAH may be a promising therapeutic target. Structure-based inhibitor design has, however, been hampered by difficulties in expressing the human FAAH enzyme. Here, we address this problem by interconverting the active sites of rat and human FAAH using site-directed mutagenesis. The resulting humanized rat (h/r) FAAH protein exhibits the inhibitor sensitivity profiles of human FAAH but maintains the high-expression yield of the rat enzyme. We report a 2.75-{angstrom} crystal structure of h/rFAAH complexed with an inhibitor, N-phenyl-4-(quinolin-3-ylmethyl)piperidine-1-carboxamide (PF-750), that shows strong preference for human FAAH. This structure offers compelling insights to explain the species selectivity of FAAH inhibitors, which should guide future drug design programs.

  20. Development and application of site mapping methods for the design of glycosaminoglycans.

    PubMed

    Agostino, Mark; Gandhi, Neha S; Mancera, Ricardo L

    2014-09-01

    Glycosaminoglycans (GAGs) are complex polysaccharides involved in a wide range of biological signaling events, as well as being important as biological structural materials. Despite the ubiquity and importance of GAG-protein interactions in biological systems and potentially as therapeutic targets, detailed structures of such interactions are sparse in availability. Computational methods can provide detailed structural knowledge of these interactions; however, they should be evaluated against suitable test systems prior to their widespread use. In this study, we have investigated the application of automated molecular docking and interaction mapping techniques to characterizing GAG-protein interactions. A series of high-resolution X-ray crystal structures of GAGs in complex with proteins was used to evaluate the approaches. Accurately scoring the pose fitting best with the crystal structure was a challenge for all docking programs evaluated. The site mapping technique offered excellent prediction of the key residues involved in ligand recognition, comparable to the best pose and improved over the top-ranked pose. A design protocol incorporating site- and ligand-based mapping techniques was developed and applied to identify GAGs capable of binding to acidic fibroblast growth factor (aFGF). The protocol was able to identify ligands known to bind to aFGF and accurately able to predict the binding modes of those ligands when using a known ligand-binding conformation of the protein. This study demonstrates the value of mapping-based techniques in identifying specific GAG epitopes recognized by proteins and for GAG-based drug design.

  1. Remedial Action Plan and site conceptual design for stabilization of the inactive uranium mill tailings site at Spook, Wyoming

    SciTech Connect

    Matthews, M L; Sullivan, M

    1990-04-01

    This Remedial Action Plan (RAP) has been developed to serve a threefold purpose. It presents the series of activities which are proposed by the US Department of Energy (DOE) to accomplish long-term stabilization and control of radioactive materials at an inactive uranium processing site northeast of Casper, Wyoming, and referred to as the Spook site. It provides a characterization of the present conditions at the site and also serves to document the concurrence of the State of Wyoming and the US Nuclear Regulatory Commission (NRC) in the remedial action. This agreement, upon execution by the DOE and the State of Wyoming, and concurrence by the NRC, becomes Appendix B of the Cooperative Agreement.

  2. Clustered DNA Lesions Containing 5-Formyluracil and AP Site: Repair via the BER System

    PubMed Central

    Belousova, Ekaterina A.; Vasil'eva, Inna A.; Moor, Nina A.; Zatsepin, Timofey S.; Oretskaya, Tatiana S.; Lavrik, Olga I.

    2013-01-01

    Lesions in the DNA arise under ionizing irradiation conditions or various chemical oxidants as a single damage or as part of a multiply damaged site within 1–2 helical turns (clustered lesion). Here, we explored the repair opportunity of the apurinic/apyrimidinic site (AP site) composed of the clustered lesion with 5-formyluracil (5-foU) by the base excision repair (BER) proteins. We found, that if the AP site is shifted relative to the 5-foU of the opposite strand, it could be repaired primarily via the short-patch BER pathway. In this case, the cleavage efficiency of the AP site-containing DNA strand catalyzed by human apurinic/apyrimidinic endonuclease 1 (hAPE1) decreased under AP site excursion to the 3'-side relative to the lesion in the other DNA strand. DNA synthesis catalyzed by DNA polymerase lambda was more accurate in comparison to the one catalyzed by DNA polymerase beta. If the AP site was located exactly opposite 5-foU it was expected to switch the repair to the long-patch BER pathway. In this situation, human processivity factor hPCNA stimulates the process. PMID:23936307

  3. Epitope-based peptide vaccine design and target site depiction against Ebola viruses: an immunoinformatics study.

    PubMed

    Khan, M A; Hossain, M U; Rakib-Uz-Zaman, S M; Morshed, M N

    2015-07-01

    Ebola viruses (EBOVs) have been identified as an emerging threat in recent year as it causes severe haemorrhagic fever in human. Epitope-based vaccine design for EBOVs remains a top priority because a mere progress has been made in this regard. Another reason is the lack of antiviral drug and licensed vaccine although there is a severe outbreak in Central Africa. In this study, we aimed to design an epitope-based vaccine that can trigger a significant immune response as well as to prognosticate inhibitor that can bind with potential drug target sites using various immunoinformatics and docking simulation tools. The capacity to induce both humoral and cell-mediated immunity by T cell and B cell was checked for the selected protein. The peptide region spanning 9 amino acids from 42 to 50 and the sequence TLASIGTAF were found as the most potential B and T cell epitopes, respectively. This peptide could interact with 12 HLAs and showed high population coverage up to 80.99%. Using molecular docking, the epitope was further appraised for binding against HLA molecules to verify the binding cleft interaction. In addition with this, the allergenicity of the epitopes was also evaluated. In the post-therapeutic strategy, docking study of predicted 3D structure identified suitable therapeutic inhibitor against targeted protein. However, this computational epitope-based peptide vaccine designing and target site prediction against EBOVs open up a new horizon which may be the prospective way in Ebola viruses research; the results require validation by in vitro and in vivo experiments.

  4. Exhaustive de novo design of low-molecular-weight fragments against the ATP-binding site of DNA-gyrase.

    PubMed

    Firth-Clark, Stuart; Todorov, Nikolay P; Alberts, Ian L; Williams, Anthony; James, Timothy; Dean, Philip M

    2006-01-01

    We present a de novo design approach to generating small fragments in the DNA-gyrase ATP-binding site using the computational drug design platform SkelGen. We have generated an exhaustive number of structural possibilities, which were subsequently filtered for site complementarity and synthetic tractability. A number of known active fragments are found, but most of the species created are potentially novel and could be valuable for further elaboration and development into lead-like structures.

  5. Activation of GLP-1 Receptor Enhances Neuronal Base Excision Repair via PI3K-AKT-Induced Expression of Apurinic/Apyrimidinic Endonuclease 1

    PubMed Central

    Yang, Jenq-Lin; Chen, Wei-Yu; Chen, Yin-Ping; Kuo, Chao-Ying; Chen, Shang-Der

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is an intestinal-secreted incretin that increases cellular glucose up-take to decrease blood sugar. Recent studies, however, suggest that the function of GLP-1 is not only to decrease blood sugar, but also acts as a neurotrophic factor that plays a role in neuronal survival, neurite outgrowth, and protects synaptic plasticity and memory formation from effects of β-amyloid. Oxidative DNA damage occurs during normal neuron-activity and in many neurological diseases. Our study describes how GLP-1 affected the ability of neurons to ameliorate oxidative DNA damage. We show that activation of GLP-1 receptor (GLP-1R) protect cortical neurons from menadione induced oxidative DNA damage via a signaling pathway involving enhanced DNA repair. GLP-1 stimulates DNA repair by activating the cyclic AMP response element binding protein (CREB) which, consequently, induces the expression of apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme in the base excision DNA repair (BER) pathway. In this study, APE1 expression was down-regulated as a consequence phosphatidylinositol-3 kinase (PI3K) suppression by the inhibitor LY294002, but not by the suppression of MEK activity. Ischemic stroke is typically caused by overwhelming oxidative-stress in brain cells. Administration of exentin-4, an analogue of GLP-1, efficiently enhanced DNA repair in brain cells of ischemic stroke rats. Our study suggests that a new function of GLP-1 is to elevate DNA repair by inducing the expression of the DNA repair protein APE1. PMID:27698937

  6. Activation of GLP-1 Receptor Enhances Neuronal Base Excision Repair via PI3K-AKT-Induced Expression of Apurinic/Apyrimidinic Endonuclease 1

    PubMed Central

    Yang, Jenq-Lin; Chen, Wei-Yu; Chen, Yin-Ping; Kuo, Chao-Ying; Chen, Shang-Der

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is an intestinal-secreted incretin that increases cellular glucose up-take to decrease blood sugar. Recent studies, however, suggest that the function of GLP-1 is not only to decrease blood sugar, but also acts as a neurotrophic factor that plays a role in neuronal survival, neurite outgrowth, and protects synaptic plasticity and memory formation from effects of β-amyloid. Oxidative DNA damage occurs during normal neuron-activity and in many neurological diseases. Our study describes how GLP-1 affected the ability of neurons to ameliorate oxidative DNA damage. We show that activation of GLP-1 receptor (GLP-1R) protect cortical neurons from menadione induced oxidative DNA damage via a signaling pathway involving enhanced DNA repair. GLP-1 stimulates DNA repair by activating the cyclic AMP response element binding protein (CREB) which, consequently, induces the expression of apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme in the base excision DNA repair (BER) pathway. In this study, APE1 expression was down-regulated as a consequence phosphatidylinositol-3 kinase (PI3K) suppression by the inhibitor LY294002, but not by the suppression of MEK activity. Ischemic stroke is typically caused by overwhelming oxidative-stress in brain cells. Administration of exentin-4, an analogue of GLP-1, efficiently enhanced DNA repair in brain cells of ischemic stroke rats. Our study suggests that a new function of GLP-1 is to elevate DNA repair by inducing the expression of the DNA repair protein APE1.

  7. Ginkgolide B revamps neuroprotective role of apurinic/apyrimidinic endonuclease 1 and mitochondrial oxidative phosphorylation against Aβ25-35 -induced neurotoxicity in human neuroblastoma cells.

    PubMed

    Kaur, Navrattan; Dhiman, Monisha; Perez-Polo, J Regino; Mantha, Anil K

    2015-06-01

    Accumulating evidence points to roles for oxidative stress, amyloid beta (Aβ), and mitochondrial dysfunction in the pathogenesis of Alzheimer's disease (AD). In neurons, the base excision repair pathway is the predominant DNA repair (BER) pathway for repairing oxidized base lesions. Apurinic/apyrimidinic endonuclease 1 (APE1), a multifunctional enzyme with DNA repair and reduction-oxidation activities, has been shown to enhance neuronal survival after oxidative stress. This study seeks to determine 1) the effect of Aβ25-35 on reactive oxygen species (ROS)/reactive nitrogen species (RNS) levels, 2) the activities of respiratory complexes (I, III, and IV), 3) the role of APE1 by ectopic expression, and 4) the neuromodulatory role of ginkgolide B (GB; from the leaves of Ginkgo biloba). The pro-oxidant Aβ25-35 peptide treatment increased the levels of ROS/RNS in human neuroblastoma IMR-32 and SH-SY5Y cells, which were decreased after pretreatment with GB. Furthermore, the mitochondrial APE1 level was found to be decreased after treatment with Aβ25-35 up to 48 hr, and the level was increased significantly in cells pretreated with GB. The oxidative phosphorylation (OXPHOS; activities of complexes I, III, and IV) indicated that Aβ25-35 treatment decreased activities of complexes I and IV, and pretreatment with GB and ectopic APE1 expression enhanced these activities significantly compared with Aβ25-35 treatment. Our results indicate that ectopic expression of APE1 potentiates neuronal cells to overcome the oxidative damage caused by Aβ25-35 . In addition, GB has been shown to modulate the mitochondrial OXPHOS against Aβ25-35 -induced oxidative stress and also to regulate the levels of ROS/RNS in the presence of ectopic APE1. This study presents findings from a new point of view to improve therapeutic potential for AD via the synergistic neuroprotective role played by APE1 in combination with the phytochemical GB.

  8. Downregulation of the DNA repair enzyme apurinic/apyrimidinic endonuclease 1 stimulates transforming growth factor-β1 production and promotes actin rearrangement.

    PubMed

    Sakai, Yuri; Yamamori, Tohru; Yasui, Hironobu; Inanami, Osamu

    2015-05-22

    The DNA repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1) plays a central role in base excision repair and functions as a reductive activator of various transcription factors. Multiple other functionalities have been ascribed to APE1 in addition to these major functions. A recent study showed that APE1 knockdown upregulated the expression of a set of genes related to extracellular matrix (ECM) production, indicating an additional novel biological role for this enzyme. Based on this finding, we have investigated the effect of APE1 downregulation on ECM-related gene expression and its biological consequences. Endogenous APE1 expression was downregulated in human cervical carcinoma HeLa cells and human lung carcinoma A549 cells using siRNA. When the expression of six ECM-related genes (TGFB1, LAMC1, FN1, COL1A1, COL3A1, and COL4A1) was evaluated, we found that APE1 knockdown upregulated the expression of TGFB1 in both cell lines. APE1 downregulation promoted actin rearrangement, inducing F-actin accumulation in HeLa cells and the dissipation of stress fibers in A549 cells. We also discovered that APE1 knockdown enhanced cellular motility in A549 cells, which was suppressed by the inhibition of transforming growth factor (TGF)-β1 signaling. These results suggested that APE1 controls the organization of actin cytoskeleton through the regulation of TGF-β1 expression, providing novel insights into the biological significance of APE1. PMID:25858321

  9. Role of the Nfo and ExoA apurinic/apyrimidinic endonucleases in repair of DNA damage during outgrowth of Bacillus subtilis spores.

    PubMed

    Ibarra, Juan R; Orozco, Alma D; Rojas, Juan A; López, Karina; Setlow, Peter; Yasbin, Ronald E; Pedraza-Reyes, Mario

    2008-03-01

    Germination and outgrowth are critical steps for returning Bacillus subtilis spores to life. However, oxidative stress due to full hydration of the spore core during germination and activation of metabolism in spore outgrowth may generate oxidative DNA damage that in many species is processed by apurinic/apyrimidinic (AP) endonucleases. B. subtilis spores possess two AP endonucleases, Nfo and ExoA; the outgrowth of spores lacking both of these enzymes was slowed, and the spores had an elevated mutation frequency, suggesting that these enzymes repair DNA lesions induced by oxidative stress during spore germination and outgrowth. Addition of H2O2 also slowed the outgrowth of nfo exoA spores and increased the mutation frequency, and nfo and exoA mutations slowed the outgrowth of spores deficient in either RecA, nucleotide excision repair (NER), or the DNA-protective alpha/beta-type small acid-soluble spore proteins (SASP). These results suggest that alpha/beta-type SASP protect DNA of germinating spores against damage that can be repaired by Nfo and ExoA, which is generated either spontaneously or promoted by addition of H2O2. The contribution of RecA and Nfo/ExoA was similar to but greater than that of NER in repair of DNA damage generated during spore germination and outgrowth. However, nfo and exoA mutations increased the spontaneous mutation frequencies of outgrown spores lacking uvrA or recA to about the same extent, suggesting that DNA lesions generated during spore germination and outgrowth are processed by Nfo/ExoA in combination with NER and/or RecA. These results suggest that Nfo/ExoA, RecA, the NER system, and alpha/beta-type SASP all contribute to the repair of and/or protection against oxidative damage of DNA in germinating and outgrowing spores.

  10. Remedial Action Plan and Site Design for Stabilization of the Inactive Uranium Mill Tailings Site, Maybell, Colorado. Remedial action selection report: Attachment 2, Geology report, Final

    SciTech Connect

    Not Available

    1994-06-01

    The Maybell uranium mill tailings site is 25 miles (mi) (40 kilometers [km]) west of the town of Craig, Colorado, in Moffat County, in the northwestern part of the state. The unincorporated town of Maybell is 5 road mi (8 km) southwest of the site. The designated site covers approximately 110 acres (ac) (45 hectares [ha]) and consists of a concave-shaped tailings pile and rubble from the demolition of the mill buildings buried in the former mill area. Contaminated materials at the Maybell processing site include the tailings pile, which has an average depth of 20 feet (ft) (6 meters [m]) and contains 2.8 million cubic yards (yd{sup 3}) (2.1 million cubic meters [m{sup 3}]) of tailings. The former mill processing area is on the north side of the site and contains 20,000 yd{sup 3} (15,000 m{sup 3}) of contaminated demolition debris. Off-pile contamination is present and includes areas adjacent to the tailings pile, as well as contamination dispersed by wind and surface water flow. The volume of off-pile contamination to be placed in the disposal cell is 550,000 yd{sup 3} (420,000 m{sup 3}). The total volume of contaminated materials to be disposed of as part of the remedial action is estimated to be 3.37 million yd{sup 3} (2.58 million m{sup 3}). Information presented in this Final Remedial Action Plan (RAP) and referenced in supporting documents represents the current disposal cell design features and ground water compliance strategy proposed by the US Department of Energy (DOE) for the Maybell, Colorado, tailings site. Both the disposal cell design and the ground water compliance strategy have changed from those proposed prior to the preliminary final RAP document as a result of prudent site-specific technical evaluations.

  11. Remedial action plan and site design for stabilization of the inactive uranium mill tailings sites at Slick Rock, Colorado: Remedial Action Selection Report. Preliminary final

    SciTech Connect

    Not Available

    1994-03-01

    This proposed remedial action plan incorporates the results of detailed investigation of geologic, geomorphic, and seismic conditions at the proposed disposal site. The proposed remedial action will consist of relocating the uranium mill tailings, contaminated vicinity property materials, demolition debris, and windblown/waterborne materials to a permanent repository at the proposed Burro Canyon disposal cell. The proposed disposal site will be geomorphically stable. Seismic design parameters were developed for the geotechnical analyses of the proposed cell. Cell stability was analyzed to ensure long-term performance of the disposal cell in meeting design standards, including slope stability, settlement, and liquefaction potential. The proposed cell cover and erosion protection features were also analyzed and designed to protect the RRM (residual radioactive materials) against surface water and wind erosion. The location of the proposed cell precludes the need for permanent drainage or interceptor ditches. Rock to be used on the cell top-, side-, and toeslopes was sized to withstand probable maximum precipitation events.

  12. Catalysis by Design: Well-Defined Single-Site Heterogeneous Catalysts.

    PubMed

    Pelletier, Jérémie D A; Basset, Jean-Marie

    2016-04-19

    Heterogeneous catalysis, a field important industrially and scientifically, is increasingly seeking and refining strategies to render itself more predictable. The main issue is due to the nature and the population of catalytically active sites. Their number is generally low to very low, their "acid strengths" or " redox properties" are not homogeneous, and the material may display related yet inactive sites on the same material. In many heterogeneous catalysts, the discovery of a structure-activity reationship is at best challenging. One possible solution is to generate single-site catalysts in which most, if not all, of the sites are structurally identical. Within this context and using the right tools, the catalyst structure can be designed and well-defined, to reach a molecular understanding. It is then feasible to understand the structure-activity relationship and to develop predictable heterogeneous catalysis. Single-site well-defined heterogeneous catalysts can be prepared using concepts and tools of surface organometallic chemistry (SOMC). This approach operates by reacting organometallic compounds with surfaces of highly divided oxides (or of metal nanoparticles). This strategy has a solid track record to reveal structure-activity relationship to the extent that it is becoming now quite predictable. Almost all elements of the periodical table have been grafted on surfaces of oxides (from simple oxides such as silica or alumina to more sophisticated materials regarding composition or porosity). Considering catalytic hydrocarbon transformations, heterogeneous catalysis outcome may now be predicted based on existing mechanistic proposals and the rules of molecular chemistry (organometallic, organic) associated with some concepts of surface sciences. A thorough characterization of the grafted metal centers must be carried out using tools spanning from molecular organometallic or surface chemistry. By selection of the metal, its ligand set, and the support taken

  13. Catalysis by Design: Well-Defined Single-Site Heterogeneous Catalysts.

    PubMed

    Pelletier, Jérémie D A; Basset, Jean-Marie

    2016-04-19

    Heterogeneous catalysis, a field important industrially and scientifically, is increasingly seeking and refining strategies to render itself more predictable. The main issue is due to the nature and the population of catalytically active sites. Their number is generally low to very low, their "acid strengths" or " redox properties" are not homogeneous, and the material may display related yet inactive sites on the same material. In many heterogeneous catalysts, the discovery of a structure-activity reationship is at best challenging. One possible solution is to generate single-site catalysts in which most, if not all, of the sites are structurally identical. Within this context and using the right tools, the catalyst structure can be designed and well-defined, to reach a molecular understanding. It is then feasible to understand the structure-activity relationship and to develop predictable heterogeneous catalysis. Single-site well-defined heterogeneous catalysts can be prepared using concepts and tools of surface organometallic chemistry (SOMC). This approach operates by reacting organometallic compounds with surfaces of highly divided oxides (or of metal nanoparticles). This strategy has a solid track record to reveal structure-activity relationship to the extent that it is becoming now quite predictable. Almost all elements of the periodical table have been grafted on surfaces of oxides (from simple oxides such as silica or alumina to more sophisticated materials regarding composition or porosity). Considering catalytic hydrocarbon transformations, heterogeneous catalysis outcome may now be predicted based on existing mechanistic proposals and the rules of molecular chemistry (organometallic, organic) associated with some concepts of surface sciences. A thorough characterization of the grafted metal centers must be carried out using tools spanning from molecular organometallic or surface chemistry. By selection of the metal, its ligand set, and the support taken

  14. Specialized control panels designed for on-site compression of natural gas

    SciTech Connect

    Kane, J.

    1995-03-01

    As the world moves into the environmentally clean burning era of alternative fuels such a CNG and LNC, Frank W. Murphy Mfr., has developed a series of specialized control panels for on-site compression of natural gas. These control panels are designated as Levels I, II and III to reflect the degree of control provided and are fully compatible with NFPA-52, NFPA-37 and industry guidelines. The new controllers, produced by Murphy in its Tulsa, Oklahoma, U.S.A. plant, have been engineered to cover a wide variety of requirements from simple start/stop operation of the compressor and driver to complete station automation with remote communication capabilities. In cases requiring greater sophistication than the standard options, the controllers have the capability of being expanded or engineered to meet application demands. This paper discusses the specifications and applications of these new controllers. 3 figs.

  15. Molecular docking sites designed for the generation of highly crystalline covalent organic frameworks

    NASA Astrophysics Data System (ADS)

    Ascherl, Laura; Sick, Torben; Margraf, Johannes T.; Lapidus, Saul H.; Calik, Mona; Hettstedt, Christina; Karaghiosoff, Konstantin; Döblinger, Markus; Clark, Timothy; Chapman, Karena W.; Auras, Florian; Bein, Thomas

    2016-04-01

    Covalent organic frameworks (COFs) formed by connecting multidentate organic building blocks through covalent bonds provide a platform for designing multifunctional porous materials with atomic precision. As they are promising materials for applications in optoelectronics, they would benefit from a maximum degree of long-range order within the framework, which has remained a major challenge. We have developed a synthetic concept to allow consecutive COF sheets to lock in position during crystal growth, and thus minimize the occurrence of stacking faults and dislocations. Hereby, the three-dimensional conformation of propeller-shaped molecular building units was used to generate well-defined periodic docking sites, which guided the attachment of successive building blocks that, in turn, promoted long-range order during COF formation. This approach enables us to achieve a very high crystallinity for a series of COFs that comprise tri- and tetradentate central building blocks. We expect this strategy to be transferable to a broad range of customized COFs.

  16. Design of multiligand inhibitors for the swine flu H1N1 neuraminidase binding site

    PubMed Central

    Narayanan, Manoj M; Nair, Chandrasekhar B; Sanjeeva, Shilpa K; Rao, PV Subba; Pullela, Phani K; Barrow, Colin J

    2013-01-01

    Viral neuraminidase inhibitors such as oseltamivir and zanamivir prevent early virus multiplication by blocking sialic acid cleavage on host cells. These drugs are effective for the treatment of a variety of influenza subtypes, including swine flu (H1N1). The binding site for these drugs is well established and they were designed based on computational docking studies. We show here that some common natural products have moderate inhibitory activity for H1N1 neuraminidase under docking studies. Significantly, docking studies using AutoDock for biligand and triligand forms of these compounds (camphor, menthol, and methyl salicylate linked via methylene bridges) indicate that they may bind in combination with high affinity to the H1N1 neuraminidase active site. These results also indicate that chemically linked biligands and triligands of these natural products could provide a new class of drug leads for the prevention and treatment of influenza. This study also highlights the need for a multiligand docking algorithm to understand better the mode of action of natural products, wherein multiple active ingredients are present. PMID:23983477

  17. 77 FR 77076 - Notice of Intent: Designation of an Expanded Ocean Dredged Material Disposal Site (ODMDS) off...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-31

    ... AGENCY Notice of Intent: Designation of an Expanded Ocean Dredged Material Disposal Site (ODMDS) off... prepare a National Environmental Policy Document for all ODMDS designations (63 FR 58045, October 1998... approximately 7.18 square miles in size, for the disposal of dredged material from the proposed harbor...

  18. 76 FR 26720 - Notice of Intent: Designation of an Expanded Ocean Dredged Material Disposal Site (ODMDS) off...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-09

    ... AGENCY Notice of Intent: Designation of an Expanded Ocean Dredged Material Disposal Site (ODMDS) off Fort... Environmental Policy Document for all ODMDS designations (63 FR 58045, October 1998). For Further Information... material from the potential construction dredging at Port Everglades Harbor. The need for an expanded...

  19. 75 FR 39523 - Notice of Intent: Designation of an Ocean Dredged Material Disposal Site (ODMDS) Off the Mouth of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-09

    ... AGENCY Notice of Intent: Designation of an Ocean Dredged Material Disposal Site (ODMDS) Off the Mouth of... policy to prepare a voluntary National Environmental Policy document for all ODMDS designations (63 FR... size, offshore the mouth of the St. Johns River for the disposal of dredged material from...

  20. 75 FR 38129 - Freescale Semiconductor, Inc., Hardware/Software Design and Manufacturing A Including On-Site...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-01

    ... published in the Federal Register on May 28, 2010 (75 FR 30070). At the request of the State Agency, the... Manufacturing A Including On-Site Leased Workers From TAC Worldwide, GDA Technologies, Inc., Manpower, Ion..., GDA Technologies, Inc., Manpower, Ion Design, Design Solutions, Inc., Veriseo, SilconElite and...

  1. Use of an Improved Matching Algorithm to Select Scaffolds for Enzyme Design Based on a Complex Active Site Model

    PubMed Central

    Huang, Xiaoqiang; Xue, Jing; Lin, Min; Zhu, Yushan

    2016-01-01

    Active site preorganization helps native enzymes electrostatically stabilize the transition state better than the ground state for their primary substrates and achieve significant rate enhancement. In this report, we hypothesize that a complex active site model for active site preorganization modeling should help to create preorganized active site design and afford higher starting activities towards target reactions. Our matching algorithm ProdaMatch was improved by invoking effective pruning strategies and the native active sites for ten scaffolds in a benchmark test set were reproduced. The root-mean squared deviations between the matched transition states and those in the crystal structures were < 1.0 Å for the ten scaffolds, and the repacking calculation results showed that 91% of the hydrogen bonds within the active sites are recovered, indicating that the active sites can be preorganized based on the predicted positions of transition states. The application of the complex active site model for de novo enzyme design was evaluated by scaffold selection using a classic catalytic triad motif for the hydrolysis of p-nitrophenyl acetate. Eighty scaffolds were identified from a scaffold library with 1,491 proteins and four scaffolds were native esterase. Furthermore, enzyme design for complicated substrates was investigated for the hydrolysis of cephalexin using scaffold selection based on two different catalytic motifs. Only three scaffolds were identified from the scaffold library by virtue of the classic catalytic triad-based motif. In contrast, 40 scaffolds were identified using a more flexible, but still preorganized catalytic motif, where one scaffold corresponded to the α-amino acid ester hydrolase that catalyzes the hydrolysis and synthesis of cephalexin. Thus, the complex active site modeling approach for de novo enzyme design with the aid of the improved ProdaMatch program is a promising approach for the creation of active sites with high catalytic

  2. Use of an Improved Matching Algorithm to Select Scaffolds for Enzyme Design Based on a Complex Active Site Model.

    PubMed

    Huang, Xiaoqiang; Xue, Jing; Lin, Min; Zhu, Yushan

    2016-01-01

    Active site preorganization helps native enzymes electrostatically stabilize the transition state better than the ground state for their primary substrates and achieve significant rate enhancement. In this report, we hypothesize that a complex active site model for active site preorganization modeling should help to create preorganized active site design and afford higher starting activities towards target reactions. Our matching algorithm ProdaMatch was improved by invoking effective pruning strategies and the native active sites for ten scaffolds in a benchmark test set were reproduced. The root-mean squared deviations between the matched transition states and those in the crystal structures were < 1.0 Å for the ten scaffolds, and the repacking calculation results showed that 91% of the hydrogen bonds within the active sites are recovered, indicating that the active sites can be preorganized based on the predicted positions of transition states. The application of the complex active site model for de novo enzyme design was evaluated by scaffold selection using a classic catalytic triad motif for the hydrolysis of p-nitrophenyl acetate. Eighty scaffolds were identified from a scaffold library with 1,491 proteins and four scaffolds were native esterase. Furthermore, enzyme design for complicated substrates was investigated for the hydrolysis of cephalexin using scaffold selection based on two different catalytic motifs. Only three scaffolds were identified from the scaffold library by virtue of the classic catalytic triad-based motif. In contrast, 40 scaffolds were identified using a more flexible, but still preorganized catalytic motif, where one scaffold corresponded to the α-amino acid ester hydrolase that catalyzes the hydrolysis and synthesis of cephalexin. Thus, the complex active site modeling approach for de novo enzyme design with the aid of the improved ProdaMatch program is a promising approach for the creation of active sites with high catalytic

  3. Emergence of new red-shifted carbon nanotube photoluminescence based on proximal doped-site design

    NASA Astrophysics Data System (ADS)

    Shiraki, Tomohiro; Shiraishi, Tomonari; Juhász, Gergely; Nakashima, Naotoshi

    2016-06-01

    Single-walled carbon nanotubes (SWNTs) show unique photoluminescence (PL) in the near-infrared (NIR) region. Here we propose a concept based on the proximal modification in local covalent functionalization of SWNTs. Quantum mechanical simulations reveal that the SWNT band gap changes specifically based on the proximal doped-site design. Thus, we synthesize newly-designed bisdiazonium molecules and conduct local fucntionalisation of SWNTs. Consequently, new red-shifted PL (E112*) from the bisdiazonium-modified SWNTs with (6, 5) chirality is recognized around 1250 nm with over ~270 nm Stokes shift from the PL of the pristine SWNTs and the PL wavelengths are shifted depending on the methylene spacer lengths of the modifiers. The present study revealed that SWNT PL modulation is enable by close-proximity-local covalent modification, which is highly important for fundamental understanding of intrinsic SWNT PL properties as well as exciton engineering-based applications including photonic devices and (bio)imaging/sensing.

  4. Emergence of new red-shifted carbon nanotube photoluminescence based on proximal doped-site design

    NASA Astrophysics Data System (ADS)

    Shiraki, Tomohiro; Shiraishi, Tomonari; Juhász, Gergely; Nakashima, Naotoshi

    2016-06-01

    Single-walled carbon nanotubes (SWNTs) show unique photoluminescence (PL) in the near-infrared (NIR) region. Here we propose a concept based on the proximal modification in local covalent functionalization of SWNTs. Quantum mechanical simulations reveal that the SWNT band gap changes specifically based on the proximal doped-site design. Thus, we synthesize newly-designed bisdiazonium molecules and conduct local fucntionalisation of SWNTs. Consequently, new red-shifted PL (E112*) from the bisdiazonium-modified SWNTs with (6, 5) chirality is recognized around 1250 nm with over ~270 nm Stokes shift from the PL of the pristine SWNTs and the PL wavelengths are shifted depending on the methylene spacer lengths of the modifiers. The present study revealed that SWNT PL modulation is enable by close-proximity-local covalent modification, which is highly important for fundamental understanding of intrinsic SWNT PL properties as well as exciton engineering–based applications including photonic devices and (bio)imaging/sensing.

  5. Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site.

    PubMed

    Kanekiyo, Masaru; Bu, Wei; Joyce, M Gordon; Meng, Geng; Whittle, James R R; Baxa, Ulrich; Yamamoto, Takuya; Narpala, Sandeep; Todd, John-Paul; Rao, Srinivas S; McDermott, Adrian B; Koup, Richard A; Rossmann, Michael G; Mascola, John R; Graham, Barney S; Cohen, Jeffrey I; Nabel, Gary J

    2015-08-27

    Epstein-Barr virus (EBV) represents a major global health problem. Though it is associated with infectious mononucleosis and ∼200,000 cancers annually worldwide, a vaccine is not available. The major target of immunity is EBV glycoprotein 350/220 (gp350) that mediates attachment to B cells through complement receptor 2 (CR2/CD21). Here, we created self-assembling nanoparticles that displayed different domains of gp350 in a symmetric array. By focusing presentation of the CR2-binding domain on nanoparticles, potent neutralizing antibodies were elicited in mice and non-human primates. The structurally designed nanoparticle vaccine increased neutralization 10- to 100-fold compared to soluble gp350 by targeting a functionally conserved site of vulnerability, improving vaccine-induced protection in a mouse model. This rational approach to EBV vaccine design elicited potent neutralizing antibody responses by arrayed presentation of a conserved viral entry domain, a strategy that can be applied to other viruses. PMID:26279189

  6. Emergence of new red-shifted carbon nanotube photoluminescence based on proximal doped-site design

    PubMed Central

    Shiraki, Tomohiro; Shiraishi, Tomonari; Juhász, Gergely; Nakashima, Naotoshi

    2016-01-01

    Single-walled carbon nanotubes (SWNTs) show unique photoluminescence (PL) in the near-infrared (NIR) region. Here we propose a concept based on the proximal modification in local covalent functionalization of SWNTs. Quantum mechanical simulations reveal that the SWNT band gap changes specifically based on the proximal doped-site design. Thus, we synthesize newly-designed bisdiazonium molecules and conduct local fucntionalisation of SWNTs. Consequently, new red-shifted PL (E112*) from the bisdiazonium-modified SWNTs with (6, 5) chirality is recognized around 1250 nm with over ~270 nm Stokes shift from the PL of the pristine SWNTs and the PL wavelengths are shifted depending on the methylene spacer lengths of the modifiers. The present study revealed that SWNT PL modulation is enable by close-proximity-local covalent modification, which is highly important for fundamental understanding of intrinsic SWNT PL properties as well as exciton engineering–based applications including photonic devices and (bio)imaging/sensing. PMID:27345862

  7. Early Site Permit Demonstration Program: Guidelines for determining design basis ground motions. Volume 1

    SciTech Connect

    Not Available

    1993-03-18

    This report develops and applies a methodology for estimating strong earthquake ground motion. The motivation was to develop a much needed tool for use in developing the seismic requirements for structural designs. An earthquake`s ground motion is a function of the earthquake`s magnitude, and the physical properties of the earth through which the seismic waves travel from the earthquake fault to the site of interest. The emphasis of this study is on ground motion estimation in Eastern North America (east of the Rocky Mountains), with particular emphasis on the Eastern United States and southeastern Canada. Eastern North America is a stable continental region, having sparse earthquake activity with rare occurrences of large earthquakes. While large earthquakes are of interest for assessing seismic hazard, little data exists from the region to empirically quantify their effects. Therefore, empirically based approaches that are used for other regions, such as Western North America, are not appropriate for Eastern North America. Moreover, recent advances in science and technology have now made it possible to combine theoretical and empirical methods to develop new procedures and models for estimating ground motion. The focus of the report is on the attributes of ground motion in Eastern North America that are of interest for the design of facilities such as nuclear power plants. Specifically considered are magnitudes M from 5 to 8, distances from 0 to 500 km, and frequencies from 1 to 35 Hz.

  8. Remedial action plan and site design for stabilization of the inactive uranium mill tailings site at Tuba City, Arizona. Text, Appendices A, B, and C: Final report

    SciTech Connect

    Not Available

    1989-08-01

    This Remedial Action Plan (RAP) has been developed to serve a threefold purpose. It presents the series of activities which are proposed by the US Department of Energy (DOE) to accomplish long-term stabilization and control of radioactive materials at the inactive uranium processing site near Tuba City, Arizona. It provides a characterization of the present conditions of the site. It also serves to document the concurrence of the Navajo Nation, the Hopi Tribe, US Bureau of Indian Affairs (BIA), and the US Nuclear Regulatory Commission (NRC) in the remedial action. This agreement, upon execution by DOE, the Navajo Nation, and the Hopi Tribe, and concurrence by NRC, becomes Appendix B of the Cooperative Agreement. Following the introduction, contents are as follows: Section 2.0 presents the EPA standards, including a discussion of their objectives. Section 3.0 summarizes the present site characteristics and provides a definition of site-specific problems. Section 4.0 is the site design for the proposed action. Section 5.0 summarizes the plan for ensuring environmental, health, and safety protection for the surrounding community and the on-site workers. Section 6.0 presents a detailed listing of the responsibilities of the project participants. Section 7.0 describes the features of the long-term surveillance and maintenance plan. Section 8.0 presents the quality assurance aspects of the project. Section 9.0 documents the ongoing activities to keep the public informed and participating in the project.

  9. Design-Basis Flood Estimation for Site Characterization at Nuclear Power Plants in the United States of America

    SciTech Connect

    Prasad, Rajiv; Hibler, Lyle F.; Coleman, Andre M.; Ward, Duane L.

    2011-11-01

    The purpose of this document is to describe approaches and methods for estimation of the design-basis flood at nuclear power plant sites. Chapter 1 defines the design-basis flood and lists the U.S. Nuclear Regulatory Commission's (NRC) regulations that require estimation of the design-basis flood. For comparison, the design-basis flood estimation methods used by other Federal agencies are also described. A brief discussion of the recommendations of the International Atomic Energy Agency for estimation of the design-basis floods in its member States is also included.

  10. Remedial Action Plan and site design for stabilization of the inactive uranium mill tailings site at Mexican Hat, Utah: Appendix E. Final report

    SciTech Connect

    1988-07-01

    This document provides Appendix E of the Remedial Action Plan (RAP) presented in 1988 for the stabilization of the inactive uranium mill tailings at the Mexican Hat, Utah site. The RAP was developed to serve a two- fold purpose. It presents the activities proposed by the Department of Energy (DOE) to accomplish long-term stabilization and control of the residual radioactive materials (RRM) from Monument Valley, Arizona, and Mexican Hat, Utah, at the Mexican Hat disposal site. It also serves to document the concurrence of both the Navajo Nation and the Nuclear Regulatory Commission (NRC) in the remedial action. This agreement, upon execution by the DOE and the Navajo Nation and concurrence by the NRC, becomes Appendix B of the Cooperative Agreement. The RAP has been structured to provide a comprehensive understanding of the remedial action proposed for the Monument Valley and Mexican Hat sites. It includes specific design and construction requirements for the remedial action.

  11. Seismic design of circular-section concrete-lined underground openings: Preclosure performance considerations for the Yucca Mountain Site

    SciTech Connect

    Richardson, A.M.; Blejwas, T.E.

    1992-07-01

    Yucca Mountain, the potential site of a repository for high-level radioactive waste, is situated in a region of natural and man-made seismicity. Underground openings excavated at this site must be designed for worker safety in the seismic environment anticipated for the preclosure period. This includes accesses developed for site characterization regardless of the ultimate outcome of the repository siting process. Experience with both civil and mining structures has shown that underground openings are much more resistant to seismic effects than surface structures, and that even severe dynamic strains can usually be accommodated with proper design. This paper discusses the design and performance of lined openings in the seismic environment of the potential site. The types and ranges of possible ground motions (seismic loads) are briefly discussed. Relevant historical records of underground opening performance during seismic loading are reviewed. Simple analytical methods of predicting liner performance under combined in situ, thermal, and seismic loading are presented, and results of calculations are discussed in the context of realistic performance requirements for concrete-lined openings for the preclosure period. Design features that will enhance liner stability and mitigate the impact of the potential seismic load are reviewed. The paper is limited to preclosure performance concerns involving worker safety because present decommissioning plans specify maintaining the option for liner removal at seal locations, thus decoupling liner design from repository postclosure performance issues.

  12. Site Identification by Ligand Competitive Saturation (SILCS) simulations for fragment-based drug design.

    PubMed

    Faller, Christina E; Raman, E Prabhu; MacKerell, Alexander D; Guvench, Olgun

    2015-01-01

    Fragment-based drug design (FBDD) involves screening low molecular weight molecules ("fragments") that correspond to functional groups found in larger drug-like molecules to determine their binding to target proteins or nucleic acids. Based on the principle of thermodynamic additivity, two fragments that bind nonoverlapping nearby sites on the target can be combined to yield a new molecule whose binding free energy is the sum of those of the fragments. Experimental FBDD approaches, like NMR and X-ray crystallography, have proven very useful but can be expensive in terms of time, materials, and labor. Accordingly, a variety of computational FBDD approaches have been developed that provide different levels of detail and accuracy.The Site Identification by Ligand Competitive Saturation (SILCS) method of computational FBDD uses all-atom explicit-solvent molecular dynamics (MD) simulations to identify fragment binding. The target is "soaked" in an aqueous solution with multiple fragments having different identities. The resulting computational competition assay reveals what small molecule types are most likely to bind which regions of the target. From SILCS simulations, 3D probability maps of fragment binding called "FragMaps" can be produced. Based on the probabilities relative to bulk, SILCS FragMaps can be used to determine "Grid Free Energies (GFEs)," which provide per-atom contributions to fragment binding affinities. For essentially no additional computational overhead relative to the production of the FragMaps, GFEs can be used to compute Ligand Grid Free Energies (LGFEs) for arbitrarily complex molecules, and these LGFEs can be used to rank-order the molecules in accordance with binding affinities. PMID:25709034

  13. Site Identification by Ligand Competitive Saturation (SILCS) Simulations for Fragment-Based Drug Design

    PubMed Central

    Faller, Christina E.; Raman, E. Prabhu; MacKerell, Alexander D.; Guvench, Olgun

    2015-01-01

    Fragment-based drug design (FBDD) involves screening low molecular weight molecules (“fragments”) that correspond to functional groups found in larger drug-like molecules to determine their binding to target proteins or nucleic acids. Based on the principle of thermodynamic additivity, two fragments that bind non-overlapping nearby sites on the target can be combined to yield a new molecule whose binding free energy is the sum of those of the fragments. Experimental FBDD approaches, like NMR and X-ray crystallography, have proven very useful but can be expensive in terms of time, materials, and labor. Accordingly, a variety of computational FBDD approaches have been developed that provide different levels of detail and accuracy. The Site Identification by Ligand Competitive Saturation (SILCS) method of computational FBDD uses all-atom explicit-solvent molecular dynamics (MD) simulations to identify fragment binding. The target is “soaked” in an aqueous solution with multiple fragments having different identities. The resulting computational competition assay reveals what small molecule types are most likely to bind which regions of the target. From SILCS simulations, 3D probability maps of fragment binding called “FragMaps” can be produced. Based on the probabilities relative to bulk, SILCS FragMaps can be used to determine “Grid Free Energies (GFEs),” which provide per-atom contributions to fragment binding affinities. For essentially no additional computational overhead relative to the production of the FragMaps, GFEs can be used to compute Ligand Grid Free Energies (LGFEs) for arbitrarily complex molecules, and these LGFEs can be used to rank-order the molecules in accordance with binding affinities. PMID:25709034

  14. Remedial action plan and site design for stabilization of the inactive uranium mill tailings sites at Slick Rock, Colorado. Final report

    SciTech Connect

    1996-08-01

    This document contains the page changes for Attachment 3, Ground Water Hydrology Report dated August, 1996 for the Remedial Action Plan and Site Design for Stabilization of the Inactive Uranium Mill Tailings at Slick Rock, Colorado. This portion of Attachment 3 contains the Table of Contents pages i and ii, and pages numbered 3-3 through 3-56 of the Ground Water Hydrology Report. Also included are the cover sheets for Appendix A, B, and C to Attachment 3.

  15. Rational Catalyst Design of Titanium-Silica Materials Aided by Site-Specific Titration Tools

    NASA Astrophysics Data System (ADS)

    Eaton, Todd Robert

    between particle and crystal size, as obtained from XRD. In the course of establishing these relationships we've gained the knowledge of how to control TiO x structure, which enables the design of new and better catalysts. Understanding the synthesis-structure-function relationships allow for the design of a tandem photo/thermocatalytic reaction system for producing and consuming H2O2. By partially overcoating a TiO 2 photocatalyst with a ˜2 nm silica layer we observe a 56-fold rate improvement compared to bare-TiO2 for H2O2 synthesis from the proton-assisted reduction of O2. Addition of metal-SiO2 thermocatalysts (metal=Ti, Nb, or Ta) with sites needed for H2O2 activation creates a tandem system wherein the H2O2 produced in situ is utilized for alkene epoxidation. Compared to a thermocatalytic-only system, the tandem system accelerates epoxidation for cis-cyclooctene(11x faster), styrene(20x) and 1-octene(30x). This approach demonstrates a means for epoxidation with O2 that avoids H2O2 purification and transport, simplifies the total process, provides new opportunities for control by independent H2O2 production and consumption in the same reactor, and enhances rates relative to thermocatalytic-only epoxidation by intimately coupling H2O2 generation and consumption. Critically, establishment of titanium-silica synthesis-structure-function relationships enables the design of new catalysts and systems that are less energy- and material-intensive, leading towards more sustainable chemistry.

  16. Pilot-scale demonstration of surfactant-enhanced PCE solubilization at the Bachman Road site. 1. Site characterization and test design.

    PubMed

    Abriola, Linda M; Drummond, Chad D; Hahn, Ernest J; Hayes, Kim F; Kibbey, Tohren C G; Lemke, Lawrence D; Pennell, Kurt D; Petrovskis, Erik A; Ramsburg, C Andrew; Rathfelder, Klaus M

    2005-03-15

    A pilot-scale demonstration of surfactant-enhanced aquifer remediation (SEAR) was conducted to recover dense nonaqueous phase liquid (DNAPL) tetrachloroethene (PCE) from a sandy glacial outwash aquifer underlying a former dry cleaning facility at the Bachman Road site in Oscoda, MI. Part one of this two-part paper describes site characterization efforts and a comprehensive approach to SEAR test design, effectively integrating laboratory and modeling studies. Aquifer coring and drive point sampling suggested the presence of PCE-DNAPL in a zone beneath an occupied building. A narrow PCE plume emanating from the vicinity of this building discharges into Lake Huron. The shallow unconfined aquifer, characterized by relatively homogeneous fine-medium sand deposits, an underlying clay layer, and the absence of significant PCE transformation products, was judged suitable for the demonstration of SEAR. Tween 80 was selected for application based upon its favorable solubilization performance in batch and two-dimensional sand tank treatability studies, biodegradation potential, and regulatory acceptance. Three-dimensional flow and transport models were employed to develop a robust design for surfactant delivery and recovery. Physical and fiscal constraints led to an unusual hydraulic design, in which surfactant was flushed across the regional groundwater gradient, facilitating the delivery of concentrations of Tween 80 exceeding 1% (wt) throughout the treatment zone. The potential influence of small-scale heterogeneity on PCE-DNAPL distribution and SEAR performance was assessed through numerical simulations incorporating geostatistical permeability fields based upon available core data. For the examined conditions simulated PCE recoveries ranged from 94to 99%. The effluent treatment system design consisted of low-profile air strippers coupled with carbon adsorption to trap off-gas PCE and discharge of treated aqueous effluent to a local wastewater treatment plant. The

  17. Paleolimnology Web Portal: A Web Site Designed to Increase Paleolimnology Data Availability

    NASA Astrophysics Data System (ADS)

    Eakin, C. M.; Moy, C. M.; Habermann, T.; Gross, W. S.; Keltner, J. M.

    2001-12-01

    Despite widespread use of lacustrine records to interpret paleolimnologic and paleoclimatic change, there is a large gap between the data published in peer-reviewed journals and those submitted for archive and available to other researchers online. A primary goal of the World Data Center (WDC) for paleoclimatology and the International Geosphere-Biosphere Programme (IGBP) - Past Global Changes (PAGES) core programme is to have full and open sharing of all data sets needed for global change studies. To help improve the quantity and quality of data submitted to the WDC for Paleoclimatology, we are developing online data submission and advanced interactive browse and access tools. Our poster presents a new web-site designed to make paleolimnology data more accessible by incorporating web-based data submission forms, a multi-proxy relational database, and interactive mapping tools. The WDC for Paleoclimatology is currently designing intuitive and streamlined web-based submission forms, which will allow investigators to quickly submit their data and metadata on-line. We are also importing all existing data and metadata in our archives into a multiproxy relational database that will allow users to quickly query and retrieve paleolimnological data, as well as display the data in various formats. Furthermore, we are implementing two Paleolimnology mapping tools that will allow users to search, display, and query data in a geographical format. The first tool, WebMapper, uses a Java applet to draw maps and display metadata. This will be supplemented by a plotting tool that will provide basic plotting functions to allow users to examine data before downloading them. The second mapping tool, ArcIMS, allows users to overlay paleoclimatic data with various GIS data sets in addition to providing basic spatial analysis functions. We believe that these new web-based features will encourage more extensive data sharing and submission, making paleolimnological data more available and

  18. Wind load comparison for the ASCE standard 7 and the Hanford site design criteria

    SciTech Connect

    Giller, R.A., Westinghouse Hanford

    1996-07-16

    This document provides calculations and discussions to compare Hanford Site wind load criteria with the current national standard for wind loads (ASCE 7, 1995). Site criteria uses the 1988 edition ASCE 7.

  19. Conceptual design study. Standard Floating Nuclear Power Plant on inshore site and Modified Floating Nuclear Power plant on upriver site

    NASA Astrophysics Data System (ADS)

    1982-02-01

    Both plants/designs are technically feasible. Both compare favorably with conventional nuclear plants with respect to licensability, quality of construction, reliability of operation, and safety. Both offer considerable reductions in construction schedule over conventional nuclear plants. It was estimated that if project durations were reduced by three years the cost of a 1100 MWe nuclear unit could be decreased by $260 million to $450 million. The allowance for funds during construction (AFDC) was estimated to be $929 million for a 1260 MWe nuclear plant with a commercial operation date in 1992. Reducing the schedule from 12 to 9 years, a reduction of 25%, implies a savings in AFDC alone of approximately $230 million. .DLN : Killed, superseded by N85-21597 NASA patent

  20. Design, construction, and performance of a single geomembrane liner system at a residual waste disposal site in western Pennsylvania

    SciTech Connect

    Khilji, K.H.; Gould, S.E.; Hamel, T.W.; Thomas, W.B.

    1997-11-01

    This paper examines the effectiveness of a single geomembrane-lined deep valley coal ash/coal mine refuse disposal site to maintain ground-water quality after 10 years of operation. The site occupies over 81 hectares (ha) [200 acres (ac)] in western Pennsylvania. The effectiveness of the liner system was evaluated based on an assessment of the site`s ground-water quality. The liner system was designed in 1983. Selection of geosynthetics and drainage materials, interface shear values, and construction control methods were based on laboratory testing, field investigations, slope stability analyses, and construction load analyses. Diligent construction quality control was applied during all aspects of site development. To examine the site`s ground-water quality, the ground-water monitoring network was sampled approximately once every six weeks for one year. Results of statistical analyses show that the liner system is effectively separating disposal site leachate from ground water and that the site is not degrading ground water.

  1. 78 FR 29687 - Ocean Dumping; Atchafalaya-West Ocean Dredged Material Disposal Site Designation

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-21

    ... evaluated ] using EPA's ocean disposal criteria at 40 CFR Part 228 and compared in the EIS. Of the sites... effects from dredged material placement in the water column, sediments, or benthos of the site. These... AGENCY 40 CFR Part 228 Ocean Dumping; Atchafalaya-West Ocean Dredged Material Disposal Site...

  2. Designing an in-flight airborne calibration site using experience from vicarious radiometric satellite calibration

    NASA Astrophysics Data System (ADS)

    Livens, Stefan; Debruyn, Walter; Sterckx, Sindy; Reusen, Ils

    2011-11-01

    Laboratory calibration of electro-optical sensors is preferably complemented by regular in-flight verification. This checks whether the lab calibration parameters remain valid or recalibration is necessary. In-flight verification can be achieved by vicarious calibration using in-flight measurements of calibration targets. We intend to identify and design a set of suitable radiometric calibration targets. For this, we borrow from expertise gained with the PROBA-V satellite calibration system, which uses multiple vicarious methods relying on diverse natural on-ground targets. Besides reflectance based calibration using ground measurements, the PROBA-V calibration methods are unproven for use in airborne calibration. The selected targets should be suitable for the calibration of both multispectral and hyperspectral imagers. We start from general requirements for radiometric targets and investigate their applicability to airborne calibration. From this we identify two possible sets of natural calibration sites in Belgium. One set, located in the Campine region, contains small water bodies and sandy lakesides. Another set is located in the Westhoek region near the Belgian coast. It offers better suitable water bodies, as well as sandy areas, grass fields and dark targets. Airborne calibration lends itself to the use of smaller artifical targets. We propose to complement the natural targets with a portable target consisting of agricultural nets with different densities. The definition of sets of calibration targets, both natural and artificial can facilitate the investigation of the usability of vicarious targets and method for inflight radiometric verification.

  3. Geotechnical, Hydrogeologic and Vegetation Data Package for 200-UW-1 Waste Site Engineered Surface Barrier Design

    SciTech Connect

    Ward, Andy L.

    2007-11-26

    Fluor Hanford (FH) is designing and assessing the performance of engineered barriers for final closure of 200-UW-1 waste sites. Engineered barriers must minimize the intrusion and water, plants and animals into the underlying waste to provide protection for human health and the environment. The Pacific Northwest National Laboratory (PNNL) developed Subsurface Transport Over Multiple Phases (STOMP) simulator is being used to optimize the performance of candidate barriers. Simulating barrier performance involves computation of mass and energy transfer within a soil-atmosphere-vegetation continuum and requires a variety of input parameters, some of which are more readily available than others. Required input includes parameter values for the geotechnical, physical, hydraulic, and thermal properties of the materials comprising the barrier and the structural fill on which it will be constructed as well as parameters to allow simulation of plant effects. This report provides a data package of the required parameters as well as the technical basis, rationale and methodology used to obtain the parameter values.

  4. Site-specific integration and tailoring of cassette design for sustainable gene transfer.

    PubMed

    Lombardo, Angelo; Cesana, Daniela; Genovese, Pietro; Di Stefano, Bruno; Provasi, Elena; Colombo, Daniele F; Neri, Margherita; Magnani, Zulma; Cantore, Alessio; Lo Riso, Pietro; Damo, Martina; Pello, Oscar M; Holmes, Michael C; Gregory, Philip D; Gritti, Angela; Broccoli, Vania; Bonini, Chiara; Naldini, Luigi

    2011-08-21

    Integrative gene transfer methods are limited by variable transgene expression and by the consequences of random insertional mutagenesis that confound interpretation in gene-function studies and may cause adverse events in gene therapy. Site-specific integration may overcome these hurdles. Toward this goal, we studied the transcriptional and epigenetic impact of different transgene expression cassettes, targeted by engineered zinc-finger nucleases to the CCR5 and AAVS1 genomic loci of human cells. Analyses performed before and after integration defined features of the locus and cassette design that together allow robust transgene expression without detectable transcriptional perturbation of the targeted locus and its flanking genes in many cell types, including primary human lymphocytes. We thus provide a framework for sustainable gene transfer in AAVS1 that can be used for dependable genetic manipulation, neutral marking of the cell and improved safety of therapeutic applications, and demonstrate its feasibility by rapidly generating human lymphocytes and stem cells carrying targeted and benign transgene insertions.

  5. Site study plan for Exploratory shaft facilities design foundation boreholes (shaft surface facility foundation borings), Deaf Smith County Site, Texas: Surface-based geotechnical field program: Preliminary draft

    SciTech Connect

    Not Available

    1987-12-01

    This site study plan describes the Exploratory Shaft Facilities (ESF) Design Foundation Boreholes field activities to be conducted during early stages of Site Characterization at the Deaf Smith County, Texas, site. The field program has been designed to provide data useful in addressing information/data needs resulting from federal/state/local regulations, and repository program requirements. Approximately 50 foundation boreholes will be drilled within the ESP location to provide data necessary for design of the ESF and to satisfy applicable shaft permitting requirements. Soils and subsurface rock will be sampled as the foundation boreholes are advanced. Soil samples or rock core will be taken through the Blackwater Draw and Ogallala Formations and the Dockum Group. Hydrologic testing will be performed in boreholes that penetrates the water table. In-situ elastic properties will be determined from both the soil strata and rock units along the length of the boreholes. Field methods/tests are chosen that provide the best or only means of obtaining the required data. The Salt Repository Project (SRP) Networks specify the schedule under which the program will operate. Drilling will not begin until after site ground water baseline conditions have been established. The Technical Field Services Contractor is responsible for conducting the field program of drilling and testing. Samples and data will be handled and reported in accordance with established SRP procedures. A quality assurance program will be utilized to assure that activities affecting quality are performed correctly and that the appropriate documentation is maintained. 25 refs., 10 figs., 6 tabs.

  6. Site Selection for the European ELT: working package included in the European FP6 ``ELT design study'' contract

    NASA Astrophysics Data System (ADS)

    Muñoz-Tuñón, C.; Sarazin, M.; Vernin, J.

    2007-10-01

    The site selection for the future European Large Telescope (E-ELT) is a key issue within the European proposal funded by the European Union (EU), within the ``ELT design study'' proposal. The organization, working scheme and baseline frameworks are reviewed. For the definition of the working package WP12000 ``Site Characterization'', important use has been done of previous work in the definition of techniques and tools for the study of the atmosphere above observing sites. We have also taken advantage of the number of data already available which have naturally defined a ranking among the known places which have also been taken as a base line for pre-selecting the candidate sites. The work will last 4 years, it started in 2005 and is organized in subtasks, working packages WP, whose main objectives are the following: WP12100: to characterize two top astronomical sites (ORM and North-Paranal) and to explore three other alternatives (Macon in Argentina, Izaña in Spain and Aklim in Morocco) suitable to install an ELT under the best conditions (Dome C is been currently under investigation, and no particular effort will be put in this site, but rather its atmospheric properties will be compared to the above mentioned sites). WP12200 is dedicated to design, build and operate a set of standard equipment in all the sites and to perform long term campaign. WP12300 will investigate wavefront properties over large baselines (50-100 m) corresponding to the size of the future ELT, as well as the fine characterization of the optical turbulence within the boundary layer. A similar plan is being carried out by the Thirty Meter Telescope (TMT) site selection team. For the sake of saving resources (budget and people), the TMT preselected sites (all in the American Continent) are not included in our European study.

  7. A terrain-based paired-site sampling design to assess biodiversity losses from eastern hemlock decline

    USGS Publications Warehouse

    Young, J.A.; Smith, D.R.; Snyder, C.D.; Lemarie, D.P.

    2002-01-01

    Biodiversity surveys are often hampered by the inability to control extraneous sources of variability introduced into comparisons of populations across a heterogenous landscape. If not specifically accounted for a priori, this noise can weaken comparisons between sites, and can make it difficult to draw inferences about specific ecological processes. We developed a terrain-based, paired-site sampling design to analyze differences in aquatic biodiversity between streams draining eastern hemlock (Tsuga canadensis) forests, and those draining mixed hardwood forests in Delaware Water Gap National Recreation Area (USA). The goal of this design was to minimize variance due to terrain influences on stream communities, while representing the range of hemlock dominated stream environments present in the park. We used geographic information systems (GIS) and cluster analysis to define and partition hemlock dominated streams into terrain types based on topographic variables and stream order. We computed similarity of forest stands within terrain types and used this information to pair hemlock-dominated streams with hardwood counterparts prior to sampling. We evaluated the effectiveness of the design through power analysis and found that power to detect differences in aquatic invertebrate taxa richness was highest when sites were paired and terrain type was included as a factor in the analysis. Precision of the estimated difference in mean richness was nearly doubled using the terrain-based, paired site design in comparison to other evaluated designs. Use of this method allowed us to sample stream communities representative of park-wide forest conditions while effectively controlling for landscape variability.

  8. Modification No. 2 to the remedial action plan and site design for stabilization of the inactive uranium mill tailings site at Green River, Utah: Final

    SciTech Connect

    1996-11-01

    Portions of the final Remedial Action Plan (RAP) for the Green River site, Volumes 1 and 2, Appendix B of the Cooperative Agreement No. DE-FC04-81AL16257, March 1991 (DOE, 1991) have been modified. The changes to the RAP are designated as RAP Modification No. 2. These changes have been placed in a three-ring binder that will supplement the original RAP (DOE, 1991), and include the following: addendum to the Executive Summary; Section 3.5 (Ground Water part of the Site Characterization Summary); Section 4.0 (Site Design); Section5.0 (Water Resources Protection Strategy Summary); Appendix D.5 (Ground Water Hydrology); and Appendix E (Ground Water Protection Strategy). In addition to these revisions, there have been editorial changes that clarify the text, but do not change the meaning. Also, certain sections of the document, which are included in the submittal for ease of review and continuity, have been updated to reflect the final ground water protection standards and the current UMTRA Project format and content of RAPs.

  9. LEAD (Pb) IN BIOTA AND PERCEPTIONS OF Pb EXPOSURE AT A RECENTLY DESIGNATED SUPERFUND BEACH SITE IN NEW JERSEY

    PubMed Central

    Burger, Joanna; Gochfeld, Michael; Jeitner, Christian; Donio, Mark; Pittfield, Taryn

    2014-01-01

    The Raritan Bay Slag Site (New Jersey) was designated a Superfund site in 2009 because the seawall, jetties, and sediment contained lead (Pb). Our objective was to compare Pb and mercury (Hg) levels in biota and public perceptions of exposure at the Superfund and reference sites. Samples (algae, invertebrates, fish) were collected from the Raritan Bay Slag Site and reference sites and analyzed for Pb and Hg. Waterfront users were interviewed using a standard questionnaire. Levels of Pb in aquatic organisms were compared to ecological and human health safety standards. Lead levels were related to location, trophic level, and mobility. Lead levels in biota were highest at the western side of the West Jetty. Mean Pb levels were highest for algae (Fucus = 53,600 ± 6990 ng/g = ppb [wet weight], Ulva = 23,900 ± 2430 ppb), intermediate for grass shrimp (7270 ± 1300 ppb, 11,600 ± 3340 ppb), and lowest for fish (Atlantic silversides 218 ± 44 ppb). Within species, Pb levels varied significantly across the sampling sites. Lead levels in algae, sometimes ingested by individuals, were sufficiently high to exceed human safety levels. Mercury levels did not differ between the Superfund and reference sites. Despite the fence and warnings, people (1) used the Superfund and reference sites similarly, (2) had similar fish consumption rates, and (3) were not concerned about Pb, although most individuals knew the metal was present. The fish sampled posed no apparent risk for human consumers, but the algae did. PMID:22409490

  10. Lead (Pb) in biota and perceptions of Pb exposure at a recently designated Superfund beach site in New Jersey.

    PubMed

    Burger, Joanna; Gochfeld, Michael; Jeitner, Christian; Donio, Mark; Pittfield, Taryn

    2012-01-01

    The Raritan Bay Slag Site (New Jersey) was designated a Superfund site in 2009 because the seawall, jetties, and sediment contained lead (Pb). Our objective was to compare Pb and mercury (Hg) levels in biota and public perceptions of exposure at the Superfund and reference sites. Samples (algae, invertebrates, fish) were collected from the Raritan Bay Slag Site and reference sites and analyzed for Pb and Hg. Waterfront users were interviewed using a standard questionnaire. Levels of Pb in aquatic organisms were compared to ecological and human health safety standards. Lead levels were related to location, trophic level, and mobility. Lead levels in biota were highest at the western side of the West Jetty. Mean Pb levels were highest for algae (Fucus = 53,600 ± 6990 ng/g = ppb [wet weight], Ulva = 23,900 ± 2430 ppb), intermediate for grass shrimp (7270 ± 1300 ppb, 11,600 ± 3340 ppb), and lowest for fish (Atlantic silversides 218 ± 44 ppb). Within species, Pb levels varied significantly across the sampling sites. Lead levels in algae, sometimes ingested by individuals, were sufficiently high to exceed human safety levels. Mercury levels did not differ between the Superfund and reference sites. Despite the fence and warnings, people (1) used the Superfund and reference sites similarly, (2) had similar fish consumption rates, and (3) were not concerned about Pb, although most individuals knew the metal was present. The fish sampled posed no apparent risk for human consumers, but the algae did. PMID:22409490

  11. Remedial action plan and site design for stabilization of the inactive uranium processing site at Naturita, Colorado. Remedial action selection report, Attachment 2, Geology report: Preliminary final

    SciTech Connect

    Not Available

    1993-08-01

    The uranium processing site near Naturita, Colorado, is one of 24 inactive uranium mill sites designated to be cleaned up by the US Department of Energy (DOE) under the Uranium Mill Tailings Radiation Control Act of 1978 (UMTRCA), Public Law 95-604. Part of the UMTRCA requires that the US Nuclear Regulatory Commission (NRC) concur with the DOE`s remedial action plan (RAP) and certify that the remedial action conducted at the site complies with the standards promulgated by the US Environmental Protection Agency (EPA). Included in the RAP is this Remedial Action Selection Report (RAS), which serves two purposes. First, it describes the activities that are proposed by the DOE to accomplish remediation and long-term stabilization and control of the radioactive materials at the inactive uranium processing site near Naturita, Colorado. Second, this document and the rest of the RAP, upon concurrence and execution by the DOE, the state of Colorado, and the NRC, become Appendix B of the cooperative agreement between the DOE and the State of Colorado.

  12. Remedial Action Plan and site design for stabilization of the inactive uranium mill tailings site at Durango, Colorado: Remedial action selection report. Revised final report

    SciTech Connect

    Not Available

    1991-12-01

    The uranium mill tailings site near Durango, Colorado, was one of 24 inactive uranium mill sites designated to be remediated by the US Department of Energy (DOE) under the Uranium Mill Tailings Radiation Control Act of 1978 (UMTRCA). Part of the UMTRCA requires that the US Nuclear Regulatory Commission (NRC) concur with the DOE`s Remedial Action Plan (RAP) and certify that the remedial action conducted at the site complies with the standards promulgated by the US Environmental Protection Agency (EPA). Included in the RAP is this Remedial Action Selection Report (RAS), which has been developed to serve a two-fold purpose. First, it describes the activities that have been conducted by the DOE to accomplish remediation and long-term stabilization and control of the radioactive materials at the inactive uranium mill processing site near Durango, Colorado. Secondly, this document and the rest of the RAP, upon concurrence and execution by the DOE, the State of Colorado, and the NRC, become Appendix B of the Cooperative Agreement between the DOE and the State of Colorado.

  13. Remedial Action Plan and site design for stabilization of the inactive uranium mill tailings site at Durango, Colorado: Remedial action selection report

    SciTech Connect

    Not Available

    1991-12-01

    The uranium mill tailings site near Durango, Colorado, was one of 24 inactive uranium mill sites designated to be remediated by the US Department of Energy (DOE) under the Uranium Mill Tailings Radiation Control Act of 1978 (UMTRCA). Part of the UMTRCA requires that the US Nuclear Regulatory Commission (NRC) concur with the DOE's Remedial Action Plan (RAP) and certify that the remedial action conducted at the site complies with the standards promulgated by the US Environmental Protection Agency (EPA). Included in the RAP is this Remedial Action Selection Report (RAS), which has been developed to serve a two-fold purpose. First, it describes the activities that have been conducted by the DOE to accomplish remediation and long-term stabilization and control of the radioactive materials at the inactive uranium mill processing site near Durango, Colorado. Secondly, this document and the rest of the RAP, upon concurrence and execution by the DOE, the State of Colorado, and the NRC, become Appendix B of the Cooperative Agreement between the DOE and the State of Colorado.

  14. Remedial Action Plan and site design for stabilization of the inactive uranium mill tailings site at Falls City, Texas. [Uranium Mill Tailings Remedial Action (UMTRA) Project

    SciTech Connect

    Chernoff, A.R. . Uranium Mill Tailings Remedial Action Project Office); Lacker, D.K. . Bureau of Radiation Control)

    1992-09-01

    The uranium processing site near Falls City, Texas, was one of 24 inactive uranium mill sites designated to be remediated by the US Department of Energy (DOE) under Title I of the Uranium Mill Tailings Radiation Control Act of 1978 (UMTRCA). The UMTRCA requires that the US Nuclear Regulatory Commission (NRC) concur with the DOE's remedial action plan (RAP) and certify that the remedial action conducted at the site complies with the standards promulgated by the US Environmental Protection Agency (EPA). The RAP, which includes this summary remedial action selection report (RAS), serves a two-fold purpose. First, it describes the activities proposed by the DOE to accomplish long-term stabilization and control of the residual radioactive materials at the inactive uranium processing site near Falls City, Texas. Second, this document and the remainder of the RAP, upon concurrence and execution by the DOE, the State of Texas, and the NRC, becomes Appendix B of the Cooperative Agreement between the DOE and the State of Texas.

  15. Preliminary thermal/thermomechanical analyses of the Site Characterization Plan's Conceptual Design for a repository containing horizontally emplaced waste packages at the Deaf Smith County site

    SciTech Connect

    Ghantous, N.Y.; Raines, G.E.

    1987-10-01

    This report presents thermal/thermomechanical analyses of the Site Characterization Plan Conceptual Design for horizontal package emplacement at the Deaf Smith County site, Texas. The repository was divided into three geometric regions. Then two-dimensional finite-element models were set up to approximate the three-dimensional nature of each region. Thermal and quasistatic thermomechanical finite-element analyses were performed to evaluate the thermal/thermomechanical responses of the three regions. The exponential-time creep law was used to represent the creep behavior of salt rock. The repository design was evaluated by comparing the thermal/thermomechanical responses obtained for the three regions with interim performance constraints. The preliminary results show that all the performance constraints are met except for those of the waste package. The following factors were considered in interpreting these results: (1) the qualitative description of the analytical responses; (2) the limitations of the analyses; and (3) either the conclusions based on overall evaluation of limitations and analytical results or the conclusions based on the fact that the repository design may be evaluated only after further analyses. Furthermore, a parametric analysis was performed to estimate the effect of material parameters on the predicted thermal/thermomechanical response. 23 refs., 34 figs., 9 tabs.

  16. Plasmin substrate binding site cooperativity guides the design of potent peptide aldehyde inhibitors.

    PubMed

    Swedberg, Joakim E; Harris, Jonathan M

    2011-10-01

    Perioperative bleeding is a cause of major blood loss and is associated with increased rates of postoperative morbidity and mortality. To combat this, antifibrinolytic inhibitors of the serine protease plasmin are commonly used to reduce bleeding during surgery. The most effective and previously widely used of these is the broad range serine protease inhibitor aprotinin. However, adverse clinical outcomes have led to use of alternative serine lysine analogues to inhibit plasmin. These compounds suffer from low selectivity and binding affinity. Consequently, a concerted effort to discover potent and selective plasmin inhibitors has developed. This study used a noncombinatorial peptide library to define plasmin's extended substrate specificity and guide the design of potent transition state analogue inhibitors. The various substrate binding sites of plasmin were found to exhibit a higher degree of cooperativity than had previously been appreciated. Peptide sequences capitalizing on these features produced high-affinity inhibitors of plasmin. The most potent of these, Lys-Met(sulfone)-Tyr-Arg-H [KM(O(2))YR-H], inhibited plasmin with a K(i) of 3.1 nM while maintaining 25-fold selectivity over plasma kallikrein. Furthermore, 125 nM (0.16 μg/mL) KM(O(2))YR-H attenuated fibrinolysis in vitro with an efficacy similar to that of 15 nM (0.20 μg/mL) aprotinin. To date, this is the most potent peptide inhibitor of plasmin that exhibits selectivity against plasma kallikrein, making this compound an attractive candidate for further therapeutic development. PMID:21877690

  17. Multiple-site replacement analogs of glucagon. A molecular basis for antagonist design.

    PubMed

    Unson, C G; Wu, C R; Fitzpatrick, K J; Merrifield, R B

    1994-04-29

    Extensive structure activity analysis has allowed us to identify specific residues in the glucagon sequence that are responsible for either receptor recognition or signal transduction. For instance, we have demonstrated that aspartic acid 9 and histidine 1 are essential for activation, and that an ionic interaction between the negative carboxylate and the protonated imidazole may contribute to the activation reaction at the molecular level. In the absence of the carboxylic group at position 9, aspartic 21 or aspartic 15 might furnish distal electrostatic effects to maintain partial agonism. Further investigation established that each of the 4 serine residues in the hormone play distinct roles. Serine 8 provides an important determinant of binding. Whereas neither serines 2, 11, nor 16 are required for receptor recognition. We have shown that serine 16 is essential for signal transduction and thus have identified it to be the third residue in glucagon to participate in a putative catalytic triad together with aspartic 9 and histidine 1, in the transduction of the glucagon response. In this work, we utilized insights into the functional significance of particular residues in the peptide appropriated from our structure-function assignments, as the basis of a molecular approach for the design of active-site directed antagonists of glucagon. The importance as well as the accuracy of our findings are confirmed by the synthesis of a series of improved glucagon antagonists based on replacements at positions 1, 9, 11, 16, and 21. The inhibition index, (I/A)50, of our best antagonist des-His1-[Nle9-Ala11-Ala16]glucagon amide, has been improved 10-fold over the previous best glucagon inhibitor. PMID:8175663

  18. Assessment, approval, design and construction of a facility on a Superfund site in 36 months

    SciTech Connect

    Drag, D.J.; Webb, C.K.; Luenenborg, G.W.

    1996-11-01

    The Union Pacific Resources Corporation (UPRC) owned and operated a 600-acre crude oil production field in Wilmington, California. UPRC granted a lease to the TCL Corporation in 1951 for the disposal of oil and gas drilling field wastes. In the 1950s and 1960s, waste materials consisting of oil-free rotary mud, as well as rotary mud containing oil and crude oil tank bottoms were accepted at the site. Site testing and record investigations have shown that some other wastes, inconsistent with those permitted by the agreement between UPRC and TCL, were also disposed of at the site. Soil samples collected from the site in 1981 showed moderately high levels of metals in the soils at the site. In 1983, the site was included on the California State Superfund list of hazardous waste contaminated sites. In 1988, UPRC signed a Consent order Agreement with the Department of Toxic Substance Control (DTSC) whereby UPRC agreed to investigate a 31-acre area of the Study Area and develop a Remedial Action Plan (RAP) with DTSC oversight. The Port of Long Beach (POLB) is assuming the responsibility for implementing subsequent investigative and remedial activities at the portions of the site which they have since purchased from UPRC. The overall project objective was to investigate a 31-acre parcel within the Study Area (TCL site), develop a RAP, remediate the oil sump soils, and develop the parcel as an automobile distribution facility to be used by Toyota Motor Sales (TMS).

  19. 75 FR 22524 - Ocean Dumping; Designation of Ocean Dredged Material Disposal Sites Offshore of the Siuslaw River...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-29

    ... affect southern green sturgeon, euchalon, eastern Stellar sea lions, blue whales, fin whales, humpback..., EPA published a proposed rule at 75 FR 5708 to designate two new ocean dredged material disposal sites... the Federal Register in 1977 (42 FR 2461), a status superseded by later statutory changes to the...

  20. Development of in-structure design spectra for dome mounted equipment on underground waste storage tanks at the Hanford Site

    SciTech Connect

    Julyk, L.J.

    1995-09-01

    In-structure response spectra for dome mounted equipment on underground waste storage tanks at the Hanford Site are developed on the basis of recent soil-structure-interaction analyses. Recommended design spectra are provided for various locations on the tank dome.

  1. User-Interface Design Characteristics of Fortune 500 B2C E-Commerce Sites and Industry Differences

    ERIC Educational Resources Information Center

    Zhao, Jensen J.; Truell, Allen D.; Alexander, Melody W.

    2006-01-01

    This study examined the user-interface design characteristics of 107 Fortune 500 B2C e-commerce Web sites and industry differences. Data were collected from corporate homepages, B2C product/service pages, B2C interactive shopping pages, as well as customer satisfaction of 321 online shoppers. The findings indicate that (a) to attract online…

  2. 78 FR 939 - Notice of Public Meeting: Designation of an Ocean Dredged Material Disposal Sites (ODMDS) in...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-07

    ...EPA Region 1 announces the rescheduled public meeting to discuss the Notice of Intent to Prepare a Supplemental Environmental Impact Statement (SEIS) to Evaluate the Potential Designation of One or More Ocean Dredged Material Disposal Sites (ODMDS) to Serve the Eastern Long Island Sound Region. The public meeting was originally scheduled for November 15, 2012, but was delayed due to the......

  3. 41 CFR 102-76.55 - What sustainable development principles must Federal agencies apply to the siting, design, and...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... and Construction Sustainable Development § 102-76.55 What sustainable development principles must... Acquisition,” Federal agencies must apply sustainable development principles to the siting, design, and... 41 Public Contracts and Property Management 3 2012-01-01 2012-01-01 false What...

  4. 41 CFR 102-76.55 - What sustainable development principles must Federal agencies apply to the siting, design, and...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... and Construction Sustainable Development § 102-76.55 What sustainable development principles must... Acquisition,” Federal agencies must apply sustainable development principles to the siting, design, and... 41 Public Contracts and Property Management 3 2013-07-01 2013-07-01 false What...

  5. 41 CFR 102-76.55 - What sustainable development principles must Federal agencies apply to the siting, design, and...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... and Construction Sustainable Development § 102-76.55 What sustainable development principles must... Acquisition,” Federal agencies must apply sustainable development principles to the siting, design, and... 41 Public Contracts and Property Management 3 2014-01-01 2014-01-01 false What...

  6. 41 CFR 102-76.55 - What sustainable development principles must Federal agencies apply to the siting, design, and...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... and Construction Sustainable Development § 102-76.55 What sustainable development principles must... Acquisition,” Federal agencies must apply sustainable development principles to the siting, design, and... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false What...

  7. 75 FR 24958 - Decision To Evaluate a Petition To Designate a Class of Employees From the Hanford Site, Richland...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-06

    ... HUMAN SERVICES Decision To Evaluate a Petition To Designate a Class of Employees From the Hanford Site... Safety and Health (NIOSH), Department of Health and Human Services (HHS). ACTION: Notice. SUMMARY: HHS... definition for the class being evaluated, subject to revision as warranted by the evaluation, is as...

  8. Self-catalyzed site-specific depurination of G residues mediated by cruciform extrusion in closed circular DNA plasmids.

    PubMed

    Amosova, Olga; Kumar, Veena; Deutsch, Aaron; Fresco, Jacques R

    2011-10-21

    A major variety of "spontaneous" genomic damage is endogenous generation of apurinic sites. Depurination rates vary widely across genomes, occurring with higher frequency at "depurination hot spots." Recently, we discovered a site-specific self-catalyzed depurinating activity in short (14-18 nucleotides) DNA stem-loop-forming sequences with a 5'-G(T/A)GG-3' loop and T·A or G·C as the first base pair at the base of the loop; the 5'-G residue of the loop self-depurinates at least 10(5)-fold faster than random "spontaneous" depurination at pH 5. Formation of the catalytic intermediate for self-depurination in double-stranded DNA requires a stem-loop to extrude as part of a cruciform. In this study, evidence is presented for self-catalyzed depurination mediated by cruciform formation in plasmid DNA in vitro. Cruciform extrusion was confirmed, and its extent was quantitated by digestion of the plasmid with single strand-specific mung bean endonuclease, followed by restriction digestion and sequencing of resulting mung bean-generated fragments. Appearance of the apurinic site in the self-depurinating stem-loop was confirmed by digestion of plasmid DNA with apurinic endonuclease IV, followed by primer extension and/or PCR amplification to detect the endonuclease-generated strand break and identify its location. Self-catalyzed depurination was contingent on the plasmid being supercoiled and was not observed in linearized plasmids, consistent with the presence of the extruded cruciform in the supercoiled plasmid and not in the linear one. These results indicate that self-catalyzed depurination is not unique to single-stranded DNA; rather, it can occur in stem-loop structures extruding from double-stranded DNA and therefore could, in principle, occur in vivo.

  9. Preliminary design of a solar central receiver for site-specific repowering application (Saguaro Power Plant). Volume II. Preliminary design. Final report, October 1982-September 1983

    SciTech Connect

    Weber, E.R.

    1983-09-01

    The solar central receiver technology, site, and specific unit for repowering were selected in prior analyses and studies. The objectives of this preliminary design study were to: develop a solar central receiver repowering design for Saguaro that (1) has potential to be economically competitive with fossil fueled plants in near and long term applications, (2) has the greatest chance for completion without further government funding, (3) will further define technical and economic feasibility of a 66 MWe gross size plant that is adequate to meet the requirements for utility and industrial process heat applications, (4) can potentially be constructed and operated within the next five years, and (5) incorporates solar central receiver technology and represents state-of-the-art development. This volume on the preliminary design includes the following sections: executive summary; introduction; changes from advanced conceptual design; preliminary design; system characteristics; economic analysis; and development plan.

  10. 40 CFR 228.15 - Dumping sites designated on a final basis.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... practicable alternatives (as defined in 40 CFR 227.16(b)) to open-water disposal in Long Island Sound and that...) Restrictions: See 40 CFR 228.15(b)(4)(vi). (c) Region I Final Other Wastes Sites. (1) No final sites. (2) (d... will be managed so as to reduce impacts within the PRA to acceptable levels in accordance with 40...

  11. Making the Most of Your School Site. School Buildings Planning, Design, and Construction Series No. 2.

    ERIC Educational Resources Information Center

    Odell, John H.

    A school construction guide offers key personnel in school development projects information on the complex task of master planning and construction of schools in Australia. This chapter of the guide provides advice on site selection covering selection criteria; traffic issues; and site services, such as water, power, and sewer. Additionally…

  12. Improvement in protein functional site prediction by distinguishing structural and functional constraints on protein family evolution using computational design.

    PubMed

    Cheng, Gong; Qian, Bin; Samudrala, Ram; Baker, David

    2005-01-01

    The prediction of functional sites in newly solved protein structures is a challenge for computational structural biology. Most methods for approaching this problem use evolutionary conservation as the primary indicator of the location of functional sites. However, sequence conservation reflects not only evolutionary selection at functional sites to maintain protein function, but also selection throughout the protein to maintain the stability of the folded state. To disentangle sequence conservation due to protein functional constraints from sequence conservation due to protein structural constraints, we use all atom computational protein design methodology to predict sequence profiles expected under solely structural constraints, and to compute the free energy difference between the naturally occurring amino acid and the lowest free energy amino acid at each position. We show that functional sites are more likely than non-functional sites to have computed sequence profiles which differ significantly from the naturally occurring sequence profiles and to have residues with sub-optimal free energies, and that incorporation of these two measures improves sequence based prediction of protein functional sites. The combined sequence and structure based functional site prediction method has been implemented in a publicly available web server.

  13. Site characterization plan: Conceptual design report: Volume 4, Appendices F-O: Nevada Nuclear Waste Storage Investigations Project

    SciTech Connect

    MacDougall, H R; Scully, L W; Tillerson, J R

    1987-09-01

    The site for the prospective repository is located at Yucca Mountain in southwestern Nevada, and the waste emplacement area will be constructed in the underlying volcanic tuffs. The target horizon for waste emplacement is a sloping bed of densely welded tuff more than 650 ft below the surface and typically more than 600 ft above the water table. The conceptual design described in this report is unique among repository designs in that it uses ramps in addition to shafts to gain access to the underground facility, the emplacement horizon is located above the water table, and it is possible that 300- to 400-ft-long horizontal waste emplacement boreholes will be used. This report summarizes the design bases, design and performance criteria, and the design analyses performed. The current status of meeting the preclosure performance objectives for licensing and of resolving the repository design and preclosure issues is presented. The repository design presented in this report will be expanded and refined during the advanced conceptual design, the license application design, and the final procurement and construction design phases. Volume 4 contains Appendices F to O.

  14. Mapping of the leptin binding sites and design of a leptin antagonist.

    PubMed

    Peelman, Frank; Van Beneden, Katrien; Zabeau, Lennart; Iserentant, Hannes; Ulrichts, Peter; Defeau, Delphine; Verhee, Annick; Catteeuw, Dominiek; Elewaut, Dirk; Tavernier, Jan

    2004-09-24

    The leptin/leptin receptor system shows strong similarities to the long-chain cytokine interleukin-6 (IL-6) and granulocyte colony-stimulating factor cytokine/receptor systems. The IL-6 family cytokines interact with their receptors through three different binding sites I-III. The leptin structure was superposed on the crystal structures of several long-chain cytokines, and a series of leptin mutants was generated focusing on binding sites I-III. The effect of the mutations on leptin receptor (LR) signaling and on binding to the membrane proximal cytokine receptor homology domain (CRH2) of the LR was determined. Mutations in binding site I at the C terminus of helix D show a modest effect on signaling and do not affect binding to CRH2. Binding site II is composed of residues at the surface of helices A and C. Mutations in this site impair binding to CRH2 but have only limited effect on signaling. Site III mutations around the N terminus of helix D impair receptor activation without affecting binding to CRH2. We identified an S120A/T121A mutant in binding site III, which lacks any signaling capacity, but which still binds to CRH2 with wild type affinity. This leptin mutant behaves as a potent leptin antagonist both in vitro and in vivo. PMID:15213225

  15. Design and Construction of Deinococcus radiodurans for Biodegradation of Organic Toxins at Radioactive DOE Waste Sites

    SciTech Connect

    Daly, Michael J.; Fredrickson, James K.; Wackett, Lawrence P.

    1999-06-01

    Immense volumes of radioactive waste, generated from nuclear weapons production during the Cold War, were disposed directly to the ground. The current expense of remediating these polluted sites is driving the development of alternative remediation strategies using microorganisms. The bacterium Deinococcus radiodurans is the most radiation resistant organism known and can grow in highly irradiating (>60 Gray/h) environments (1). Numerous microorganisms (e.g., Pseudomonas sp.) have been described, and studied in detail, for their ability to transform and degrade a variety of organic pollutants (e.g., toluene), present at many radioactive DOE waste sites. Detoxification of the organic toxins at these sites is an important goal in remediating or stabilizing contaminated sites as well as preventing their further dissemination. The aim of this project is to engineer strains of D. radiodurans that are capable of degrading organic/aromatic hydrocarbons present in radioactive mixed waste sites--sites that contain mixtures of toxic organic compounds, radionuclides and heavy metals. Conventional bioremediating organisms are unable to survive at many of these sites because of their sensitivity to radiation. Generally, microorganisms are sensitive to the damaging effects of ionizing radiation, and most of the bacteria currently being studied as candidates for bioremediation are no exception. For example, Pseudomonas sp. is very sensitive to radiation (more sensitive than E. coli) and is not suited to remediate radioactive wastes. Therefore, radiation resistant microorganisms that can remediate toxic organic compounds need to be found in nature or engineered in the laboratory to address this problem.

  16. Remedial action plan and site design for stabilization of the inactive Uranium Mill Tailings Site at Lowman, Idaho. Attachment 4, Water resources protection strategy: Final report

    SciTech Connect

    Not Available

    1991-09-01

    The DOE proposes to achieve compliance with the proposed EPA groundwater protection standards (Subparts A and B of 40 CFR 192) by meeting the EPA maximum concentration limits (MCLs) or background concentrations for designated hazardous constituents in groundwater in the uppermost aquifer (alluvium/weathered granodiorite) at the point of compliance (POC) at the Lowman disposal site near Lowman, Idaho. The proposed remedial action in conjunction with existing hydrogeological conditions at the Lowman site will ensure sufficient protection of human health and the environment. The DOE has concluded that the EPA groundwater protection standards will be met at the POC because, with the exception of antimony, none of the hazardous constituents that exceed laboratory method detection limits within the radioactive sand pore fluids were above the proposed concentration limits. The DOE has demonstrated that antimony will meet the proposed concentration limits at the POC through attenuation in subsoils beneath the disposal cell and by dilution in groundwater underflow. The Lowman processing site is in compliance with Subpart B of 40 CFR 192 because statistical analyses of groundwater samples indicate no groundwater contamination.

  17. Remedial Action Plan and site design for stabilization of the inactive uranium mill tailings site at Mexican Hat, Utah: Text, Appendices A--C. Final report

    SciTech Connect

    1988-07-01

    This Remedial Action Plan (RAP) has been developed to serve a two- fold purpose. It presents the activities proposed by the Department of Energy (DOE) to accomplish long-term stabilization and control of the residual radioactive materials (RRM) from Monument Valley Arizona, and Mexican Hat, Utah, at the Mexican Hat disposal site. It also serves to document the concurrence of both the Navajo Nation and the Nuclear Regulatory Commission (NRC) in the remedial action. This agreement, upon execution by DOE and the Navajo Nation and concurrence by the NRC, becomes Appendix B of the Cooperative Agreement. This document has been structured to provide a comprehensive understanding of the remedial action proposed for the Monument Valley and Mexican Hat sites. It includes specific design and construction requirements for the remedial action. Pertinent information and data are included with reference given to the supporting documents. Appendices A,B, and C are provided as part of this document. Appendix A presents regulatory compliance issues, Appendix B provides details of the engineering design, and Appendix C presents the radiological support plan.

  18. [Rapid site-directed mutagenesis on full-length plasmid DNA by using designed restriction enzyme assisted mutagenesis].

    PubMed

    Zhang, Baozhong; Ran, Duoliang; Zhang, Xin; An, Xiaoping; Shan, Yunzhu; Zhou, Yusen; Tong, Yigang

    2009-02-01

    To use the designed restriction enzyme assisted mutagenesis technique to perform rapid site-directed mutagenesis on double-stranded plasmid DNA. The target amino acid sequence was reversely translated into DNA sequences with degenerate codons, resulting in large amount of silently mutated sequences containing various restriction endonucleases (REs). Certain mutated sequence with an appropriate RE was selected as the target DNA sequence for designing mutation primers. The full-length plasmid DNA was amplified with high-fidelity Phusion DNA polymerase and the amplified product was 5' phosphorylated by T4 polynucleotide kinase and then self-ligated. After transformation into an E. coli host the transformants were rapidly screened by cutting with the designed RE. With this strategy we successfully performed the site-directed mutagenesis on an 8 kb plasmid pcDNA3.1-pIgR and recovered the wild-type amino acid sequence of human polymeric immunoglobulin receptor (pIgR). A novel site-directed mutagenesis strategy based on DREAM was developed which exploited RE as a rapid screening measure. The highly efficient, high-fidelity Phusion DNA polymerase was applied to ensure the efficient and faithful amplification of the full-length sequence of a plasmid of up to 8 kb. This rapid mutagenesis strategy avoids using any commercial site-directed mutagenesis kits, special host strains or isotopes. PMID:19459340

  19. Trends in Culturally Relevant Interface Design Features for Latino Web Site Users

    ERIC Educational Resources Information Center

    Sachau, Lori L.; Hutchinson, Susan R.

    2012-01-01

    There is a lack of published research on designing Web-based instruction for the adult U.S. Latino population. Instructional designers need guidance on how to design culturally relevant learning environments for this audience, particularly for Latino people from Mexican heritage. The authors used content analysis to investigate the extent to which…

  20. 24 CFR 3285.103 - Site suitability with design zone maps.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... is to be installed. The design zone maps are those identified in part 3280 of this chapter. (a) Wind zone. Manufactured homes must not be installed in a wind zone that exceeds the design wind loads for which the home has been designed, as evidenced by the wind zone indicated on the home's data plate...

  1. 40 CFR 228.15 - Dumping sites designated on a final basis.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... practicable alternatives (as defined in 40 CFR 227.16(b)) to open-water disposal in Long Island Sound and that...) Restrictions: See 40 CFR 228.15(b)(4)(vi). (c) Region I Final Other Wastes Sites. (1) No final sites. (2) (d... as to reduce impacts within the PRA to acceptable levels in accordance with 40 CFR 228.11(c). Use...

  2. 40 CFR 228.15 - Dumping sites designated on a final basis.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... practicable alternatives (as defined in 40 CFR 227.16(b)) to open-water disposal in Long Island Sound and that...) Restrictions: See 40 CFR 228.15(b)(4)(vi). (c) Region I Final Other Wastes Sites. (1) No final sites. (2) (d... as to reduce impacts within the PRA to acceptable levels in accordance with 40 CFR 228.11(c). Use...

  3. 40 CFR 228.15 - Dumping sites designated on a final basis.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... practicable alternatives (as defined in 40 CFR 227.16(b)) to open-water disposal in Long Island Sound and that...) Restrictions: See 40 CFR 228.15(b)(4)(vi). (c) Region I Final Other Wastes Sites. (1) No final sites. (2) (d... as to reduce impacts within the PRA to acceptable levels in accordance with 40 CFR 228.11(c). Use...

  4. 40 CFR 228.15 - Dumping sites designated on a final basis.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... practicable alternatives (as defined in 40 CFR 227.16(b)) to open-water disposal in Long Island Sound and that...) Restrictions: See 40 CFR 228.15(b)(4)(vi). (c) Region I Final Other Wastes Sites. (1) No final sites. (2) (d... as to reduce impacts within the PRA to acceptable levels in accordance with 40 CFR 228.11(c). Use...

  5. Development of Site-Specific Soil Design Basis Earthquake (DBE) Parameters for the Integrated Waste Treatment Unit (IWTU)

    SciTech Connect

    Payne, Suzette

    2008-08-01

    Horizontal and vertical PC 3 (2,500 yr) Soil Design Basis Earthquake (DBE) 5% damped spectra, corresponding time histories, and strain-compatible soil properties were developed for the Integrated Waste Treatment Unit (IWTU). The IWTU is located at the Idaho Nuclear Technology and Engineering Center (INTEC) at the Idaho National Laboratory (INL). Mean and 84th percentile horizontal DBE spectra derived from site-specific site response analyses were evaluated for the IWTU. The horizontal and vertical PC 3 (2,500 yr) Soil DBE 5% damped spectra at the 84th percentile were selected for Soil Structure Interaction (SSI) analyses at IWTU. The site response analyses were performed consistent with applicable Department of Energy (DOE) Standards, recommended guidance of the Nuclear Regulatory Commission (NRC), American Society of Civil Engineers (ASCE) Standards, and recommendations of the Blue Ribbon Panel (BRP) and Defense Nuclear Facilities Safety Board (DNFSB).

  6. Bifunctional chelating agent for the design and development of site specific radiopharmaceuticals and biomolecule conjugation strategy

    DOEpatents

    Katti, Kattesh V.; Prabhu, Kandikere R.; Gali, Hariprasad; Pillarsetty, Nagavara Kishore; Volkert, Wynn A.

    2003-10-21

    There is provided a method of labeling a biomolecule with a transition metal or radiometal in a site specific manner to produce a diagnostic or therapeutic pharmaceutical compound by synthesizing a P.sub.2 N.sub.2 -bifunctional chelating agent intermediate, complexing the intermediate with a radio metal or a transition metal, and covalently linking the resulting metal-complexed bifunctional chelating agent with a biomolecule in a site specific manner. Also provided is a method of synthesizing the --PR.sub.2 containing biomolecules by synthesizing a P.sub.2 N.sub.2 -bifunctional chelating agent intermediate, complexing the intermediate with a radiometal or a transition metal, and covalently linking the resulting radio metal-complexed bifunctional chelating agent with a biomolecule in a site specific manner. There is provided a therapeutic or diagnostic agent comprising a --PR.sub.2 containing biomolecule.

  7. Environmental design criteria for the 1/3 scale OTEC cold water pipe at-sea test site off Honolulu, Hawaii

    NASA Astrophysics Data System (ADS)

    1983-01-01

    In order to expedite development of the design of the 1/3 scale At-Sea Test CWP/Platform/Mooring System, environmental design criteria data at the proposed At-Sea Test site evaluated from available historic data is provided. An evaluation of the available data to date is described. It is expected that as the design develops actual site specific observation will be obtained to verify these critical design criteria.

  8. Facility design criteria AN/GSC-39(V) 1 Earth terminal complex fixed site configuration. Addendum 1. HEMP considerations

    NASA Astrophysics Data System (ADS)

    Clark, S. A., Jr.; Chase, R. J.; Penar, J. D.

    1981-03-01

    This addendum provides high altitude electromagnetic pulse (HEMP) hardening design criteria for the AN/GSC-39 Earth Terminal Complex fixed site facilities. In addition to other criteria, this addendum is to be used for preparing construction plans and specifications for the Earth terminal complex. These HEMP criteria are based on two reports for HEMP hardening of the AN/FSC-78 Satellite Communications Terminal. The hardening measures developed in this Addendum will enhance protection for the digital communications subsystem.

  9. Sampling design and procedures for fixed surface-water sites in the Georgia-Florida coastal plain study unit, 1993

    USGS Publications Warehouse

    Hatzell, H.H.; Oaksford, E.T.; Asbury, C.E.

    1995-01-01

    The implementation of design guidelines for the National Water-Quality Assessment (NAWQA) Program has resulted in the development of new sampling procedures and the modification of existing procedures commonly used in the Water Resources Division of the U.S. Geological Survey. The Georgia-Florida Coastal Plain (GAFL) study unit began the intensive data collection phase of the program in October 1992. This report documents the implementation of the NAWQA guidelines by describing the sampling design and procedures for collecting surface-water samples in the GAFL study unit in 1993. This documentation is provided for agencies that use water-quality data and for future study units that will be entering the intensive phase of data collection. The sampling design is intended to account for large- and small-scale spatial variations, and temporal variations in water quality for the study area. Nine fixed sites were selected in drainage basins of different sizes and different land-use characteristics located in different land-resource provinces. Each of the nine fixed sites was sampled regularly for a combination of six constituent groups composed of physical and chemical constituents: field measurements, major ions and metals, nutrients, organic carbon, pesticides, and suspended sediments. Some sites were also sampled during high-flow conditions and storm events. Discussion of the sampling procedure is divided into three phases: sample collection, sample splitting, and sample processing. A cone splitter was used to split water samples for the analysis of the sampling constituent groups except organic carbon from approximately nine liters of stream water collected at four fixed sites that were sampled intensively. An example of the sample splitting schemes designed to provide the sample volumes required for each sample constituent group is described in detail. Information about onsite sample processing has been organized into a flowchart that describes a pathway for each of

  10. Teaching E-Commerce Web Page Evaluation and Design: A Pilot Study Using Tourism Destination Sites

    ERIC Educational Resources Information Center

    Susser, Bernard; Ariga, Taeko

    2006-01-01

    This study explores a teaching method for improving business students' skills in e-commerce page evaluation and making Web design majors aware of business content issues through cooperative learning. Two groups of female students at a Japanese university studying either tourism or Web page design were assigned tasks that required cooperation to…

  11. Design, development and evaluation of a tree planting-site-specific fumigant applicator

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The goal of this research was to use recent advances in the global positioning system (GPS) and computer technology to apply just the right amount of fumigant where it is most needed (i.e., tree-planting-site-specific application) to decrease the incidence of replant disease, and achieve the environ...

  12. Developing Educational Materials about Risks on Social Network Sites: A Design Based Research Approach

    ERIC Educational Resources Information Center

    Vanderhoven, Ellen; Schellens, Tammy; Vanderlinde, Ruben; Valcke, Martin

    2016-01-01

    Nearly all of today's Western teenagers have a profile on a social network site (SNS). As many risks have been reported, researchers and governments have emphasized the role of school education to teach teenagers how to deal safely with SNSs. However, little is known about the specific characteristics which would make interventions effective.…

  13. Impact of habitat variability on biological assessments at hazardous waste sites -- design and data interpretation considerations

    SciTech Connect

    Henry, R.

    1994-12-31

    Biological assessment methods that use aquatic macroinvertebrate communities to assess environmental impacts have been developed and used at hazardous waste sites. Shifts in community structure and function typically are attributed to the availability and toxicity of a contaminant, and information of this nature may be incorporated into remedial decisions. However, chemical stressors are often associated with habitat characteristics that may result in or contribute to an observed biological response. An ecological assessment focusing on benthic macroinvertebrates was conducted in a third order stream adjacent to a hazardous waste site. Habitat variability throughout the study area complicated the selection of sampling locations and equipment, and threatened to obscure potential ecological impairment associated with contaminants. For example, a 540 hectare impoundment exists approximately 100 meters upstream of the site which affects water quality, nutrient availability, and hydrology. Furthermore, portions of the stream adjacent to and immediately downstream of the site consist of a series of small, interconnecting braids that form the central core of a riparian wetland hydrosystem. Finally, historic and current riparian landaus includes mining, industrial, commercial, residential, and forested areas. Several reference areas, replicate and multihabitat samples, and careful habitat analysis were used to discriminate between habitat and contaminant effects. Although contaminants were detected in the stream, results of the macroinvertebrate survey and habitat analysis suggest that shifts in community structure and function were driven by habitat characteristics and that contaminants were not biologically available or present in toxic concentrations.

  14. 78 FR 73097 - Ocean Dumping; Sabine-Neches Waterway (SNWW) Ocean Dredged Material Disposal Site Designation

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-05

    ... estuarine nursery areas. The water column and benthic effects associated with ocean disposal of dredged... using EPA's ocean disposal criteria at 40 CFR part 228 and compared in the EIS. Of the sites that.... Ocean disposal of dredged material in the past has not interfered with other uses. 9. Existing...

  15. Computational design of an endo-1,4-[beta]-xylanase ligand binding site

    SciTech Connect

    Morin, Andrew; Kaufmann, Kristian W.; Fortenberry, Carie; Harp, Joel M.; Mizoue, Laura S.; Meiler, Jens

    2012-09-05

    The field of computational protein design has experienced important recent success. However, the de novo computational design of high-affinity protein-ligand interfaces is still largely an open challenge. Using the Rosetta program, we attempted the in silico design of a high-affinity protein interface to a small peptide ligand. We chose the thermophilic endo-1,4-{beta}-xylanase from Nonomuraea flexuosa as the protein scaffold on which to perform our designs. Over the course of the study, 12 proteins derived from this scaffold were produced and assayed for binding to the target ligand. Unfortunately, none of the designed proteins displayed evidence of high-affinity binding. Structural characterization of four designed proteins revealed that although the predicted structure of the protein model was highly accurate, this structural accuracy did not translate into accurate prediction of binding affinity. Crystallographic analyses indicate that the lack of binding affinity is possibly due to unaccounted for protein dynamics in the 'thumb' region of our design scaffold intrinsic to the family 11 {beta}-xylanase fold. Further computational analysis revealed two specific, single amino acid substitutions responsible for an observed change in backbone conformation, and decreased dynamic stability of the catalytic cleft. These findings offer new insight into the dynamic and structural determinants of the {beta}-xylanase proteins.

  16. "Less Clicking, More Watching": Results from the User-Centered Design of a Multi-Institutional Web Site for Art and Culture.

    ERIC Educational Resources Information Center

    Vergo, John; Karat, Clare-Marie; Karat, John; Pinhanez, Claudio; Arora, Renee; Cofino, Thomas; Riecken, Doug; Podlaseck, Mark

    This paper summarizes a 10-month long research project conducted at the IBM T.J. Watson Research Center aimed at developing the design concept of a multi-institutional art and culture web site. The work followed a user-centered design (UCD) approach, where interaction with prototypes and feedback from potential users of the web site were sought…

  17. 3D design tools improve efficiency and accuracy of a Hanford site nuclear waste storage project

    SciTech Connect

    NIELSEN, B.L.

    2003-03-23

    The complex effort of cleaning up the Hanford K Basins is separated into several individual projects. Fluor Hanford and Fluor Federal Services modeled key elements using a 3D parametric modeling program for mechanical design with training animations.

  18. Issues in Designing and Implementing a Spanish-Language Multi-Site Clinical Trial

    PubMed Central

    Suarez-Morales, Lourdes; Matthews, Julie; Martino, Steve; Ball, Samuel A.; Rosa, Carmen; Farentinos, Christine; Szapocznik, José; Carroll, Kathleen M.

    2013-01-01

    To address at least in part health disparities in Hispanic populations, the NIDA Clinical Trials Network implemented the first multi-site randomized clinical trial of substance abuse treatment conducted entirely in Spanish. This trial was intended to evaluate the effectiveness of Motivational Enhancement Therapy in a diverse population of Hispanics. In the conduct of this trial, several barriers to the successful implementation of a Spanish-language multi-site trial had to be addressed, including the appropriate translation of assessment instruments, shortage of appropriately trained Spanish-speaking clinical staff, and barriers to recruitment and retention of this population. To encourage similar research, strategies are described that were developed by the study team to meet these challenges. PMID:17612825

  19. A quantitative method for groundwater surveillance monitoring network design at the Hanford Site

    SciTech Connect

    Meyer, P.D.

    1993-12-01

    As part of the Environmental Surveillance Program at the Hanford Site, mandated by the US Department of Energy, hundreds of groundwater wells are sampled each year, with each sample typically analyzed for a variety of constituents. The groundwater sampling program must satisfy several broad objectives. These objectives include an integrated assessment of the condition of groundwater and the identification and quantification of existing, emerging, or potential groundwater problems. Several quantitative network desip objectives are proposed and a mathematical optimization model is developed from these objectives. The model attempts to find minimum cost network alternatives that maximize the amount of information generated by the network. Information is measured both by the rats of change with respect to time of the contaminant concentration and the uncertainty in contaminant concentration. In an application to tritium monitoring at the Hanford Site, both information measures were derived from historical data using time series analysis.

  20. Remedial Action Plan and site design for stabilization of the inactive uranium mill tailings site at Gunnison, Colorado. Attachment 5, Supplemental radiological data: Final report

    SciTech Connect

    Not Available

    1992-10-01

    Diffusion coefficients for radon gas in earthen materials are required to design suitable radon-barrier covers for uranium tailings impoundments and other materials that emit radon gas. Many early measurements of radon diffusion coefficients relied on the differences in steady-state radon fluxes measured from radon source before and after installation of a cover layer of the material being tested. More recent measurements have utilized the small-sample transient (SST) technique for greater control on moistures and densities of the test soils, greater measurement precision, and reduced testing time and costs. Several of the project sites for the US Department of Energy`s Uranium Mill Tailings Remedial Action (UMTRA) Program contain radiologically contaminated subsurface material composed predominantly of cobbles, gravels andsands. Since remedial action designs require radon diffusion coefficients for the source materials as well as the cover materials, these cobbly and gravelly materials also must be tested. This report contains the following information: a description of the test materials used and the methods developed to conduct the SST radon diffusion measurements on cobbly soils; the protocol for conducting radon diffusion tests oncobbly soils; the results of measurements on the test samples; and modifications to the FITS computer code for analyzing the time-dependent radon diffusion data.

  1. Environmental Aspects of Two Volatile Organic Compound Groundwater Treatment Designs at the Rocky Flats Site - 13135

    SciTech Connect

    Michalski, Casey C.; DiSalvo, Rick; Boylan, John

    2013-07-01

    DOE's Rocky Flats Site in Colorado is a former nuclear weapons production facility that began operations in the early 1950's. Because of releases of hazardous substances to the environment, the federally owned property and adjacent offsite areas were placed on the CERCLA National Priorities List in 1989. The final remedy was selected in 2006. Engineered components of the remedy include four groundwater treatment systems that were installed before closure as CERCLA-accelerated actions. Two of the systems, the Mound Site Plume Treatment System and the East Trenches Plume Treatment System, remove low levels of volatile organic compounds using zero-valent iron media, thereby reducing the loading of volatile organic compounds in surface water resulting from the groundwater pathway. However, the zero-valent iron treatment does not reliably reduce all volatile organic compounds to consistently meet water quality goals. While adding additional zero-valent iron media capacity could improve volatile organic compound removal capability, installation of a solar powered air-stripper has proven an effective treatment optimization in further reducing volatile organic compound concentrations. A comparison of the air stripper to the alternative of adding additional zero-valent iron capacity to improve Mound Site Plume Treatment System and East Trenches Plume Treatment System treatment based on several key sustainable remediation aspects indicates the air stripper is also more 'environmentally friendly'. These key aspects include air pollutant emissions, water quality, waste management, transportation, and costs. (authors)

  2. Activation of protein phosphatase 1 by a small molecule designed to bind to the enzyme's regulatory site.

    PubMed

    Tappan, Erin; Chamberlin, A Richard

    2008-02-01

    The activity of protein phosphatase 1 (PP1), a serine-threonine phosphatase that participates ubiquitously in cellular signaling, is controlled by a wide variety of regulatory proteins that interact with PP1 at an allosteric regulatory site that recognizes a "loose" consensus sequence (usually designated as RVXF) found in all such regulatory proteins. Peptides containing the regulatory consensus sequence have been found to recapitulate the binding and PP1 activity modulation of the regulatory proteins, suggesting that it might be possible to design small-molecule surrogates that activate PP1 rather than inhibiting it. This prospect constitutes a largely unexplored way of controlling signaling pathways that could be functionally complementary to the much more extensively explored stratagem of kinase inhibition. Based on these principles, we have designed a microcystin analog that activates PP1. PMID:18291321

  3. Remedial action and site design for stabilization of the inactive uranium mill tailings sites at Slick Rock, Colorado. Attachment 3, Groundwater hydrology report

    SciTech Connect

    Not Available

    1993-07-01

    The US Environmental Protection Agency (EPA) has established health and environmental protection regulations to correct and prevent groundwater contamination resulting from processing activities at inactive uranium milling sites (EPA, 1987). According to the Uranium Mill Tailings Radiation Control Act (UMTRCA) of 1978 Public Law (PL) 95-604 (PL 95-604), the US Department of Energy (DOE) is responsible for assessing the inactive uranium processing sites. The DOE has determined that for Slick Rock, this assessment shall include hydrogeologic site characterization for two separate uranium processing sites, the Union Carbide (UC) site and the North Continent (NC) site, and for the proposed Burro Canyon disposal site.

  4. Remedial Action Plan and Site Design for stabilization of the inactive Uranium Mill Tailings sites at Slick Rock, Colorado: Appendix C to Attachment 3, Calculations. Final

    SciTech Connect

    1995-09-01

    This volume contains calculations for: Slick Rock processing sites background ground water quality; Slick Rock processing sites lysimeter water quality; Slick Rock processing sites on-site and downgradient ground water quality; Slick Rock disposal site background water quality; Burro Canyon disposal site, Slick Rock, Colorado, average hydraulic gradients and average liner ground water velocities in the upper, middle, and lower sandstone units of the Burro Canyon formation; Slick Rock--Burro Canyon disposal site, Burro Canyon pumping and slug tests--analyses; water balance and surface contours--Burro Canyon disposal cell; and analytical calculation of drawdown in a hypothetical well completed in the upper sandstone unit of the Burro Canyon formation.

  5. Engineered materials characterization report for the Yucca Mountain Site Characterization Project. Volume 2, Design data

    SciTech Connect

    Konynenburg, R.A.; McCright, R.D.; Roy, A.K.; Jones, D.A.

    1995-08-01

    This is Volume 2 of the Engineered Materials Characterization Report which presents the design data for candidate materials needed in fabricating different components for both large and medium multi-purpose canister (MPC) disposal containers, waste packages for containing uncanistered spent fuel (UCF), and defense high-level waste (HLW) glass disposal containers. The UCF waste package consists of a disposal container with a basket therein. It is assumed that the waste packages will incorporate all-metallic multibarrier disposal containers to accommodate medium and large MPCs, ULCF, and HLW glass canisters. Unless otherwise specified, the disposal container designs incorporate an outer corrosion-allowance metal barrier over an inner corrosion-resistant metal barrier. The corrosion-allowance barrier, which will be thicker than the inner corrosion-resistant barrier, is designed to undergo corrosion-induced degradation at a very low rate, thus providing the inner barrier protection from the near-field environment for a prolonged service period.

  6. Bayesian geostatistical design: Task-driven optimal site investigation when the geostatistical model is uncertain

    NASA Astrophysics Data System (ADS)

    Nowak, W.; de Barros, F. P. J.; Rubin, Y.

    2010-03-01

    Geostatistical optimal design optimizes subsurface exploration for maximum information toward task-specific prediction goals. Until recently, most geostatistical design studies have assumed that the geostatistical description (i.e., the mean, trends, covariance models and their parameters) is given a priori. This contradicts, as emphasized by Rubin and Dagan (1987a), the fact that only few or even no data at all offer support for such assumptions prior to the bulk of exploration effort. We believe that geostatistical design should (1) avoid unjustified a priori assumptions on the geostatistical description, (2) instead reduce geostatistical model uncertainty as secondary design objective, (3) rate this secondary objective optimal for the overall prediction goal, and (4) be robust even under inaccurate geostatistical assumptions. Bayesian Geostatistical Design follows these guidelines by considering uncertain covariance model parameters. We transfer this concept from kriging-like applications to geostatistical inverse problems. We also deem it inappropriate to consider parametric uncertainty only within a single covariance model. The Matérn family of covariance functions has an additional shape parameter. Controlling model shape by a parameter converts covariance model selection to parameter identification and resembles Bayesian model averaging over a continuous spectrum of covariance models. This is appealing since it generalizes Bayesian model averaging from a finite number to an infinite number of models. We illustrate how our approach fulfills the above four guidelines in a series of synthetic test cases. The underlying scenarios are to minimize the prediction variance of (1) contaminant concentration or (2) arrival time at an ecologically sensitive location by optimal placement of hydraulic head and log conductivity measurements. Results highlight how both the impact of geostatistical model uncertainty and the sampling network design vary according to the

  7. X-ray structure of active site-inhibited clotting factor Xa. Implications for drug design and substrate recognition.

    PubMed

    Brandstetter, H; Kühne, A; Bode, W; Huber, R; von der Saal, W; Wirthensohn, K; Engh, R A

    1996-11-22

    The 3.0-A resolution x-ray structure of human des-Gla-coagulation factor Xa (fXa) has been determined in complex with the synthetic inhibitor DX-9065a. The binding geometry is characterized primarily by two interaction sites: the naphthamidine group is fixed in the S1 pocket by a typical salt bridge to Asp-189, while the pyrrolidine ring binds in the unique aryl-binding site (S4) of fXa. Unlike the large majority of inhibitor complexes with serine proteinases, Gly-216 (S3) does not contribute to hydrogen bond formation. In contrast to typical thrombin binding modes, the S2 site of fXa cannot be used by DX-9065a since it is blocked by Tyr-99, and the aryl-binding site (S4) of fXa is lined by carbonyl oxygen atoms that can accommodate positive charges. This has implications for natural substrate recognition as well as for drug design. PMID:8939944

  8. Making Creative Spaces: The Art and Design Classroom as a Site of Performativity

    ERIC Educational Resources Information Center

    Wild, Carol

    2011-01-01

    Rather than taking a transformational role in schools, new art and design teachers quickly become subject to "school art" orthodoxy. Theories of subjectivity and the development of professional identity within communities of practice can feel far removed from the classroom. This article seeks to make clearer the processes by which teacher identity…

  9. The Design and Implementation of Aircraft Maintenance On-site Control System

    NASA Astrophysics Data System (ADS)

    Zhou, Guilin; Zhang, Huawei

    Based on the desire of aircraft maintenance, combined with the situation in work, this paper present the design and implementation of aircraft maintenance system based dot Net. For a partial page refresh object, AJAX is used through the system. New technology is used in a creative way and will promote innovation and transformation of the business.

  10. 24 CFR 3285.103 - Site suitability with design zone maps.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... § 3285.315 for Special Snow Load Conditions. (c) Thermal zone. Manufactured homes must not be installed in a thermal zone that exceeds the thermal zone for which the home has been designed, as evidenced by the thermal zone indicated on the heating/cooling certificate and insulation zone map and as...

  11. 24 CFR 3285.103 - Site suitability with design zone maps.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... § 3285.315 for Special Snow Load Conditions. (c) Thermal zone. Manufactured homes must not be installed in a thermal zone that exceeds the thermal zone for which the home has been designed, as evidenced by the thermal zone indicated on the heating/cooling certificate and insulation zone map and as...

  12. 7 CFR Exhibit B to Subpart C of... - Site Development Design Requirements

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Local Total, Both Sides 2 26 32 36 (1) At least one parking space per dwelling is provided off-street. (2) No parking spaces are provided off-street. Table 2—Street Design (feet) Terrain Ordinary Rolling... return frequency from ponding over 6 inches deep, streets shall be made passable for local commonly...

  13. Design, Technology, and Science: Sites for Learning, Resistance, and Social Reproduction in Urban Schools.

    ERIC Educational Resources Information Center

    Seiler, Gale; Tobin, Kenneth; Sokolic, Joseph

    2001-01-01

    Presents a study that took place in an inner-city neighborhood school populated mainly by African American students characterized by poverty. Explores the discourse and practices of students and three co-teachers as a curriculum was enacted to provide opportunities for students to learn about the physics of motion through designing, building, and…

  14. 24 CFR 3285.103 - Site suitability with design zone maps.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... § 3285.315 for Special Snow Load Conditions. (c) Thermal zone. Manufactured homes must not be installed in a thermal zone that exceeds the thermal zone for which the home has been designed, as evidenced by the thermal zone indicated on the heating/cooling certificate and insulation zone map and as...

  15. 24 CFR 3285.103 - Site suitability with design zone maps.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... § 3285.315 for Special Snow Load Conditions. (c) Thermal zone. Manufactured homes must not be installed in a thermal zone that exceeds the thermal zone for which the home has been designed, as evidenced by the thermal zone indicated on the heating/cooling certificate and insulation zone map and as...

  16. Exploring the Molecular Design of Protein Interaction Sites with Molecular Dynamics Simulations and Free Energy Calculations†

    PubMed Central

    Liang, Shide; Li, Liwei; Hsu, Wei-Lun; Pilcher, Meaghan N.; Uversky, Vladimir; Zhou, Yaoqi; Dunker, A. Keith; Meroueh, Samy O.

    2009-01-01

    The significant work that has been invested toward understanding protein–protein interaction has not translated into significant advances in structure-based predictions. In particular redesigning protein surfaces to bind to unrelated receptors remains a challenge, partly due to receptor flexibility, which is often neglected in these efforts. In this work, we computationally graft the binding epitope of various small proteins obtained from the RCSB database to bind to barnase, lysozyme, and trypsin using a previously derived and validated algorithm. In an effort to probe the protein complexes in a realistic environment, all native and designer complexes were subjected to a total of nearly 400 ns of explicit-solvent molecular dynamics (MD) simulation. The MD data led to an unexpected observation: some of the designer complexes were highly unstable and decomposed during the trajectories. In contrast, the native and a number of designer complexes remained consistently stable. The unstable conformers provided us with a unique opportunity to define the structural and energetic factors that lead to unproductive protein–protein complexes. To that end we used free energy calculations following the MM-PBSA approach to determine the role of nonpolar effects, electrostatics and entropy in binding. Remarkably, we found that a majority of unstable complexes exhibited more favorable electrostatics than native or stable designer complexes, suggesting that favorable electrostatic interactions are not prerequisite for complex formation between proteins. However, nonpolar effects remained consistently more favorable in native and stable designer complexes reinforcing the importance of hydrophobic effects in protein–protein binding. While entropy systematically opposed binding in all cases, there was no observed trend in the entropy difference between native and designer complexes. A series of alanine scanning mutations of hot-spot residues at the interface of native and

  17. High-resolution seismic exploration methods for boreholes and tunnels: experiments, results and test site design

    NASA Astrophysics Data System (ADS)

    Giese, R.; Harms, U.; Jaksch, K.; Krüger, K.

    2012-12-01

    While surface to ground seismic exploration methods are well known, the utilization of seismic waves for underground surveying is less developed. The major challenge in subsurface seismics is the spatial ambiguity of the recorded wave field due to limited aperture of seismic source and receiver survey geometry. We developed novel imaging techniques and the appropriate measurement systems like phased array borehole sources for directional enhancement of seismic wave energy. Different procedures such as 3-component Kirchhoff-Migration and Fresnel-Volume-Migration were tested and improved to enhance the spatial resolution. The goal of these new approaches is to advance instruments for the detection of small-scale tectonic features or lithological changes in boreholes and tunnels. The key component for the experiments was the setup of our underground lab 150 m below surface (education and research mine Reiche Zeche, TU Freiberg, SE Germany). Surrounded by three galleries, the site comprises a block of homogeneous high-grade gneisses of about 50 m width and 100 m length ensuring constant environmental conditions. Along the galleries thirty 3-component geophones are anchored 1-2 m deep with a distance of 4-9 m from each other. Within this test site, two horizontal 8 ½" boreholes (20 and 30 m long) as well as a vertical hole (70 m depth) allow for 3D nearfield seismic experiments for high-resolution exploration and monitoring of geological structures.

  18. Discovery of novel STAT3 small molecule inhibitors via in silico site-directed fragment-based drug design.

    PubMed

    Yu, Wenying; Xiao, Hui; Lin, Jiayuh; Li, Chenglong

    2013-06-13

    Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been validated as an attractive therapeutic target for cancer therapy. To stop both STAT3 activation and dimerization, a viable strategy is to design inhibitors blocking its SH2 domain phosphotyrosine binding site that is responsible for both actions. A new fragment-based drug design (FBDD) strategy, in silico site-directed FBDD, was applied in this study. A designed novel compound, 5,8-dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-sulfonamide (LY5), was confirmed to bind to STAT3 SH2 by fluorescence polarization assay. In addition, four out of the five chosen compounds have IC50 values lower than 5 μM for the U2OS cancer cells. 8 (LY5) has an IC50 range in 0.5-1.4 μM in various cancer cell lines. 8 also suppresses tumor growth in an in vivo mouse model. This study has demonstrated the utility of this approach and could be used to other drug targets in general. PMID:23651330

  19. A Pilot Study of the Interface Design of Cross-Cultural Web Sites through Usability Testing of Multilanguage Web Sites and Determining the Preferences of Taiwanese and American Users

    ERIC Educational Resources Information Center

    Ku, David Tawei; Chang, Chia-Chi

    2014-01-01

    By conducting usability testing on a multilanguage Web site, this study analyzed the cultural differences between Taiwanese and American users in the performance of assigned tasks. To provide feasible insight into cross-cultural Web site design, Microsoft Office Online (MOO) that supports both traditional Chinese and English and contains an almost…

  20. Remedial action plan and site design for stabilization of the inactive uranium mill tailings site at Lowman, Idaho: Remedial action selection report for the Lowman UMTRA project site, Idaho. Final report

    SciTech Connect

    Matthews, M.L.; Nagel, J.

    1991-09-01

    The inactive uranium mill tailings site near Lowman, Idaho, was designated as one of 24 abandoned uranium tailings sites to be remediated by the US Department of Energy (DOE) under the Uranium Mill Tailings Radiation Control Act of 1978 (UMTRCA). The UMTRCA requires that the US Nuclear Regulatory Commission (NRC) concur with the DOE`s remedial action plan and certify that the remedial action complies with the standards promulgated by the US Environmental Protection Agency (EPA). The remedial action plan (RAP), which includes this remedial action selection report (RAS), has been developed to serve a two-fold purpose. First, it describes the activities that are proposed by the DOE to accomplish long-term stabilization and control of residual radioactive materials at the inactive uranium processing site near Lowman, Idaho. Second, this document and the remainder of the RAP, upon concurrence and execution by the DOE, the State of Idaho, and the NRC, becomes Appendix B of the Cooperative Agreement (No. DE-FC04-85AL20535) between the DOE and the State of Idaho.

  1. Remedial action plan and site design for stabilization of the inactive uranium mill tailings site at Lowman, Idaho: Remedial action selection report for the Lowman UMTRA project site, Idaho

    SciTech Connect

    Matthews, M.L. . Uranium Mill Tailings Remedial Action Project Office); Nagel, J. . Div. of Environmental Quality)

    1991-09-01

    The inactive uranium mill tailings site near Lowman, Idaho, was designated as one of 24 abandoned uranium tailings sites to be remediated by the US Department of Energy (DOE) under the Uranium Mill Tailings Radiation Control Act of 1978 (UMTRCA). The UMTRCA requires that the US Nuclear Regulatory Commission (NRC) concur with the DOE's remedial action plan and certify that the remedial action complies with the standards promulgated by the US Environmental Protection Agency (EPA). The remedial action plan (RAP), which includes this remedial action selection report (RAS), has been developed to serve a two-fold purpose. First, it describes the activities that are proposed by the DOE to accomplish long-term stabilization and control of residual radioactive materials at the inactive uranium processing site near Lowman, Idaho. Second, this document and the remainder of the RAP, upon concurrence and execution by the DOE, the State of Idaho, and the NRC, becomes Appendix B of the Cooperative Agreement (No. DE-FC04-85AL20535) between the DOE and the State of Idaho.

  2. Elucidating the design principles of photosynthetic electron-transfer proteins by site-directed spin labeling EPR spectroscopy.

    PubMed

    Ishara Silva, K; Jagannathan, Bharat; Golbeck, John H; Lakshmi, K V

    2016-05-01

    Site-directed spin labeling electron paramagnetic resonance (SDSL EPR) spectroscopy is a powerful tool to determine solvent accessibility, side-chain dynamics, and inter-spin distances at specific sites in biological macromolecules. This information provides important insights into the structure and dynamics of both natural and designed proteins and protein complexes. Here, we discuss the application of SDSL EPR spectroscopy in probing the charge-transfer cofactors in photosynthetic reaction centers (RC) such as photosystem I (PSI) and the bacterial reaction center (bRC). Photosynthetic RCs are large multi-subunit proteins (molecular weight≥300 kDa) that perform light-driven charge transfer reactions in photosynthesis. These reactions are carried out by cofactors that are paramagnetic in one of their oxidation states. This renders the RCs unsuitable for conventional nuclear magnetic resonance spectroscopy investigations. However, the presence of native paramagnetic centers and the ability to covalently attach site-directed spin labels in RCs makes them ideally suited for the application of SDSL EPR spectroscopy. The paramagnetic centers serve as probes of conformational changes, dynamics of subunit assembly, and the relative motion of cofactors and peptide subunits. In this review, we describe novel applications of SDSL EPR spectroscopy for elucidating the effects of local structure and dynamics on the electron-transfer cofactors of photosynthetic RCs. Because SDSL EPR Spectroscopy is uniquely suited to provide dynamic information on protein motion, it is a particularly useful method in the engineering and analysis of designed electron transfer proteins and protein networks. This article is part of a Special Issue entitled Biodesign for Bioenergetics--the design and engineering of electronic transfer cofactors, proteins and protein networks, edited by Ronald L. Koder and J.L. Ross Anderson.

  3. Elucidating the design principles of photosynthetic electron-transfer proteins by site-directed spin labeling EPR spectroscopy.

    PubMed

    Ishara Silva, K; Jagannathan, Bharat; Golbeck, John H; Lakshmi, K V

    2016-05-01

    Site-directed spin labeling electron paramagnetic resonance (SDSL EPR) spectroscopy is a powerful tool to determine solvent accessibility, side-chain dynamics, and inter-spin distances at specific sites in biological macromolecules. This information provides important insights into the structure and dynamics of both natural and designed proteins and protein complexes. Here, we discuss the application of SDSL EPR spectroscopy in probing the charge-transfer cofactors in photosynthetic reaction centers (RC) such as photosystem I (PSI) and the bacterial reaction center (bRC). Photosynthetic RCs are large multi-subunit proteins (molecular weight≥300 kDa) that perform light-driven charge transfer reactions in photosynthesis. These reactions are carried out by cofactors that are paramagnetic in one of their oxidation states. This renders the RCs unsuitable for conventional nuclear magnetic resonance spectroscopy investigations. However, the presence of native paramagnetic centers and the ability to covalently attach site-directed spin labels in RCs makes them ideally suited for the application of SDSL EPR spectroscopy. The paramagnetic centers serve as probes of conformational changes, dynamics of subunit assembly, and the relative motion of cofactors and peptide subunits. In this review, we describe novel applications of SDSL EPR spectroscopy for elucidating the effects of local structure and dynamics on the electron-transfer cofactors of photosynthetic RCs. Because SDSL EPR Spectroscopy is uniquely suited to provide dynamic information on protein motion, it is a particularly useful method in the engineering and analysis of designed electron transfer proteins and protein networks. This article is part of a Special Issue entitled Biodesign for Bioenergetics--the design and engineering of electronic transfer cofactors, proteins and protein networks, edited by Ronald L. Koder and J.L. Ross Anderson. PMID:26334844

  4. A designed DNA binding motif that recognizes extended sites and spans two adjacent major grooves†

    PubMed Central

    Rodríguez, Jéssica; Mosquera, Jesús; García-Fandiño, Rebeca; Vázquez, M. Eugenio; Mascareñas, José L.

    2016-01-01

    We report the rational design of a DNA-binding peptide construct composed of the DNA-contacting regions of two transcription factors (GCN4 and GAGA) linked through an AT-hook DNA anchor. The resulting chimera, which represents a new, non-natural DNA binding motif, binds with high affinity and selectivity to a long composite sequence of 13 base pairs (TCAT-AATT-GAGAG). PMID:27252825

  5. Design, technology, and science: Sites for learning, resistance, and social reproduction in urban schools

    NASA Astrophysics Data System (ADS)

    Seiler, Gale; Tobin, Kenneth; Sokolic, Joseph

    2001-09-01

    The teaching of science through activities that emphasize design and technology has been advocated as a vehicle for accomplishing science for all students. This study was situated in an inner7-city neighborhood school populated mainly by African American students from life worlds characterized by poverty. The article explores the discourse and practices of students and three coteachers as a curriculum was enacted to provide opportunities for students to learn about the physics of motion through designing, building, and testing a model car. Some students participated in ways that led to their building viable model cars and interacting with one another in ways that suggest design and technological competence. However, there also was evidence of resistance from students who participated sporadically and refused to cooperate with teachers as they endeavored to structure the environment in ways that would lead to a deeper understanding of science. Analysis of in-class interactions reveals an untapped potential for the emergence of a sciencelike discourse and diverse outcomes. Among the challenges explored in this article is a struggle for respect that permeates the students' lives on the street and bleeds into the classroom environment. Whereas teachers enacted the curriculum as if learning was the chief goal for students, it is apparent that students used the class opportunistically to maintain and earn the respect of peers.

  6. Eggs in the Freezer: Energetic Consequences of Nest Site and Nest Design in Arctic Breeding Shorebirds

    PubMed Central

    Tulp, Ingrid; Schekkerman, Hans; de Leeuw, Joep

    2012-01-01

    Birds construct nests for several reasons. For species that breed in the Arctic, the insulative properties of nests are very important. Incubation is costly there and due to an increasing surface to volume ratio, more so in smaller species. Small species are therefore more likely to place their nests in thermally favourable microhabitats and/or to invest more in nest insulation than large species. To test this hypothesis, we examined characteristics of nests of six Arctic breeding shorebird species. All species chose thermally favourable nesting sites in a higher proportion than expected on the basis of habitat availability. Site choice did not differ between species. Depth to frozen ground, measured near the nests, decreased in the course of the season at similar non-species-specific speeds, but this depth increased with species size. Nest cup depth and nest scrape depth (nest cup without the lining) were unrelated to body mass (we applied an exponent of 0.73, to account for metabolic activity of the differently sized species). Cup depth divided by diameter2 was used as a measure of nest cup shape. Small species had narrow and deep nests, while large species had wide shallow nests. The thickness of nest lining varied between 0.1 cm and 7.6 cm, and decreased significantly with body mass. We reconstruct the combined effect of different nest properties on the egg cooling coefficient using previously published quantitative relationships. The predicted effect of nest cup depth and lining depth on heat loss to the frozen ground did not correlate with body mass, but the sheltering effect of nest cup diameter against wind and the effects of lining material on the cooling coefficient increased with body mass. Our results suggest that small arctic shorebirds invest more in the insulation of their nests than large species. PMID:22701596

  7. Eggs in the freezer: energetic consequences of nest site and nest design in Arctic breeding shorebirds.

    PubMed

    Tulp, Ingrid; Schekkerman, Hans; de Leeuw, Joep

    2012-01-01

    Birds construct nests for several reasons. For species that breed in the Arctic, the insulative properties of nests are very important. Incubation is costly there and due to an increasing surface to volume ratio, more so in smaller species. Small species are therefore more likely to place their nests in thermally favourable microhabitats and/or to invest more in nest insulation than large species. To test this hypothesis, we examined characteristics of nests of six Arctic breeding shorebird species. All species chose thermally favourable nesting sites in a higher proportion than expected on the basis of habitat availability. Site choice did not differ between species. Depth to frozen ground, measured near the nests, decreased in the course of the season at similar non-species-specific speeds, but this depth increased with species size. Nest cup depth and nest scrape depth (nest cup without the lining) were unrelated to body mass (we applied an exponent of 0.73, to account for metabolic activity of the differently sized species). Cup depth divided by diameter(2) was used as a measure of nest cup shape. Small species had narrow and deep nests, while large species had wide shallow nests. The thickness of nest lining varied between 0.1 cm and 7.6 cm, and decreased significantly with body mass. We reconstruct the combined effect of different nest properties on the egg cooling coefficient using previously published quantitative relationships. The predicted effect of nest cup depth and lining depth on heat loss to the frozen ground did not correlate with body mass, but the sheltering effect of nest cup diameter against wind and the effects of lining material on the cooling coefficient increased with body mass. Our results suggest that small arctic shorebirds invest more in the insulation of their nests than large species. PMID:22701596

  8. Remedial action plan and site design for stabilization of the Inactive Uranium Mill Tailings Site, Maybell, Colorado. Final report, Appendixes to attachment 3

    SciTech Connect

    Not Available

    1994-06-01

    This document contains supporting appendices to attachment 3 for the remedial action and site stabilization plan for Maybell, Colorado UMTRA site. Appendix A includes the Hydrological Services Calculations and Appendix B contains Ground Water Quality by Location data.

  9. Design and field-scale implementation of an "on site" bioremediation treatment in PAH-polluted soil.

    PubMed

    Pelaez, A I; Lores, I; Sotres, A; Mendez-Garcia, C; Fernandez-Velarde, C; Santos, J A; Gallego, J L R; Sanchez, J

    2013-10-01

    An "on site" bioremediation program was designed and implemented in soil polluted with polycyclic aromatic hydrocarbons (PAHs), especially naphthalene. We began by characterizing the soil's physical and chemical properties. A microbiological screening corroborated the presence of microorganisms capable of metabolizing PAHs. We then analyzed the viability of bioremediation by developing laboratory microcosms and pilot scale studies, to optimize the costs and time associated with remediation. The treatment assays were based on different types of biostimulants, such as a slow or fast-release fertilizer, combined with commercial surfactants. Once the feasibility of the biostimulation was confirmed, a real-scale bioremediation program was undertaken in 900 m(3) of contaminated soil. The three-step design reduced PAH contamination by 94.4% at the end of treatment (161 days). The decrease in pollutants was concomitant with the selection of autochthonous bacteria capable of degrading PAHs, with Bacillus and Pseudomonas the most abundant genera.

  10. Rational design of carbon nitride photocatalysts by identification of cyanamide defects as catalytically relevant sites.

    PubMed

    Lau, Vincent Wing-Hei; Moudrakovski, Igor; Botari, Tiago; Weinberger, Simon; Mesch, Maria B; Duppel, Viola; Senker, Jürgen; Blum, Volker; Lotsch, Bettina V

    2016-01-01

    The heptazine-based polymer melon (also known as graphitic carbon nitride, g-C3N4) is a promising photocatalyst for hydrogen evolution. Nonetheless, attempts to improve its inherently low activity are rarely based on rational approaches because of a lack of fundamental understanding of its mechanistic operation. Here we employ molecular heptazine-based model catalysts to identify the cyanamide moiety as a photocatalytically relevant 'defect'. We exploit this knowledge for the rational design of a carbon nitride polymer populated with cyanamide groups, yielding a material with 12 and 16 times the hydrogen evolution rate and apparent quantum efficiency (400 nm), respectively, compared with the unmodified melon. Computational modelling and material characterization suggest that this moiety improves coordination (and, in turn, charge transfer kinetics) to the platinum co-catalyst and enhances the separation of the photogenerated charge carriers. The demonstrated knowledge transfer for rational catalyst design presented here provides the conceptual framework for engineering high-performance heptazine-based photocatalysts. PMID:27387536

  11. Rational design of carbon nitride photocatalysts by identification of cyanamide defects as catalytically relevant sites

    PubMed Central

    Lau, Vincent Wing-hei; Moudrakovski, Igor; Botari, Tiago; Weinberger, Simon; Mesch, Maria B.; Duppel, Viola; Senker, Jürgen; Blum, Volker; Lotsch, Bettina V.

    2016-01-01

    The heptazine-based polymer melon (also known as graphitic carbon nitride, g-C3N4) is a promising photocatalyst for hydrogen evolution. Nonetheless, attempts to improve its inherently low activity are rarely based on rational approaches because of a lack of fundamental understanding of its mechanistic operation. Here we employ molecular heptazine-based model catalysts to identify the cyanamide moiety as a photocatalytically relevant ‘defect'. We exploit this knowledge for the rational design of a carbon nitride polymer populated with cyanamide groups, yielding a material with 12 and 16 times the hydrogen evolution rate and apparent quantum efficiency (400 nm), respectively, compared with the unmodified melon. Computational modelling and material characterization suggest that this moiety improves coordination (and, in turn, charge transfer kinetics) to the platinum co-catalyst and enhances the separation of the photogenerated charge carriers. The demonstrated knowledge transfer for rational catalyst design presented here provides the conceptual framework for engineering high-performance heptazine-based photocatalysts. PMID:27387536

  12. Rational design of carbon nitride photocatalysts by identification of cyanamide defects as catalytically relevant sites.

    PubMed

    Lau, Vincent Wing-Hei; Moudrakovski, Igor; Botari, Tiago; Weinberger, Simon; Mesch, Maria B; Duppel, Viola; Senker, Jürgen; Blum, Volker; Lotsch, Bettina V

    2016-07-08

    The heptazine-based polymer melon (also known as graphitic carbon nitride, g-C3N4) is a promising photocatalyst for hydrogen evolution. Nonetheless, attempts to improve its inherently low activity are rarely based on rational approaches because of a lack of fundamental understanding of its mechanistic operation. Here we employ molecular heptazine-based model catalysts to identify the cyanamide moiety as a photocatalytically relevant 'defect'. We exploit this knowledge for the rational design of a carbon nitride polymer populated with cyanamide groups, yielding a material with 12 and 16 times the hydrogen evolution rate and apparent quantum efficiency (400 nm), respectively, compared with the unmodified melon. Computational modelling and material characterization suggest that this moiety improves coordination (and, in turn, charge transfer kinetics) to the platinum co-catalyst and enhances the separation of the photogenerated charge carriers. The demonstrated knowledge transfer for rational catalyst design presented here provides the conceptual framework for engineering high-performance heptazine-based photocatalysts.

  13. Rational design of carbon nitride photocatalysts by identification of cyanamide defects as catalytically relevant sites

    NASA Astrophysics Data System (ADS)

    Lau, Vincent Wing-Hei; Moudrakovski, Igor; Botari, Tiago; Weinberger, Simon; Mesch, Maria B.; Duppel, Viola; Senker, Jürgen; Blum, Volker; Lotsch, Bettina V.

    2016-07-01

    The heptazine-based polymer melon (also known as graphitic carbon nitride, g-C3N4) is a promising photocatalyst for hydrogen evolution. Nonetheless, attempts to improve its inherently low activity are rarely based on rational approaches because of a lack of fundamental understanding of its mechanistic operation. Here we employ molecular heptazine-based model catalysts to identify the cyanamide moiety as a photocatalytically relevant `defect'. We exploit this knowledge for the rational design of a carbon nitride polymer populated with cyanamide groups, yielding a material with 12 and 16 times the hydrogen evolution rate and apparent quantum efficiency (400 nm), respectively, compared with the unmodified melon. Computational modelling and material characterization suggest that this moiety improves coordination (and, in turn, charge transfer kinetics) to the platinum co-catalyst and enhances the separation of the photogenerated charge carriers. The demonstrated knowledge transfer for rational catalyst design presented here provides the conceptual framework for engineering high-performance heptazine-based photocatalysts.

  14. Design of a Soil Cutting Resistance Sensor for Application in Site-Specific Tillage

    PubMed Central

    Agüera, Juan; Carballido, Jacob; Gil, Jesús; Gliever, Chris J.; Perez-Ruiz, Manuel

    2013-01-01

    One objective of precision agriculture is to provide accurate information about soil and crop properties to optimize the management of agricultural inputs to meet site-specific needs. This paper describes the development of a sensor equipped with RTK-GPS technology that continuously and efficiently measures soil cutting resistance at various depths while traversing the field. Laboratory and preliminary field tests verified the accuracy of this prototype soil strength sensor. The data obtained using a hand-operated soil cone penetrometer was used to evaluate this field soil compaction depth profile sensor. To date, this sensor has only been tested in one field under one gravimetric water content condition. This field test revealed that the relationships between the soil strength profile sensor (SSPS) cutting force and soil cone index values are assumed to be quadratic for the various depths considered: 0–10, 10–20 and 20–30 cm (r2 = 0.58, 0.45 and 0.54, respectively). Soil resistance contour maps illustrated its practical value. The developed sensor provides accurate, timely and affordable information on soil properties to optimize resources and improve agricultural economy. PMID:23666127

  15. Rational design of an on-site volume reduction system for source-separated urine.

    PubMed

    Pahore, Muhammad Masoom; Ito, Ryusei; Funamizu, Naoyuki

    2010-04-01

    Human urine contains nitrogen, phosphorus and potassium, which can be applied as fertilizer in agriculture, replacing commercial fertilizer. However, owing to the low nutrient content of the urine, huge quantities must be transported to farmland to meet the nutrient demand of crops. This highly increases the transportation cost for the farmers. To address the transportation issue, a new on-site volume reduction system was tested at the laboratory scale based on water evaporation from vertical gauze sheets. A mathematical water transport model was proposed to evaluate the performance of the system. The mass transfer coefficient and the resistance of water flow through the sheet in the water transport model were obtained from the experiments. The results agreed with the simulated data, thereby confirming the proposed model. The model was then applied to the dry climate of southern Pakistan, having an air temperature of 30-40 degrees C and air humidity of 20-40%, for an 80% volume reduction of 10 L urine per day, which corresponds to a family of 10 members (average for a household in Pakistan). The findings revealed that the estimated size of the vertical sheet is 440-2060 cm2, which is only a small area for setting up the system at a household level. PMID:20450114

  16. CRISPRdirect: software for designing CRISPR/Cas guide RNA with reduced off-target sites

    PubMed Central

    Naito, Yuki; Hino, Kimihiro; Bono, Hidemasa; Ui-Tei, Kumiko

    2015-01-01

    Summary: CRISPRdirect is a simple and functional web server for selecting rational CRISPR/Cas targets from an input sequence. The CRISPR/Cas system is a promising technique for genome engineering which allows target-specific cleavage of genomic DNA guided by Cas9 nuclease in complex with a guide RNA (gRNA), that complementarily binds to a ∼20 nt targeted sequence. The target sequence requirements are twofold. First, the 5′-NGG protospacer adjacent motif (PAM) sequence must be located adjacent to the target sequence. Second, the target sequence should be specific within the entire genome in order to avoid off-target editing. CRISPRdirect enables users to easily select rational target sequences with minimized off-target sites by performing exhaustive searches against genomic sequences. The server currently incorporates the genomic sequences of human, mouse, rat, marmoset, pig, chicken, frog, zebrafish, Ciona, fruit fly, silkworm, Caenorhabditis elegans, Arabidopsis, rice, Sorghum and budding yeast. Availability: Freely available at http://crispr.dbcls.jp/. Contact: y-naito@dbcls.rois.ac.jp Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25414360

  17. Design and Synthesis of Irreversible Analogues of Bardoxolone Methyl for the Identification of Pharmacologically Relevant Targets and Interaction Sites.

    PubMed

    Wong, Michael H L; Bryan, Holly K; Copple, Ian M; Jenkins, Rosalind E; Chiu, Pak Him; Bibby, Jaclyn; Berry, Neil G; Kitteringham, Neil R; Goldring, Christopher E; O'Neill, Paul M; Park, B Kevin

    2016-03-24

    Semisynthetic triterpenoids such as bardoxolone methyl (methyl-2-cyano 3,12-dioxooleano-1,9-dien-28-oate; CDDO-Me) (4) are potent inducers of antioxidant and anti-inflammatory signaling pathways, including those regulated by the transcription factor Nrf2. However, the reversible nature of the interaction between triterpenoids and thiols has hindered attempts to identify pharmacologically relevant targets and characterize the sites of interaction. Here, we report a shortened synthesis and SAR profiling of 4, enabling the design of analogues that react irreversibly with model thiols, as well as the model protein glutathione S-transferase P1, in vitro. We show that one of these analogues, CDDO-epoxide (13), is comparable to 4 in terms of cytotoxicity and potency toward Nrf2 in rat hepatoma cells and stably modifies specific cysteine residues (namely, Cys-257, -273, -288, -434, -489, and -613) within Keap1, the major repressor of Nrf2, both in vitro and in living cells. Supported by molecular modeling, these data demonstrate the value of 13 for identifying site(s) of interaction with pharmacologically relevant targets and informing the continuing development of triterpenoids as novel drug candidates.

  18. MDC-Analyzer: a novel degenerate primer design tool for the construction of intelligent mutagenesis libraries with contiguous sites.

    PubMed

    Tang, Lixia; Wang, Xiong; Ru, Beibei; Sun, Hengfei; Huang, Jian; Gao, Hui

    2014-06-01

    Recent computational and bioinformatics advances have enabled the efficient creation of novel biocatalysts by reducing amino acid variability at hot spot regions. To further expand the utility of this strategy, we present here a tool called Multi-site Degenerate Codon Analyzer (MDC-Analyzer) for the automated design of intelligent mutagenesis libraries that can completely cover user-defined randomized sequences, especially when multiple contiguous and/or adjacent sites are targeted. By initially defining an objective function, the possible optimal degenerate PCR primer profiles could be automatically explored using the heuristic approach of Greedy Best-First-Search. Compared to the previously developed DC-Analyzer, MDC-Analyzer allows for the existence of a small amount of undesired sequences as a tradeoff between the number of degenerate primers and the encoded library size while still providing all the benefits of DC-Analyzer with the ability to randomize multiple contiguous sites. MDC-Analyzer was validated using a series of randomly generated mutation schemes and experimental case studies on the evolution of halohydrin dehalogenase, which proved that the MDC methodology is more efficient than other methods and is particularly well-suited to exploring the sequence space of proteins using data-driven protein engineering strategies.

  19. Structure based design towards the identification of novel binding sites and inhibitors for the chikungunya virus envelope proteins.

    PubMed

    Rashad, Adel A; Keller, Paul A

    2013-07-01

    Chikungunya virus is an emerging arbovirus that is widespread in tropical regions and is spreading quickly to temperate climates with recent epidemics in Africa, Asia, Europe and the Americas. It is having an increasingly major impact on humans with potentially life-threatening and debilitating arthritis. Thus far, neither vaccines nor medications are available to treat or control the virus and therefore, the development of medicinal chemistry is a vital and immediate issue that needs to be addressed. The viral envelope proteins play a major role during infection through mediation of binding and fusion with the infected cell surfaces. The possible binding target sites of the chikungunya virus envelope proteins have not previously been investigated; we describe here for the first time the identification of novel sites for potential binding on the chikungunya glycoprotein complexes and the identification of possible antagonists for these sites through virtual screening using two successive docking scores; FRED docking for fast precise screening, with the top hits then subjected to a ranking scoring using the AUTODOCK algorithm. Both the immature and the mature forms of the chikungunya envelope proteins were included in the study to increase the probability of finding positive and reliable hits. Some small molecules have been identified as good in silico chikungunya virus envelope proteins inhibitors and these could be good templates for drug design targeting this virus.

  20. Lessons learned from the preclosure performance assessment review of the Fluor Technology, Inc. , draft site characterization plan conceptual design report

    SciTech Connect

    Mayberry, J.J.

    1987-06-09

    This report presents the lessons learned from the preclosure performance assessment review (PAR) of the Draft Site Characterization Plan---Conceptual Design Report (SCP-CDR). The PAR analyzes the operations of the waste handling facilities as presented in the SCP-CDR against appropriate regulatory and design criteria. The PAR applies to the design presented in a working draft released in April, 1986. We will analyze the design presented in the SCP-CDR, the other is to test safety assessment methods and tools. This report addresses only the second of these objectives. The PAR analysis consists of assessments of offsite and occupational doses resulting from routine and accidental events during preclosure operations at the repository. The activities related to the PAR are divided into subject areas. These areas include (1) the description of repository facilities and operations, (2) the development of radioactive material inventories and radiation dose rates, (3) the development of radioactive material-release scenarios and source terms, (4) the assessment of offsite dose equivalents, and (5) the assessment of occupational radiation dose equivalents. This report contains a summary of the analyses in these fives areas and lists those preclosure analyses not performed as part of the PAR. Chapters detail the strengths and weaknesses of each analysis and include recommendations for improving the analyses. 15 refs., 1 fig., 1 tab.

  1. Design of the primary pre-TRMM and TRMM ground truth site

    NASA Technical Reports Server (NTRS)

    Garstang, Michael

    1988-01-01

    The primary objective of the Tropical Rain Measuring Mission (TRMM) were to: integrate the rain gage measurements with radar measurements of rainfall using the KSFC/Patrick digitized radar and associated rainfall network; delineate the major rain bearing systems over Florida using the Weather Service reported radar/rainfall distributions; combine the integrated measurements with the delineated rain bearing systems; use the results of the combined measurements and delineated rain bearing systems to represent patterns of rainfall which actually exist and contribute significantly to the rainfall to test sampling strategies and based on the results of these analyses decide upon the ground truth network; and complete the design begun in Phase 1 of a multi-scale (space and time) surface observing precipitation network centered upon KSFC. Work accomplished and in progress is discussed.

  2. Designing for selectivity: weak interactions and the competition for reactive sites on gold catalysts.

    PubMed

    Siler, C G F; Madix, R J; Friend, C M

    2016-07-01

    A major challenge in heterogeneous catalysis is controlling reaction selectivity, especially in complex environments. When more than one species is present in the gas mixture, the competition for binding sites on the surface of a catalyst is an important factor in determining reaction selectivity and activity. We establish an experimental hierarchy for the binding of a series of reaction intermediates on Au(111) and demonstrate that this hierarchy accounts for reaction selectivity on both the single crystal surface and under operating catalytic conditions at atmospheric pressure using a nanoporous Au catalyst. A partial set of measurements of relative binding has been measured by others on other catalyst materials, including Ag, Pd and metal oxide surfaces; a comparison demonstrates the generality of this concept and identifies differences in the trends. Theoretical calculations for a subset of reactants on Au(111) show that weak van der Waals interactions are key to predicting the hierarchy of binding strengths for alkoxides bound to Au(111). This hierarchy is key to the control of the selectivity for partial oxidation of alcohols to esters on both Au surfaces and under working catalytic conditions using nanoporous gold. The selectivity depends on the competition for active sites among key intermediates. New results probing the effect of fluorine substitution are also presented to extend the relation of reaction selectivity to the hierarchy of binding. Motivated by an interest in synthetic manipulation of fluorinated organics, we specifically investigated the influence of the -CF3 group on alcohol reactivity and selectivity. 2,2,2-Trifluoroethanol couples on O-covered Au(111) to yield CF3CH2O-C([double bond, length as m-dash]O)(CF3), but in the presence of methanol or ethanol it preferentially forms the respective 2,2,2-trifluoroethoxy-esters. The ester is not the dominant product in any of these cases, though, indicating that the rate of β-H elimination from

  3. Energy conserving site design: Greenbrier case study, Chesapeake, Virginia. Final report

    SciTech Connect

    Not Available

    1980-04-01

    A specific case study of project planning for energy conservation for a major planned unit development at the 3000-acre Greenbrier development site in Chesapeake, Virginia, is summarized. The research suggests that very considerable reductions in energy conservation can be achieved within the confines of private-sector land development and residential construction with increased incremental costs of $200.00 to $3150.00 per dwelling unit. It is hypothesized that energy consumption at Greenbrier can be reduced by one-half with an average annual savings of 21,275 kWh per residential unit, using state-of-the-art technology with careful planning and control. This represents an annual savings $750.00 per unit at the current utility rate of 3.5 cents per kWh. These savings can be achieved through reduction in heating and cooling loads and application of more-efficient heating and cooling of the remaining loads. The reduction in loads are achieved by redesign of the land plan to include a higher percentage of south-facing lots, use of vegetation to modify microclimate, decreases in air infiltration, the use of 2 x 6 framing, better insulation, and the use of an insulated slab-on-grade foundation. Further energy savings can be expected by increased efficiencies in mechanical systems used for space heating and cooling and domestic hot water. When applied to the single-family portion of Greenbrier, containing 541 dwelling units, these options reduce the total end-use energy consumption 54.7%. This reduction represents an annual savings of $432,800.00 for an initial capital investment of $1.7 million.

  4. Use of Ground Penetrating Radar for Site Investigation of Low-Volume Roadways and Design Recommendations

    NASA Astrophysics Data System (ADS)

    Scullion, T.; Saarenketo, T.

    2002-07-01

    This report will present several case studies describing the use of ground penetrating radar (GPR) technology for site investigations. Two types of GPR will be described-the air-launched and ground-coupled systems. The use of air-launched radar is well established within the Texas Department of Transportation (TxDOT). The limitation of this technology is its depth of penetration. While providing very useful information on the surface and base layers, it provides little information on the sub-grade soils. The use of low-frequency ground-coupled radar systems will provide little useful near-surface information but it can provide data on sub-grade properties and how they vary along a project. Combining both radar types can potentially provide a comprehensive subsurface investigative tool for both new pavement construction and for major pavement rehabilitation projects. In this report a brief description will be provided of the different systems together with the software used to process the GPR signals. Air-launched data are processed with the COLORMAP system developed by the Texas Transportation Institute. The ground-coupled data are processed using the Road Doctor system developed by Roadscanners, Inc. of Finland. The case studies presented were collected on actual TxDOT evaluation projects mainly in the Bryan District. They range from near-surface applications where the goal was to identify changes in pavement structure which were not available in construction records to identifying the areas beneath the pavement subsidence associated with strip mining activities.

  5. A versatile photoactivatable probe designed to label the diphosphate binding site of farnesyl diphosphate utilizing enzymes.

    PubMed

    Henry, Olivier; Lopez-Gallego, Fernando; Agger, Sean A; Schmidt-Dannert, Claudia; Sen, Stephanie; Shintani, David; Cornish, Katrina; Distefano, Mark D

    2009-07-01

    Farnesyl diphosphate (FPP) is a substrate for a diverse number of enzymes found in nature. Photoactive analogues of isoprenoid diphosphates containing either benzophenone, diazotrifluoropropionate or azide groups have been useful for studying both the enzymes that synthesize FPP as well as those that employ FPP as a substrate. Here we describe the synthesis and properties of a new class of FPP analogues that links an unmodified farnesyl group to a diphosphate mimic containing a photoactive benzophenone moiety; thus, importantly, these compounds are photoactive FPP analogues that contain no modifications of the isoprenoid portion of the molecule that may interfere with substrate binding in the active site of an FPP utilizing enzyme. Two isomeric compounds containing meta- and para-substituted benzophenones were prepared. These two analogues inhibit Saccharomyces cerevisiae protein farnesyltransferase (ScPFTase) with IC(50) values of 5.8 (meta isomer) and 3.0 microM (para isomer); the more potent analogue, the para isomer, was shown to be a competitive inhibitor of ScPFTase with respect to FPP with a K(I) of 0.46 microM. Radiolabeled forms of both analogues selectively labeled the beta-subunit of ScPFTase. The para isomer was also shown to label Escherichia coli farnesyl diphosphate synthase and Drosophila melanogaster farnesyl diphosphate synthase. Finally, the para isomer was shown to be an alternative substrate for a sesquiterpene synthase from Nostoc sp. strain PCC7120, a cyanobacterial source; the compound also labeled the purified enzyme upon photolysis. Taken together, these results using a number of enzymes demonstrate that this new class of probes should be useful for a plethora of studies of FPP-utilizing enzymes. PMID:19447628

  6. Compressed air energy storage: Preliminary design and site development program in an aquifer. Task 1: Establish facility design criteria and utility benefits

    NASA Astrophysics Data System (ADS)

    1980-10-01

    Compressed air energy storage (CAES) stores mechanical energy in the form of compressed air during off-peak hours, using power supplied by a large, high efficiency baseload power plant. At times of high electrical demand, the compressed air is drawn from storage and is heated in a combustor by the burning of fuel oil, after which the air is expanded in a turbine. Essentially all of the turbine output can be applied to the generation of electricity, unlike a conventional gas turbine which expends approximately two-thirds of the turbine shaft power in driving the air compressor. The separation of the compression and generation modes in the system results in increased net generation and greater premium fuel economy. Work performed in establishing facility design criteria for a CAES system with aquifer storage includes: determination of initial design bases; preliminary analysis of the CAES system; development of data for site-specific analysis of the CAES system; detailed analysis of the CAES system for three selected heat cycles; CAES power plant design; and an economic analysis of CAES.

  7. Compressed air energy storage: preliminary design and site development program in an aquifer. Final draft, Task 1: establish facility design criteria and utility benefits

    SciTech Connect

    1980-10-01

    Compressed air energy storage (CAES) has been identified as one of the principal new energy storage technologies worthy of further research and development. The CAES system stores mechanical energy in the form of compressed air during off-peak hours, using power supplied by a large, high-efficiency baseload power plant. At times of high electrical demand, the compressed air is drawn from storage and is heated in a combustor by the burning of fuel oil, after which the air is expanded in a turbine. In this manner, essentially all of the turbine output can be applied to the generation of electricity, unlike a conventional gas turbine which expends approximately two-thirds of the turbine shaft power in driving the air compressor. The separation of the compression and generation modes in the CAES system results in increased net generation and greater premium fuel economy. The use of CAES systems to meet the utilities' high electrical demand requirements is particularly attractive in view of the reduced availability of premium fuels such as oil and natural gas. This volume documents the Task 1 work performed in establishing facility design criteria for a CAES system with aquifer storage. Information is included on: determination of initial design bases; preliminary analysis of the CAES system; development of data for site-specific analysis of the CAES system; detailed analysis of the CAES system for three selected heat cycles; CAES power plant design; and an economic analysis of CAES.

  8. "Intelligent design" of a 3D reflection survey for the SAFOD drill-hole site

    NASA Astrophysics Data System (ADS)

    Alvarez, G.; Hole, J. A.; Klemperer, S. L.; Biondi, B.; Imhof, M.

    2003-12-01

    SAFOD seeks to better understand the earthquake process by drilling though the San Andreas fault (SAF) to sample an earthquake in situ. To capitalize fully on the opportunities presented by the 1D drill-hole into a complex fault zone we must characterize the surrounding 3D geology at a scale commensurate with the drilling observations, to provide the structural context to extrapolate 1D drilling results along the fault plane and into the surrounding 3D volume. Excellent active-2D and passive-3D seismic observations completed and underway lack the detailed 3D resolution required. Only an industry-quality 3D reflection survey can provide c. 25 m subsurface sample-spacing horizontally and vertically. A 3D reflection survey will provide subsurface structural and stratigraphic control at the 100-m level, mapping major geologic units, structural boundaries, and subsurface relationships between the many faults that make up the SAF fault system. A principal objective should be a reflection-image (horizon-slice through the 3D volume) of the near-vertical fault plane(s) to show variations in physical properties around the drill-hole. Without a 3D reflection image of the fault zone, we risk interpreting drilled anomalies as ubiquitous properties of the fault, or risk missing important anomalies altogether. Such a survey cannot be properly costed or technically designed without major planning. "Intelligent survey design" can minimize source and receiver effort without compromising data-quality at the fault target. Such optimization can in principal reduce the cost of a 3D seismic survey by a factor of two or three, utilizing the known surface logistic constraints, partially-known sub-surface velocity field, and the suite of scientific targets at SAFOD. Our methodology poses the selection of the survey parameters as an optimization process that allows the parameters to vary spatially in response to changes in the subsurface. The acquisition geometry is locally optimized for

  9. Designating Earth's Moon as a United Nations World Heritage Site - Permanently Protected from Commercial or Military Uses

    NASA Astrophysics Data System (ADS)

    Steiner, R. G.

    2002-01-01

    This paper proposes that Earth's Moon, in its entirety, be designated a United Nations World Heritage Site (WHS), permanently protected from any and all commercial or military utilization and reserved exclusively for scientific and aesthetic purposes. The paper discusses: 1) the extraordinary importance of the Moon for science, culture, and religion - past, present and future; 2) the history of proposals to exploit the Moon for commercial and military purposes and the shortcomings of this colonial, exploitation paradigm; and 3) the necessity, policy mechanisms, and political dynamics of designating the Moon as a World Heritage Site, permanently protected from commercial and/or military uses. The first part of the paper discusses the extraordinary importance of the Moon as it exists today - as a scientific laboratory, a source of beauty and inspiration throughout human evolution, a source for artistic expression, and as an object that is considered sacred by many cultures. Next, the paper traces the history of specific proposals for the exploitation of the Moon for commercial and/or military purposes - including plans by the U.S. Air Force in 1959 to detonate a nuclear explosion on the Moon, proposals to strip-mine the lunar regolith for helium-3 and rocket-fuel hydrogen; construction of solar power plants to transmit energy to Earth, and proposals to use the lunar surface as a billboard upon which to project commercial advertisements visible from Earth. The profound ethical, legal, and scientific shortcomings of this exploitation paradigm are described as an emerging Extraterrestrial Manifest Destiny that we have a collective obligation to challenge and constrain. The paper proposes that space exploration be infused with an ethical commitment to compassion, reverence, conservation, and non-interference to abiotic and biotic systems alike; as opposed to the expansion and extraterrestrial imposition of the colonization, exploitation, domination, and despoliation

  10. Improving the Applicability of Tomographic GPR for Crosshole Site Characterization Through Data Acquisition Design

    NASA Astrophysics Data System (ADS)

    Flaxman, A. O.; Hou, Z.

    2008-12-01

    Tomographic ground penetrating radar (GPR) traveltime data has been widely used for hydrologic parameter estimation in the shallow subsurface. However, hydrogeological information extracted from tomographic GPR data is subject to great uncertainty because of the nonlinear and non-unique relationships between hydrogeological and geophysical attributes, and the spatial heterogeneity of these attributes. Such uncertainty relies heavily on the data acquisition parameters. Good data acquisition can make the hydrogeological parameter estimation problems less ill-posed. However, few efforts have been made to evaluate the impacts of different data acquisition parameters (soil type, borehole geometry, antenna locations and spacing, soil saturation conditions, etc.) on the borehole radar responses. The inaccuracy of geophysical forward models also increases the level of uncertainty in parameter estimation. Here we adopt a finite-difference method that solves the Eikonal equation to obtain accurate radar travel times, by taking all possible wave paths into account through a local traveltime computation algorithm. In this study, we treat the data acquisition parameters as random variables which are characterized by their probabilistic density distributions. Through stochastic sampling approach, we generate multiple fields with different data acquisition parameters; then the eikonal solver method is used to compute the corresponding GPR responses; and finally, we use a Bayesian inverse approach to estimate hydrogeological parameters for different field conditions. In this way, the impact of data acquisition parameters on the applicability of the borehole radar data can be systematically evaluated. Therefore, this study provides useful information on borehole radar data acquisition design.

  11. Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/ref-1) and DNA damage in the caudal region of acute and chronic spinal cord injured rats treated by embryonic neural stem cells.

    PubMed

    DAGCI, T; ARMAGAN, G; KONYALIOGLU, S; YALCIN, A

    2009-01-01

    The oxidative mechanisms of injury-induced damage of neurons within the spinal cord are not very well understood. We used a model of T8-T9 spinal cord injury (SCI) in the rat to induce neuronal degeneration. In this spinal cord injury model, unilateral avulsion of the spinal cord causes oxidative stress of neurons. We tested the hypothesis that apurinic/apyrimidinic endonuclease (or redox effector factor-1, APE/Ref-1) regulates this neuronal oxidation mechanism in the spinal cord region caudal to the lesion, and that DNA damage is an early upstream signal. The embryonic neural stem cell therapy significantly decreased DNA-damage levels in both study groups - acutely (followed up to 7 days after SCI), and chronically (followed up to 28 days after SCI) injured animals. Meanwhile, mRNA levels of APE/Ref-1 significantly increased after embryonic neural stem cell therapy in acutely and chronically injured animals when compared to acute and chronic sham groups. Our data has demonstrated that an increase of APE/Ref-1 mRNA levels in the caudal region of spinal cord strongly correlated with DNA damage after traumatic spinal cord injury. We suggest that DNA damage can be observed both in lesional and caudal regions of the acutely and chronically injured groups, but DNA damage is reduced with embryonic neural stem cell therapy.

  12. Fragment-Based Design of Ligands Targeting a Novel Site on the Integrase Enzyme of Human Immunodeficiency Virus;#8197;1

    SciTech Connect

    Wielens, Jerome; Headey, Stephen J.; Deadman, John J.; Rhodes, David I.; Parker, Michael W.; Chalmers, David K.; Scanlon, Martin J.

    2011-08-17

    Fragment-based screening has been used to identify a novel ligand binding site on HIV-1 integrase. Crystal structures of fragments bound at this site (shown) have been used to design elaborated second-generation compounds that bind with higher affinity and good ligand efficiency.

  13. Learning to Design and Implement Educational Web Sites within Pre-Service Training: A Project-Based Learning Environment and Its Impact on Student Teachers

    ERIC Educational Resources Information Center

    Papastergiou, Marina

    2005-01-01

    This paper reports on a project-based learning (PBL) environment targeted towards introducing student teachers to the design and development of educational web sites. The participants were 46 student teachers who constructed 16 web sites for primary school. A survey of their views, before and after the projects, and an evaluation of the web sites…

  14. Learning to Design and Implement Educational Web Sites within Pre-Service Training: a Project-Based Learning Environment and its Impact on Student Teachers

    ERIC Educational Resources Information Center

    Papastergiou, Marina

    2005-01-01

    This paper reports on a project-based learning (PBL) environment targeted towards introducing student teachers to the design and development of educational web sites. The participants were 46 student teachers who constructed 16 web sites for primary school. A survey of their views, before and after the projects, and an evaluation of the web sites…

  15. Annual survival estimation of migratory songbirds confounded by incomplete breeding site-fidelity: Study designs that may help

    USGS Publications Warehouse

    Marshall, M.R.; Diefenbach, D.R.; Wood, L.A.; Cooper, R.J.

    2004-01-01

    Many species of bird exhibit varying degrees of site-fidelity to the previous year's territory or breeding area, a phenomenon we refer to as incomplete breeding site-fidelity. If the territory they occupy is located beyond the bounds of the study area or search area (i.e., they have emigrated from the study area), the bird will go undetected and is therefore indistinguishable from dead individuals in capture-mark-recapture studies. Differential emigration rates confound inferences regarding differences in survival between sexes and among species if apparent survival rates are used as estimates of true survival. Moreover, the bias introduced by using apparent survival rates for true survival rates can have profound effects on the predictions of population persistence through time, source/sink dynamics, and other aspects of life-history theory. We investigated four study design and analysis approaches that result in apparent survival estimates that are closer to true survival estimates. Our motivation for this research stemmed from a multi-year capture-recapture study of Prothonotary Warblers (Protonotaria citrea) on multiple study plots within a larger landscape of suitable breeding habitat where substantial inter-annual movements of marked individuals among neighboring study plots was documented. We wished to quantify the effects of this type of movement on annual survival estimation. The first two study designs we investigated involved marking birds in a core area and resighting them in the core as well as an area surrounding the core. For the first of these two designs, we demonstrated that as the resighting area surrounding the core gets progressively larger, and more "emigrants" are resighted, apparent survival estimates begin to approximate true survival rates (bias < 0.01). However, given observed inter-annual movements of birds, it is likely to be logistically impractical to resight birds on sufficiently large surrounding areas to minimize bias. Therefore

  16. HotSpot Wizard 2.0: automated design of site-specific mutations and smart libraries in protein engineering.

    PubMed

    Bendl, Jaroslav; Stourac, Jan; Sebestova, Eva; Vavra, Ondrej; Musil, Milos; Brezovsky, Jan; Damborsky, Jiri

    2016-07-01

    HotSpot Wizard 2.0 is a web server for automated identification of hot spots and design of smart libraries for engineering proteins' stability, catalytic activity, substrate specificity and enantioselectivity. The server integrates sequence, structural and evolutionary information obtained from 3 databases and 20 computational tools. Users are guided through the processes of selecting hot spots using four different protein engineering strategies and optimizing the resulting library's size by narrowing down a set of substitutions at individual randomized positions. The only required input is a query protein structure. The results of the calculations are mapped onto the protein's structure and visualized with a JSmol applet. HotSpot Wizard lists annotated residues suitable for mutagenesis and can automatically design appropriate codons for each implemented strategy. Overall, HotSpot Wizard provides comprehensive annotations of protein structures and assists protein engineers with the rational design of site-specific mutations and focused libraries. It is freely available at http://loschmidt.chemi.muni.cz/hotspotwizard.

  17. HotSpot Wizard 2.0: automated design of site-specific mutations and smart libraries in protein engineering.

    PubMed

    Bendl, Jaroslav; Stourac, Jan; Sebestova, Eva; Vavra, Ondrej; Musil, Milos; Brezovsky, Jan; Damborsky, Jiri

    2016-07-01

    HotSpot Wizard 2.0 is a web server for automated identification of hot spots and design of smart libraries for engineering proteins' stability, catalytic activity, substrate specificity and enantioselectivity. The server integrates sequence, structural and evolutionary information obtained from 3 databases and 20 computational tools. Users are guided through the processes of selecting hot spots using four different protein engineering strategies and optimizing the resulting library's size by narrowing down a set of substitutions at individual randomized positions. The only required input is a query protein structure. The results of the calculations are mapped onto the protein's structure and visualized with a JSmol applet. HotSpot Wizard lists annotated residues suitable for mutagenesis and can automatically design appropriate codons for each implemented strategy. Overall, HotSpot Wizard provides comprehensive annotations of protein structures and assists protein engineers with the rational design of site-specific mutations and focused libraries. It is freely available at http://loschmidt.chemi.muni.cz/hotspotwizard. PMID:27174934

  18. HotSpot Wizard 2.0: automated design of site-specific mutations and smart libraries in protein engineering

    PubMed Central

    Bendl, Jaroslav; Stourac, Jan; Sebestova, Eva; Vavra, Ondrej; Musil, Milos; Brezovsky, Jan; Damborsky, Jiri

    2016-01-01

    HotSpot Wizard 2.0 is a web server for automated identification of hot spots and design of smart libraries for engineering proteins’ stability, catalytic activity, substrate specificity and enantioselectivity. The server integrates sequence, structural and evolutionary information obtained from 3 databases and 20 computational tools. Users are guided through the processes of selecting hot spots using four different protein engineering strategies and optimizing the resulting library's size by narrowing down a set of substitutions at individual randomized positions. The only required input is a query protein structure. The results of the calculations are mapped onto the protein's structure and visualized with a JSmol applet. HotSpot Wizard lists annotated residues suitable for mutagenesis and can automatically design appropriate codons for each implemented strategy. Overall, HotSpot Wizard provides comprehensive annotations of protein structures and assists protein engineers with the rational design of site-specific mutations and focused libraries. It is freely available at http://loschmidt.chemi.muni.cz/hotspotwizard. PMID:27174934

  19. Remedial action plan and site design for stabilization of the inactive uranium mill tailings sites at Slick Rock, Colorado. Attachment 3, Ground water hydrology report: Preliminary final

    SciTech Connect

    Not Available

    1994-03-04

    The US Environmental Protection Agency (EPA) has established health and environmental protection regulations to correct and prevent ground water contamination resulting from processing activities at inactive uranium milling sites (52 FR 36000 (1987)). According to the Uranium Mill Tailings Radiation Control Act (UMTRCA) of 1978, 42 USC {section}7901 et seq., the US Department of Energy (DOE) is responsible for assessing the inactive uranium processing sites. The DOE has determined that for Slick Rock, this assessment shall include hydrogeologic site characterization for two separate uranium processing sites, the Union Carbide (UC) site and the North Continent (NC) site, and for the proposed Burro Canyon disposal site. The water resources protection strategy that describes how the proposed action will comply with the EPA ground water protection standards is presented in Attachment 4. The following site characterization activities are discussed in this attachment: Characterization of the hydrogeologic environment, including hydrostratigraphy, ground water occurrence, aquifer parameters, and areas of recharge and discharge. Characterization of existing ground water quality by comparison with background water quality and the maximum concentration limits (MCL) of the proposed EPA ground water protection standards. Definition of physical and chemical characteristics of the potential contaminant source, including concentration and leachability of the source in relation to migration in ground water and hydraulically connected surface water. Description of local water resources, including current and future use, availability, and alternative supplies.

  20. Rational design of a protein that binds integrin αvβ3 outside the ligand binding site

    PubMed Central

    Turaga, Ravi Chakra; Yin, Lu; Yang, Jenny J.; Lee, Hsiauwei; Ivanov, Ivaylo; Yan, Chunli; Yang, Hua; Grossniklaus, Hans E.; Wang, Siming; Ma, Cheng; Sun, Li; Liu, Zhi-Ren

    2016-01-01

    Integrin αvβ3 expression is altered in various diseases and has been proposed as a drug target. Here we use a rational design approach to develop a therapeutic protein, which we call ProAgio, that binds to integrin αvβ3 outside the classical ligand-binding site. We show ProAgio induces apoptosis of integrin αvβ3-expressing cells by recruiting and activating caspase 8 to the cytoplasmic domain of integrin αvβ3. ProAgio also has anti-angiogenic activity and strongly inhibits growth of tumour xenografts, but does not affect the established vasculature. Toxicity analyses demonstrate that ProAgio is not toxic to mice. Our study reports a new integrin-targeting agent with a unique mechanism of action, and provides a template for the development of integrin-targeting therapeutics. PMID:27241473

  1. Rational design of a protein that binds integrin αvβ3 outside the ligand binding site.

    PubMed

    Turaga, Ravi Chakra; Yin, Lu; Yang, Jenny J; Lee, Hsiauwei; Ivanov, Ivaylo; Yan, Chunli; Yang, Hua; Grossniklaus, Hans E; Wang, Siming; Ma, Cheng; Sun, Li; Liu, Zhi-Ren

    2016-05-31

    Integrin αvβ3 expression is altered in various diseases and has been proposed as a drug target. Here we use a rational design approach to develop a therapeutic protein, which we call ProAgio, that binds to integrin αvβ3 outside the classical ligand-binding site. We show ProAgio induces apoptosis of integrin αvβ3-expressing cells by recruiting and activating caspase 8 to the cytoplasmic domain of integrin αvβ3. ProAgio also has anti-angiogenic activity and strongly inhibits growth of tumour xenografts, but does not affect the established vasculature. Toxicity analyses demonstrate that ProAgio is not toxic to mice. Our study reports a new integrin-targeting agent with a unique mechanism of action, and provides a template for the development of integrin-targeting therapeutics.

  2. A coupled simulation-optimization approach for groundwater remediation design under uncertainty: an application to a petroleum-contaminated site.

    PubMed

    He, L; Huang, G H; Lu, H W

    2009-01-01

    This study provides a coupled simulation-optimization approach for optimal design of petroleum-contaminated groundwater remediation under uncertainty. Compared to the previous approaches, it has the advantages of: (1) addressing the stochasticity of the modeling parameters in simulating the flow and transport of NAPLs in groundwater, (2) providing a direct and response-rapid bridge between remediation strategies (pumping rates) and remediation performance (contaminant concentrations) through the created proxy models, (3) alleviating the computational cost in searching for optimal solutions, and (4) giving confidence levels for the obtained optimal remediation strategies. The approach is applied to a practical site in Canada for demonstrating its performance. The results show that mitigating the effects of uncertainty on optimal remediation strategies (through enhancing the confidence level) would lead to the rise of remediation cost due to the increase in the total pumping rate.

  3. Judgments of policies designed to elicit local cooperation on LLRW disposal siting: Comparing the public and decision makers

    SciTech Connect

    Bord, R.J.

    1987-01-01

    The study reported here solicited the opinions of the general public of the State of Pennsylvania and of key decision makers in environmental, civic, industry, and health groups, on various policy issues connected with the establishment of low-level radioactive waste disposal sites. Specifically, the focus was on their judgment of options designed to elicit local cooperation and their trust in various officials and agencies. The data indicates that the general public views both compensation and power sharing options as important in promoting local cooperation. However, power sharing options are viewed as more important than incentives. The general public consistently demonstrates a preference for options which put control of the site in the hands of locals. On the other hand, influential decision-makers, with the exception of those representing environmental advocacy organizations, tend to view compensation as more important than local power sharing. Their preferences mirror those programs currently being pursued by federal and state officials. Preferences exhibited by leaders of environmental advocacy organizations parallel those of the general public.

  4. Volunteers Oriented Interface Design for the Remote Navigation of Rescue Robots at Large-Scale Disaster Sites

    NASA Astrophysics Data System (ADS)

    Yang, Zhixiao; Ito, Kazuyuki; Saijo, Kazuhiko; Hirotsune, Kazuyuki; Gofuku, Akio; Matsuno, Fumitoshi

    This paper aims at constructing an efficient interface being similar to those widely used in human daily life, to fulfill the need of many volunteer rescuers operating rescue robots at large-scale disaster sites. The developed system includes a force feedback steering wheel interface and an artificial neural network (ANN) based mouse-screen interface. The former consists of a force feedback steering control and a six monitors’ wall. It provides a manual operation like driving cars to navigate a rescue robot. The latter consists of a mouse and a camera’s view displayed in a monitor. It provides a semi-autonomous operation by mouse clicking to navigate a rescue robot. Results of experiments show that a novice volunteer can skillfully navigate a tank rescue robot through both interfaces after 20 to 30 minutes of learning their operation respectively. The steering wheel interface has high navigating speed in open areas, without restriction of terrains and surface conditions of a disaster site. The mouse-screen interface is good at exact navigation in complex structures, while bringing little tension to operators. The two interfaces are designed to switch into each other at any time to provide a combined efficient navigation method.

  5. On the Proper Estimation of the Confidence Interval for the Design Formula of Blast-Induced Vibrations with Site Records

    NASA Astrophysics Data System (ADS)

    Yan, W. M.; Yuen, Ka-Veng

    2015-01-01

    Blast-induced ground vibration has received much engineering and public attention. The vibration is often represented by the peak particle velocity (PPV) and the empirical approach is employed to describe the relationship between the PPV and the scaled distance. Different statistical methods are often used to obtain the confidence level of the prediction. With a known scaled distance, the amount of explosives in a planned blast can then be determined by a blast engineer when the PPV limit and the confidence level of the vibration magnitude are specified. This paper shows that these current approaches do not incorporate the posterior uncertainty of the fitting coefficients. In order to resolve this problem, a Bayesian method is proposed to derive the site-specific fitting coefficients based on a small amount of data collected at an early stage of a blasting project. More importantly, uncertainty of both the fitting coefficients and the design formula can be quantified. Data collected from a site formation project in Hong Kong is used to illustrate the performance of the proposed method. It is shown that the proposed method resolves the underestimation problem in one of the conventional approaches. The proposed approach can be easily conducted using spreadsheet calculation without the need for any additional tools, so it will be particularly welcome by practicing engineers.

  6. sgRNAcas9: a software package for designing CRISPR sgRNA and evaluating potential off-target cleavage sites.

    PubMed

    Xie, Shengsong; Shen, Bin; Zhang, Chaobao; Huang, Xingxu; Zhang, Yonglian

    2014-01-01

    Although the CRISPR/Cas9/sgRNA system efficiently cleaves intracellular DNA at desired target sites, major concerns remain on potential "off-target" cleavage that may occur throughout the whole genome. In order to improve CRISPR-Cas9 specificity for targeted genome editing and transcriptional control, we describe a bioinformatics tool "sgRNAcas9", which is a software package developed for fast design of CRISPR sgRNA with minimized off-target effects. This package consists of programs to perform a search for CRISPR target sites (protospacers) with user-defined parameters, predict genome-wide Cas9 potential off-target cleavage sites (POT), classify the POT into three categories, batch-design oligonucleotides for constructing 20-nt (nucleotides) or truncated sgRNA expression vectors, extract desired length nucleotide sequences flanking the on- or off-target cleavage sites for designing PCR primer pairs to validate the mutations by T7E1 cleavage assay. Importantly, by identifying potential off-target sites in silico, the sgRNAcas9 allows the selection of more specific target sites and aids the identification of bona fide off-target sites, significantly facilitating the design of sgRNA for genome editing applications. sgRNAcas9 software package is publicly available at BiooTools website (www.biootools.com) under the terms of the GNU General Public License.

  7. Remedial Action Plan and site design for stabilization of the inactive uranium mill tailings site at Durango, Colorado: Attachment 3, Groundwater hydrology report. Revised final report

    SciTech Connect

    Not Available

    1991-12-01

    The US Environmental Protection Agency (EPA) has established health and environmental protection regulations to correct and prevent groundwater contamination resulting from processing activities at inactive uranium milling sites. According to the Uranium Mill Tailings Radiation Control Act of 1978, (UMTRCA) the US Department of Energy (DOE) is responsible for assessing the inactive uranium processing sites. The DOE has determined this assessment shall include information on hydrogeologic site characterization. The water resources protection strategy that describes how the proposed action will comply with the EPA groundwater protection standards is presented in Attachment 4. Site characterization activities discussed in this section include: Characterization of the hydrogeologic environment; characterization of existing groundwater quality; definition of physical and chemical characteristics of the potential contaminant source; and description of local water resources.

  8. Remedial action and site design for stabilization of the inactive uranium mill tailings sites at Slick Rock, Colorado. Attachment 2, Geology report

    SciTech Connect

    Not Available

    1993-07-01

    This report presents geologic considerations that are pertinent to the Remedial Action Plan for Slick Rock mill tailings. Topics covered include regional geology, site geology, geologic stability, and geologic suitability.

  9. REVIEW REPORT: BUILDING C-400 THERMAL TREATMENT 90 PERCENT REMEDIAL DESIGN REPORT AND SITE INVESTIGATION, PGDP, PADUCAH, KENTUCKY

    SciTech Connect

    Looney, B; Jed Costanza, J; Eva Davis, E; Joe Rossabi, J; Lloyd Stewart, L; Hans Stroo, H

    2007-08-15

    On 9 April 2007, the U.S. Department of Energy (DOE) Headquarters, Office of Soil and Groundwater Remediation (EM-22) initiated an Independent Technical Review (ITR) of the 90% Remedial Design Report (RDR) and Site Investigation (RDSI) for thermal treatment of trichloroethylene (TCE) in the soil and groundwater in the vicinity of Building C-400 at the Paducah Gaseous Diffusion Plant (PGDP). The general ITR goals were to assess the technical adequacy of the 90% RDSI and provide recommendations sufficient for DOE to determine if modifications are warranted pertaining to the design, schedule, or cost of implementing the proposed design. The ultimate goal of the effort was to assist the DOE Paducah/Portsmouth Project Office (PPPO) and their contractor team in ''removing'' the TCE source zone located near the C-400 Building. This report provides the ITR findings and recommendations and supporting evaluations as needed to facilitate use of the recommendations. The ITR team supports the remedial action objective (RAO) at C-400 to reduce the TCE source area via subsurface Electrical Resistance Heating (ERH). Further, the ITR team commends PPPO, their contractor team, regulators, and stakeholders for the significant efforts taken in preparing the 90% RDR. To maximize TCE removal at the target source area, several themes emerge from the review which the ITR team believes should be considered and addressed before implementing the thermal treatment. These themes include the need for: (1) Accurate and site-specific models as the basis to verify the ERH design for full-scale implementation for this challenging hydrogeologic setting; (2) Flexible project implementation and operation to allow the project team to respond to observations and data collected during construction and operation; (3) Defensible performance metrics and monitoring, appropriate for ERH, to ensure sufficient and efficient clean-up; and (4) Comprehensive (creative and diverse) contingencies to address the

  10. Use of Mathematical Models in the Design and Performance Evaluation of a Surfactant Flushing Demonstration at the Bachman Road Site

    NASA Astrophysics Data System (ADS)

    Abriola, L. M.; Drummond, C. D.; Lemke, L. D.; Rathfelder, K. M.; Pennell, K. D.

    2001-05-01

    This presentation provides an overview of the design and performance evaluation of a surfactant enhanced remediation pilot demonstration conducted in the summer of 2000 at a former dry cleaning facility in Oscoda, Michigan, USA. The unconfined contaminated formation is composed of relatively homogeneous glacial outwash sands, underlain by a thick clay layer. Core samples have revealed the presence of a reasonably persistent coarse sand and gravel layer at a depth of 11-16 feet and a sand/silt/clay transition zone at the base of the aquifer. A narrow tetrachloroethylene (PCE) plume emanates from the suspected source area, beneath the former dry cleaning building, and discharges into Lake Huron, approximately 700 feet down gradient. There is little evidence of microbial plume attenuation at the site. Aqueous samples from multilevel piezometers installed beneath the building have confirmed the presence of residual PCE within the coarse sand and gravel layer and have detected consistently high PCE concentrations at the base of the aquifer. The actual distribution and volume of entrapped PCE, however, is unknown. A surfactant injection and recovery scheme was designed and implemented to effectively flush the identified source area beneath the building. In this scheme, a line of water injection wells was installed behind the surfactant injection points to control surfactant delivery and maximize solubilized plume capture. Prior to surfactant injection, conservative and partitioning tracer tests were also conducted to confirm sweep and estimate source zone mass. Mass recovery calculations indicate that more than 94% of the injected surfactant and approximately 19 liters of PCE were recovered during the test. This volume of DNAPL is consistent with estimated low saturations within the swept zone. Single and multiphase transport models were employed to aid in remedial design and predict system performance. For the model simulations, input parameters were determined from

  11. Site-Directed Mutagenesis of a Hyperthermophilic Endoglucanase Cel12B from Thermotoga maritima Based on Rational Design

    PubMed Central

    Zhang, Jinfeng; Shi, Hao; Xu, Linyu; Zhu, Xiaoyan; Li, Xiangqian

    2015-01-01

    To meet the demand for the application of high activity and thermostable cellulases in the production of new-generation bioethanol from nongrain-cellulose sources, a hyperthermostable β-1,4-endoglucase Cel12B from Thermotoga maritima was selected for further modification by gene site-directed mutagenesis method in the present study, based on homology modeling and rational design. As a result, two recombinant enzymes showed significant improvement in enzyme activity by 77% and 87%, respectively, higher than the parental enzyme TmCel12B. Furthermore, the two mutants could retain 80% and 90.5% of their initial activity after incubation at 80°C for 8 h, while only 45% for 5 h to TmCel12B. The Km and Vmax of the two recombinant enzymes were 1.97±0.05 mM, 4.23±0.15 μmol·mg-1·min-1 of TmCel12B-E225H-K207G-D37V, and 2.97±0.12 mM, 3.15±0.21 μmol·mg-1·min-1 of TmCel12B-E225H-K207G, respectively, when using CMC-Na as the substrate. The roles of the mutation sites were also analyzed and evaluated in terms of electron density, hydrophobicity of the modeled protein structures. The recombinant enzymes may be used in the hydrolysis of cellulose at higher temperature in the future. It was concluded that the gene mutagenesis approach of a certain active residues may effectively improve the performance of cellulases for the industrial applications and contribute to the study the thermostable mechanism of thermophilic enzymes. PMID:26218520

  12. Theoretical and experimental design of site-specific applicators and heating protocols for interstitial ultrasound thermal therapy

    NASA Astrophysics Data System (ADS)

    Tyreus, Per Daniel; Nau, William H.; Wu, Alex; Diederich, Chris J.

    2003-06-01

    Theoretical and experimental approaches were used to develop and evaluate site-specific designs of internally cooled direct coupled (ICDC) and catheter-cooled (CC) ultrasound applicators for thermal coagulation of disease in the prostate, liver, brain, and uterus. The diameter of an interstitial applicator can influence its clinical practicality and effectiveness as well as application site. One purpose of this study was to determine whether the use of larger ultrasound transducers and the inherent increase in applicator size could be justified by potentially producing larger lesion diameters. A second purpose was to explore how the response of tissue acoustic attenuation to heating effects lesion size and preferred applicator configuration. Four applicator configurations and sizes were studied using ex vivo tissue experiments in liver and beef and using acoustic and biothermal simulations. Transmission attenuation measurements showed a 6 to 8 fold increase in baseline tissue attenution inside interstitial ultrasound lesions. Formation of these high attenuation zones in lesions reduced potential lesion size. Larger applicators produced lesions with radial penetration depths superior to their smaller counterparts at power levels in the 20-40W /cm range. The higher cooling rates along the outer surface of the larger diameter applicators due to their greater surface area was a dominant factor in increasing lesion size. The higher cooling rates pushed the maximum temperature farther from the applicator surface and reduced the formation of high acoustic attenuation tissue zones. Acoustic and biothermal simulations matched the experimental data well and were applied to model these applicators within sites of clinical interest such as prostate, uterine fibroid, brain, and normal liver. Lesions of 3.9 to 4.7cm diameter were predicted for moderately perfused tissues such as prostate and fibroid and 2.8 to 3.2cm for highly perfused tissues such as normal liver. Feedback

  13. Thermodynamic impact of abasic sites on simulated translesion DNA synthesis.

    PubMed

    Malina, Jaroslav; Brabec, Viktor

    2014-06-16

    Loss of a base in DNA and the creation of an abasic (apurinic/apyrimidinic, AP) site is a frequent lesion that may occur spontaneously, or as a consequence of the action of DNA-damaging agents. The AP lesion is mutagenic or lethal if not repaired. We report a systematic thermodynamic investigation by differential scanning calorimetry on the evolution, during primer extension, of a model AP site in chemically simulated DNA translesion synthesis. Incorporation of dAMP (deoxyadenosine monophosphate), as well as dTMP (deoxythymidine monophosphate), opposite an AP site is enthalpically unfavorable, although incorporation of dTMP is more enthalpically unfavorable than that of dAMP. This finding is in a good agreement with experimental data showing that AP sites block various DNA polymerases of eukaryotic and prokaryotic origin and that, if bypassed, dAMP is preferentially inserted, whereas insertion of dTMP is less likely. The results emphasize the importance of thermodynamic contributions to the insertion of nucleotides opposite an AP site by DNA polymerases.

  14. Remedial Action Plan and site design for stabilization of the inactive uranium mill tailings site at Gunnison, Colorado. Appendix A to Attachment 3, Tables: Final report

    SciTech Connect

    Not Available

    1992-10-01

    This volume contains the following tables: monitoring well information; static ground water levels; background ground water quality data by parameter; 1984 lysimeter tailings pore water quality by parameter; lysimeter tailings pore fluid quality data by parameter; and on site/downgradient ground water quality data by parameter.

  15. Knock down of the dual functional protein apurinic /apyrimidinic endonuclease 1 enhances the killing effect of hematoporphrphyrin derivative-mediated photodynamic therapy on non-small cell lung cancer cells in vitro and in a xenograft model.

    PubMed

    Yang, Zhen-Zhou; Li, Meng-Xia; Zhang, Yun-Song; Xiang, De-Bing; Dai, Nan; Zeng, Lin-Li; Li, Zeng-Peng; Wang, Ge; Wang, Dong

    2010-01-01

    Photodynamic therapy (PDT) is considered to be effective treatment for many cancers including lung cancer, head and neck cancers, and prostate cancer. It uses the combination of nontoxic photosensitizers and harmless visible light to generate reactive oxygen species and kill cells. However, DNA repair and reactive oxygen species-induced signaling pathway activation play crucial roles in cellular response to PDT and may also result in therapeutic limitation of PDT. To improve the cancer therapeutic efficacy of PDT, we targeted apurinic/apyrimidinic endonuclease (APE1), which is essential for both DNA repair and redox regulation of gene transcription, as a potential candidate for PDT combined gene therapy. In our study, an adenovirus-mediated APE1 silencing strategy was introduced to test its therapeutic enhancement for the non-small cell lung cancer cell line A549 both in vitro and in vivo after hematoporphrphyrin derivative (HpD)-mediated PDT. The adenovirus vector Ad5/F35-shAPE1 was validated to significantly suppress the protein expression of APE1 in cultured A549 cell and in its xenograft of nude mice. Ad5/F35-shAPE1 effectively inhibited APE1 protein upregulation induced by PDT and resulted in an increase in A549 cell killing by photoirradiation compared with the hematoporphrphyrin derivative-PDT alone group. Ad5/F35-shAPE1 suppressed the DNA repair capacity for single-strand breaks and abolished the activation of some stress-related transcription factors such as hypoxia-induced factor (HIF)-1 that consequently lead to increased cell apoptosis after PDT. Additionally, knock down of APE1 enhanced the tumor suppression efficacy of PDT on the A549 xenograft. Our study indicated that APE1-targeted gene therapy combined with PDT is a promising strategy for enhancement of the efficacy of PDT in treatment of non-small cell lung cancer.

  16. Femtomolar Zn(II) affinity in a peptide-based ligand designed to model thiolate-rich metalloprotein active sites.

    PubMed

    Petros, Amy K; Reddi, Amit R; Kennedy, Michelle L; Hyslop, Alison G; Gibney, Brian R

    2006-12-11

    Metal-ligand interactions are critical components of metalloprotein assembly, folding, stability, electrochemistry, and catalytic function. Research over the past 3 decades on the interaction of metals with peptide and protein ligands has progressed from the characterization of amino acid-metal and polypeptide-metal complexes to the design of folded protein scaffolds containing multiple metal cofactors. De novo metalloprotein design has emerged as a valuable tool both for the modular synthesis of these complex metalloproteins and for revealing the fundamental tenets of metalloprotein structure-function relationships. Our research has focused on using the coordination chemistry of de novo designed metalloproteins to probe the interactions of metal cofactors with protein ligands relevant to biological phenomena. Herein, we present a detailed thermodynamic analysis of Fe(II), Co(II), Zn(II), and[4Fe-4S]2(+/+) binding to IGA, a 16 amino acid peptide ligand containing four cysteine residues, H2N-KLCEGG-CIGCGAC-GGW-CONH2. These studies were conducted to delineate the inherent metal-ion preferences of this unfolded tetrathiolate peptide ligand as well as to evaluate the role of the solution pH on metal-peptide complex speciation. The [4Fe-4S]2(+/+)-IGA complex is both an excellent peptide-based synthetic analogue for natural ferredoxins and is flexible enough to accommodate mononuclear metal-ion binding. Incorporation of a single ferrous ion provides the FeII-IGA complex, a spectroscopic model of a reduced rubredoxin active site that possesses limited stability in aqueous buffers. As expected based on the Irving-Williams series and hard-soft acid-base theory, the Co(II) and Zn(II) complexes of IGA are significantly more stable than the Fe(II) complex. Direct proton competition experiments, coupled with determinations of the conditional dissociation constants over a range of pH values, fully define the thermodynamic stabilities and speciation of each MII-IGA complex. The

  17. Computerized stratified random site-selection approaches for design of a ground-water-quality sampling network

    USGS Publications Warehouse

    Scott, J.C.

    1990-01-01

    Computer software was written to randomly select sites for a ground-water-quality sampling network. The software uses digital cartographic techniques and subroutines from a proprietary geographic information system. The report presents the approaches, computer software, and sample applications. It is often desirable to collect ground-water-quality samples from various areas in a study region that have different values of a spatial characteristic, such as land-use or hydrogeologic setting. A stratified network can be used for testing hypotheses about relations between spatial characteristics and water quality, or for calculating statistical descriptions of water-quality data that account for variations that correspond to the spatial characteristic. In the software described, a study region is subdivided into areal subsets that have a common spatial characteristic to stratify the population into several categories from which sampling sites are selected. Different numbers of sites may be selected from each category of areal subsets. A population of potential sampling sites may be defined by either specifying a fixed population of existing sites, or by preparing an equally spaced population of potential sites. In either case, each site is identified with a single category, depending on the value of the spatial characteristic of the areal subset in which the site is located. Sites are selected from one category at a time. One of two approaches may be used to select sites. Sites may be selected randomly, or the areal subsets in the category can be grouped into cells and sites selected randomly from each cell.

  18. Probabilistic Seismic Hazard Characterization and Design Parameters for the Sites of the Nuclear Power Plants of Ukraine

    SciTech Connect

    Savy, J.B.; Foxall, W.

    2000-01-26

    The U.S. Department of Energy (US DOE), under the auspices of the International Nuclear Safety Program (INSP) is supporting in-depth safety assessments (ISA) of nuclear power plants in Eastern Europe and the former Soviet Union for the purpose of evaluating the safety and upgrades necessary to the stock of nuclear power plants in Ukraine. For this purpose the Hazards Mitigation Center at Lawrence Livermore National Laboratory (LLNL) has been asked to assess the seismic hazard and design parameters at the sites of the nuclear power plants in Ukraine. The probabilistic seismic hazard (PSH) estimates were updated using the latest available data and knowledge from LLNL, the U.S. Geological Survey, and other relevant recent studies from several consulting companies. Special attention was given to account for the local seismicity, the deep focused earthquakes of the Vrancea zone, in Romania, the region around Crimea and for the system of potentially active faults associated with the Pripyat Dniepro Donnetts rift. Aleatory (random) uncertainty was estimated from the available data and the epistemic (knowledge) uncertainty was estimated by considering the existing models in the literature and the interpretations of a small group of experts elicited during a workshop conducted in Kiev, Ukraine, on February 2-4, 1999.

  19. Computer-based design of novel HIV-1 entry inhibitors: neomycin conjugated to arginine peptides at two specific sites.

    PubMed

    Berchanski, Alexander; Lapidot, Aviva

    2009-03-01

    Aminoglycoside-arginine conjugates (AAC and APAC) are multi-target inhibitors of human immunodeficiency virus type-1 (HIV-1). Here, we predict new conjugates of neomycin with two arginine peptide chains binding at specific sites on neomycin [poly-arginine-neomycin-poly-arginine (PA-Neo-PA)]. The rationale for the design of such compounds is to separate two short arginine peptides with neomycin, which may extend the binding region of the CXC chemokine receptor type 4 (CXCR4). We used homology models of CXCR4 and unliganded envelope glycoprotein 120 (HIV-1(IIIB) gp120) and docked PA-Neo-PAs and APACs to these using a multistep docking procedure. The results indicate that PA-Neo-PAs spread over two negatively charged patches of CXCR4. PA-Neo-PA-CXCR4 complexes are energetically more favorable than AACs/APAC-CXCR4 complexes. Notably, our CXCR4 model and docking procedure can be applied to predict new compounds that are either inhibitors of gp120-CXCR4 binding without affecting stromal cell-derived factor 1 alpha (SDF-1 alpha) chemotaxis activity, or inhibitors of SDF-1 alpha-CXCR4 binding resulting in an anti-metastasis effect. We also predict that PA-Neo-PAs and APACs can interfere with CD4-gp120 binding in unliganded conformation.

  20. Thermal calculations for the design, construction, operation, and evaluation of the Spent Fuel Test - Climax, Nevada Test Site

    SciTech Connect

    Montan, D.N.; Patrick, W.C.

    1981-09-30

    The Spent Fuel Test-Climax (SFT-C) is a test of retrievable deep geologic storage of commercially generated spent nuclear reactor fuel in granitic rock. Eleven spent fuel assemblies, together with six electrical simulators and 20 guard heaters, are emplaced 420 m below the surface in the Climax granite at the US Department of Energy Nevada Test Site. On June 2, 1978 LLNL secured funding for the SFT-C, and completed spent fuel emplacement May 28, 1980. This report documents a series of thermal calculations that were performed in support of the SFT-C. Early calculations employed analytical solutions to address such design and construction issues as drift layout and emplacement hole spacings. Operational aspects of the test required more detailed numerical solutions dealing with ventilation and guard-heater power levels. The final set of calculations presented here provides temperature histories throughout the test facility for evaluation of the response of the SFT-C and for comparison of calculations with acquired data. This final set of calculations employs the as-built test geometry and best-available material properties.

  1. Exploration of the active site of neuronal nitric oxide synthase by the design and synthesis of pyrrolidinomethyl 2-aminopyridine derivatives.

    PubMed

    Ji, Haitao; Delker, Silvia L; Li, Huiying; Martásek, Pavel; Roman, Linda J; Poulos, Thomas L; Silverman, Richard B

    2010-11-11

    Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8-34) was designed and synthesized. A structure-activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((±)-32 and (±)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3'-[2''-(3'''-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine (4) also were synthesized. It was found that (3'R,4'R)-4 can induce enzyme elasticity to generate a new "hot spot" for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3'R,4'R)-3'-[2''-(3'''-fluorophenethylamino)ethylamino]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine ((3'R,4'R)-3) (J. Am. Chem. Soc. 2010, 132 (15), 5437 - 5442). On the basis of structure-activity relationships of 8-34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed.

  2. Design of aquifer remediation systems: (2) estimating site-specific performance and benefits of partial source removal.

    PubMed

    Wood, A Lynn; Enfield, Carl G; Espinoza, Felipe P; Annable, Michael; Brooks, Michael C; Rao, P S C; Sabatini, David; Knox, Robert

    2005-12-01

    A Lagrangian stochastic model is proposed as a tool that can be utilized in forecasting remedial performance and estimating the benefits (in terms of flux and mass reduction) derived from a source zone remedial effort. The stochastic functional relationships that describe the hydraulic "structure" and non-aqueous phase liquid (NAPL) "architecture" have been described in a companion paper (Enfield, C.G., Wood, A.L., Espinoza, F.P., Brooks, M.C., Annable, M., Rao, P.S.C., this issue. Design of aquifer remediation systems: (1) describing hydraulic structure and NAPL architecture using tracers. J. Contam. Hydrol.). The previously defined functions were used along with the properties of the remedial fluids to describe remedial performance. There are two objectives for this paper. First, is to show that a simple analytic element model can be used to give a reasonable estimate of system performance. This is accomplished by comparing forecast performance to observed performance. The second objective is to display the model output in terms of change in mass flux and mass removal as a function of pore volumes of remedial fluid injected. The modelling results suggest that short term benefits are obtained and related to mass reduction at the sites where the model was tested.

  3. Design wind speeds for high hazard, moderate hazard, important/low hazard and general use facilities at the Savannah River Site

    SciTech Connect

    King, H.H.

    1989-09-11

    The design wind speeds for High Hazard, Moderate Hazard, Important/Low Hazard and General Use facilities at the Savannah River Site are developed below using the procedures and site-specific hazards model required by DOE Order 6430.1A. These are less than the previously required Design Wind Speeds and are: (1) High Hazard (Maximum Resistance) Facility, 185 mph; (2) Moderate Hazard (High Resistance) Facility, 37 mph; (3) Important/Low Hazard (Intermediate) Facility, 83 mph; and, (4) General Use (Standard) Facility, 78 mph.

  4. Estimating site occupancy rates for aquatic plants using spatial sub-sampling designs when detection probabilities are less than one

    USGS Publications Warehouse

    Nielson, Ryan M.; Gray, Brian R.; McDonald, Lyman L.; Heglund, Patricia J.

    2011-01-01

    Estimation of site occupancy rates when detection probabilities are <1 is well established in wildlife science. Data from multiple visits to a sample of sites are used to estimate detection probabilities and the proportion of sites occupied by focal species. In this article we describe how site occupancy methods can be applied to estimate occupancy rates of plants and other sessile organisms. We illustrate this approach and the pitfalls of ignoring incomplete detection using spatial data for 2 aquatic vascular plants collected under the Upper Mississippi River's Long Term Resource Monitoring Program (LTRMP). Site occupancy models considered include: a naïve model that ignores incomplete detection, a simple site occupancy model assuming a constant occupancy rate and a constant probability of detection across sites, several models that allow site occupancy rates and probabilities of detection to vary with habitat characteristics, and mixture models that allow for unexplained variation in detection probabilities. We used information theoretic methods to rank competing models and bootstrapping to evaluate the goodness-of-fit of the final models. Results of our analysis confirm that ignoring incomplete detection can result in biased estimates of occupancy rates. Estimates of site occupancy rates for 2 aquatic plant species were 19–36% higher compared to naive estimates that ignored probabilities of detection <1. Simulations indicate that final models have little bias when 50 or more sites are sampled, and little gains in precision could be expected for sample sizes >300. We recommend applying site occupancy methods for monitoring presence of aquatic species.

  5. Remedial action plan and site conceptual design for stabilization of the inactive uranium mill tailings site at Ambrosia Lake, New Mexico. Volume 1, Text, Appendices A, B, and C: Final report

    SciTech Connect

    Matthews, M.L.; Mitzelfelt, R.

    1991-11-01

    This Remedial Action Plan (RAP) has been developed to serve a dual purpose. It presents the series of activities that is proposed by the US Department of Energy (DOE) to stabilize and control radioactive materials at the inactive Phillips/United Nuclear uranium processing site designated as the Ambrosia Lake site in McKinley County, New Mexico. It also serves to document the concurrence of both State of New Mexico and the US Nuclear Regulatory Commission (NRC) in the remedial action. This agreement, upon execution by the DOE and the state and concurrence by NRC, becomes Appendix B of the Cooperative Agreement.

  6. The future through the past: The use of analog sites for design criteria and long-term performance assessment of evapotranspiration landfill covers.

    SciTech Connect

    David Shafer; Julianne Miller; Susan Edwards; Stuart Rawlinson

    2001-10-18

    There is growing support for using evapotranspiration (ET) covers for closure of low-level waste (LLW) and other types of waste disposal sites, particularly in the lower latitude arid regions of the western United States. For the Nevada Test Site (NTS), monolayer ET covers is the baseline technology for closure of LLW and mixed LLW cells. To better predict the long-term performance of monolayer ET covers, as well as to identify design criteria that will potentially improve their performance, the properties of, and processes occurring on, analog sites for ET covers on the NTS are being studied. Four analog sites on the NTS have been selected to predict performance of ET covers over a 1,000-year compliance period. Two are relatively recently disturbed sites (within the last 50 years) and have been selected for the evaluation of processes and changes on ET covers for the early period of post-institutional controls when cover maintenance would be discontinued. Two other sites, late to mid-Holocene in age, are intended as analogs for the end (1,000 years or more) of the compliance period. The late to mid-Holocene surfaces are both abandoned alluvial/colluvial deposits, dated by thermoluminescence analysis. The history of the early post-institutional control analog sites is being evaluated by an archaeologist to help determine when the sites were last disturbed or modified and the mode of disturbance, to help set baseline conditions. Similar to the other ''landforms,'' ET covers will evolve over time because of pedogenic, biotic, and climatic processes. Properties of analog sites that could affect ET water-balance performance will be evaluated to help understand ET cover performance over time. Results of analog site work and resultant modifications to design, monitoring and maintenance of ET covers on the NTS will be compared with results of a similar study being done at Sandia National Laboratories (SNL), where ET cover closures are planned as well. The comparison will

  7. Trans-complementation by human apurinic endonuclease (Ape) of hypersensitivity to DNA damage and spontaneous mutator phenotype in apn1-yeast.

    PubMed Central

    Wilson, D M; Bennett, R A; Marquis, J C; Ansari, P; Demple, B

    1995-01-01

    Abasic (AP) sites in DNA are potentially lethal and mutagenic. 'Class II' AP endonucleases initiate the repair of these and other DNA lesions. In yeast, the predominant enzyme of this type is Apn1, and its elimination sensitizes the cells to killing by simple alkylating agents or oxidants, and raises the rate of spontaneous mutation. We investigated the ability of the major human class II AP endonuclease, Ape, which is structurally unrelated to Apn1, to replace the yeast enzyme in vivo. Confocal immunomicroscopy studies indicate that approximately 25% of the Ape expressed in yeast is present in the nucleus. High-level Ape expression corresponding to approximately 7000 molecules per nucleus, equal to the normal Apn1 copy number, restored resistance to methyl methanesulfonate to near wild-type levels in Apn1-deficient (apn1-) yeast. Ape expression in apn1- yeast provided little protection against H2O2 challenges, consistent with the weak 3'-repair diesterase activity of the human enzyme. Ape expression at approximately 2000 molecules per nucleus reduced the spontaneous mutation rate of apn1- yeast to that seen for wild-type cells. Because Ape has a powerful AP endonuclease but weak 3'-diesterase activity, these findings indicate that endogenously generated AP sites can drive spontaneous mutagenesis. Images PMID:8559661

  8. Cloning and expression of APE, the cDNA encoding the major human apurinic endonuclease: definition of a family of DNA repair enzymes.

    PubMed Central

    Demple, B; Herman, T; Chen, D S

    1991-01-01

    Abasic (AP) sites are common, potentially mutagenic DNA damages that are attacked by AP endonucleases. The biological roles of these enzymes in metazoans have not been tested. We have cloned the human cDNA (APE) that encodes the main nuclear AP endonuclease. The predicted Ape protein, which contains likely nuclear transport signals, is a member of a family of DNA repair enzymes that includes two bacterial AP endonucleases (ExoA protein of Streptococcus pneumoniae and exonuclease III of Escherichia coli) and Rrp1 protein of Drosophila melanogaster. Purified Ape protein lacks the 3'-exonuclease activity against undamaged DNA that is found in the bacterial and Drosophila enzymes, but the lack of obvious amino acid changes to account for this difference suggests that the various enzyme functions evolved by fine tuning a conserved active site. Expression of the active human enzyme in AP endonuclease-deficient E. coli conferred significant resistance to killing by the DNA-alkylating agent methyl methanesulfonate. The APE cDNA provides a molecular tool for analyzing the role of this central enzyme in maintaining genetic stability in humans. Images PMID:1722334

  9. A thick homogeneous vegetated cover design proves cost - and schedule-effective for the reclamation of uranium mills sites near Spokane, Washington

    SciTech Connect

    Blacklaw, J.; Robertson, G.; Stoffel, D.; Ahmad, J.; Fordham, E.

    1997-08-01

    The Washington State Department of Health (WDOH) has licensed two medium sized uranium mills with tailings impoundments covering 28 and 40 hectares (70 and 100 acres), respectively, The uranium mill licensees have submitted closure and reclamation plans to the state, and site-specific conditions have determined the closure design features, Conventional uranium mill cover designs usually incorporate an overall cap of one to three meters, which includes a low-permeability clay barrier layer. A technical evaluation of several uranium mill facilities that used this design was published in the fall of 1994 and reported that unexpected vegetation root damage had occurred in the low-permeability clay (or bentonite amended) barrier layers. The technical report suggested that the low-permeability design feature at some sites could be compromised within a very short time and the regulatory goal of 1,000 years performance might not be achieved. In October 1994, WDOH sponsored a technical forum meeting to consider design alternatives to address these reliability concerns. Representatives from the federal government, nuclear industry, licensees, engineering firms, and state regulatory agencies attended the workshop. Risk factors considered in the evaluation of the uranium mill reclamation plans include: (1) radon gas emanation through the cover (the air pathway), and (2) migration of hazardous and/or radioactive constituents (the groundwater pathway). Additional design considerations include site structural stability, longevity of 1,000 years, and no active (ongoing) maintenance. 9 refs.

  10. Quantitative measurement of the Brönsted acid sites in solid acids: toward a single-site design of Mo-modified ZSM-5 zeolite.

    PubMed

    Tessonnier, Jean-Philippe; Louis, Benoît; Walspurger, Stephane; Sommer, Jean; Ledoux, Marc-Jacques; Pham-Huu, Cuong

    2006-06-01

    On the basis of our previous H/D exchange studies devoted to the quantification of the number of Brönsted acid sites in solid acids, we report here an innovative approach to determine both the amount and the localization of Mo atoms inside the Mo/ZSM-5 catalyst, commonly used for the methane dehydroaromatization reaction. The influence of Mo introduction in the MFI framework was studied by means of BET, X-ray diffraction, 27Al magic angle spinning NMR, NH3 temperature-programmed desorption, and H/D isotopic exchange techniques. A dependence was found between the decrease of acidic OH groups and the Mo content. Depending on the Si/Al ratio of the zeolite, i.e., the proximity of two Brönsted acid sites, the Mo atoms substitute a different number of OH groups. Consequently, a chemical structure was proposed to describe the geometry of the Mo complex in the channels of the ZSM-5 zeolite.

  11. Numerical simulation of a geothermal reservoir in Tuscany (Italy) with application of "Optimal Experimental Design" for finding optimal slimhole sites

    NASA Astrophysics Data System (ADS)

    Ebigbo, Anozie; Padalkina, Katharina; Seidler, Ralf; Thorwart, Martin; Niederau, Jan; Marquart, Gabriele; Dini, Ivano

    2015-04-01

    We study an area of high heat flow, adjacent to the Larderello-Travale and Mt. Amiata geothermal fields in southern Tuscany (Italy) in respect to conductive and advective heat transport in various rock units. We construct a geological three dimensional gridded model, assigned rock properties deduced from logging data in nearby boreholes and rock sample petrophysical lab measurements, and applied numerical simulation technique to resolve the subsurface temperature field and rock units of high fluid flow. We calibrate the model with available temperature depth data from a few shallow and two deep boreholes. We found two rock units (i.e. two depth regions) with permeabilities on the order of 10-14 m2 and considerable fluid flow. In the upper regions fluid flow is mainly driven by topography related pressure gradients while in the deeper layer convective heat transport prevails caused by a deep heat source due to a young granitic intrusion. In a second step we study the problem of finding optimal sites for a slim hole to measure a temperature depth profile for determining the (effective) permeability of a certain rock unit which is not intersected by the slimhole. This question is tackled by methods from optimal experimental design (OED) applied to the numerical simulation model. OED demands the calculation of the Fisher Matrix depending on the slimhole location and the expected permeability of the rock unit in question. An optimization criterion allows finding the optimal locations for a slimhole to minimize the error in determining the permeability of the rock unit. For our study reservoir optimal slimhole locations coincide with regions of high flow rates and large deviations from the mean temperature of the reservoir layer in question.

  12. Conformational Transitions in Human AP Endonuclease 1 and Its Active Site Mutant during Abasic Site Repair†

    PubMed Central

    Kanazhevskaya, Lyubov Yu.; Koval, Vladimir V.; Zharkov, Dmitry O.; Strauss, Phyllis R.; Fedorova, Olga S.

    2010-01-01

    AP endonuclease 1 (APE 1) is a crucial enzyme of the base excision repair pathway (BER) in human cells. APE1 recognizes apurinic/apyrimidinic (AP) sites and makes a nick in the phosphodiester backbone 5′ to them. The conformational dynamics and presteady-state kinetics of wild-type APE1 and its active site mutant, Y171F-P173L-N174K, have been studied. To observe conformational transitions occurring in the APE1 molecule during the catalytic cycle, we detected intrinsic tryptophan fluorescence of the enzyme under single turnover conditions. DNA duplexes containing a natural AP site, its tetrahydrofuran analogue, or a 2′-deoxyguanosine residue in the same position were used as specific substrates or ligands. The stopped-flow experiments have revealed high flexibility of the APE1 molecule and the complexity of the catalytic process. The fluorescent traces indicate that wild-type APE1 undergoes at least four conformational transitions during the processing of abasic sites in DNA. In contrast, nonspecific interactions of APE1 with undamaged DNA can be described by a two-step kinetic scheme. Rate and equilibrium constants were extracted from the stopped-flow and fluorescence titration data for all substrates, ligands, and products. A replacement of three residues at the enzymatic active site including the replacement of tyrosine 171 with phenylalanine in the enzyme active site resulted in a 2 × 104-fold decrease in the reaction rate and reduced binding affinity. Our data indicate the important role of conformational changes in APE1 for substrate recognition and catalysis. PMID:20575528

  13. Site characterization plan conceptual design report for a high-level nuclear waste repository in salt, vertical emplacement mode: Volume 1

    SciTech Connect

    Not Available

    1987-12-01

    This Conceptual Design Report describes the conceptual design of a high-level nuclear waste repository in salt at a proposed site in Deaf Smith County, Texas. Waste receipt, processing, packing, and other surface facility operations are described. Operations in the shafts underground are described, including waste hoisting, transfer, and vertical emplacement. This report specifically addresses the vertical emplacement mode, the reference design for the repository. Waste retrieval capability is described. The report includes a description of the layout of the surface, shafts, and underground. Major equipment items are identified. The report includes plans for decommissioning and sealing of the facility. The report discusses how the repository will satisfy performance objectives. Chapters are included on basis for design, design analyses, and data requirements for completion of future design efforts. 105 figs., 52 tabs.

  14. A Strategy and Case Study Example for Designing and Implementing Environmental Long-Term Monitoring at Legacy Management Sites

    SciTech Connect

    Earl D. Mattson; Roelof J. Versteeg; Mark Ankeny; Gail Heath; Alex Richardson

    2004-04-01

    Environmental monitoring objectives of site owners, regulators, consultants, and scientists typically share the common elements of (1) cost management, (2) risk management, and (3) information management (Figure 1). Many site owners focus on minimizing monitoring costs while regulators typically focus on risk and regulatory compliance. Scientists and consultants typically provide information management in the form of spreadsheets with extracted information provided in reports to other users. This common piecemeal approach upon individual focus on elements of the monitoring objectives, rather than the common objective of minimizing cost and risk using site information, results in missed opportunities for cost savings, environmental protection, and improved understanding of site performance.

  15. 41 CFR 102-76.55 - What sustainable development principles must Federal agencies apply to the siting, design, and...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... construction of new facilities, which include— (a) Optimizing site potential; (b) Minimizing non-renewable energy consumption; (c) Using environmentally preferable products; (d) Protecting and conserving...

  16. The National Cross-Site Evaluation of High-Risk Youth Programs: Findings on Designing and Implementing Effective Prevention Programs for Youth at High Risk. Monograph Series.

    ERIC Educational Resources Information Center

    Hermann, Jack; Sambrano, Soledad; Springer, J. Fred; Nister, Mary; Sale, Elizabeth; Brounstein, Paul J.; Cordray, David; Shadish, Will; Kasim, Rafa; Pan, Wei

    This document summarizes findings from the Center for Substance Abuse Prevention's National Cross-Site Evaluation of High-Risk Youth Programs, which identified characteristics associated with strong substance abuse prevention outcomes in 48 prevention programs. It provides concrete guidance regarding what elements of design and implementation are…

  17. Remedial action plan and site design for stabilization of the inactive uranium processing site at Naturita, Colorado. Appendix A of Attachment 3: Calculations, Final

    SciTech Connect

    Not Available

    1994-03-01

    This report contains calculations for: hydraulic gradients for Alluvial Aquifer and Salt Wash Aquifer; slug test analysis to determine hydraulic conductivity for Alluvial Aquifer and Salt Wash Aquifer; average linear groundwater velocity for Alluvial Aquifer and Salt Wash Aquifer; statistical analysis of the extent of existing groundwater contamination; hydraulic gradients for Dakota/Burro Canyon Formation and Salt Wash Aquifer; slug test analysis to determine hydraulic conductivity for Dakota/Burro Canyon Formation and Perched Salt Wash Aquifer; determination of hydraulic conductivity of the Dakota/Burro Canyon Formation from Packer Tests; average linear groundwater velocity for Dakota/Burro Canyon and Salt Wash Aquifer; chemical and mineralogical characterization of core samples from the Dry Flats Disposal Site; and demonstration of low groundwater yield from Uppermost Aquifer.

  18. SU-D-213-05: Design, Evaluation and First Applications of a Off-Site State-Of-The-Art 3D Dosimetry System

    SciTech Connect

    Malcolm, J; Mein, S; McNiven, A; Letourneau, D; Oldham, M

    2015-06-15

    Purpose: To design, construct and commission a prototype in-house three dimensional (3D) dose verification system for stereotatic body radiotherapy (SBRT) verification at an off-site partner institution. To investigate the potential of this system to achieve sufficient performance (1mm resolution, 3% noise, within 3% of true dose reading) for SBRT verification. Methods: The system was designed utilizing a parallel ray geometry instigated by precision telecentric lenses and an LED 630nm light source. Using a radiochromic dosimeter, a 3D dosimetric comparison with our gold-standard system and treatment planning software (Eclipse) was done for a four-field box treatment, under gamma passing criteria of 3%/3mm/10% dose threshold. Post off-site installation, deviations in the system’s dose readout performance was assessed by rescanning the four-field box irradiated dosimeter and using line-profiles to compare on-site and off-site mean and noise levels in four distinct dose regions. As a final step, an end-to-end test of the system was completed at the off-site location, including CT-simulation, irradiation of the dosimeter and a 3D dosimetric comparison of the planned (Pinnacle{sup 3}) to delivered dose for a spinal SBRT treatment(12 Gy per fraction). Results: The noise level in the high and medium dose regions of the four field box treatment was relatively 5% pre and post installation. This reflects the reduction in positional uncertainty through the new design. This At 1mm dose voxels, the gamma pass rates(3%,3mm) for our in-house gold standard system and the off-site system were comparable at 95.8% and 93.2% respectively. Conclusion: This work will describe the end-to-end process and results of designing, installing, and commissioning a state-of-the-art 3D dosimetry system created for verification of advanced radiation treatments including spinal radiosurgery.

  19. Wait for the Bus: How Lowcountry School Site Selection and Design Deter Walking to School and Contribute to Urban Sprawl.

    ERIC Educational Resources Information Center

    Kouri, Christopher

    This paper presents a study on how the South Carolina school site selection process can affect the quality of the students' experience and access to their schools. Focusing on students options for getting to school, e.g., hazards that prevent students from walking to school and the size of school sites that place schools on the edge of…

  20. 77 FR 20590 - Ocean Dumping; Designation of Ocean Dredged Material Disposal Sites Offshore of Yaquina Bay, OR

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-05

    ... central Oregon Coast. The proposed Yaquina North Site would be located about 1.7 nautical miles northwest..., or Passage Areas of Living Resources in Adult or Juvenile Phases (40 CFR 228.6(a)(2)). The proposed Sites are not located in exclusive breeding, spawning, nursery, feeding or passage areas for adult...

  1. 75 FR 5708 - Ocean Dumping; Designation of Ocean Dredged Material Disposal Sites Offshore of the Siuslaw River...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-04

    ... any person, EPA and the Corps must evaluate the project according to the ocean dumping regulatory... ocean. Should a site use conflict be identified, site use could be modified according to the SMMP to... through the water column. All dredged material proposed for disposal will be evaluated according to...

  2. Construction of a family of Cys2His2 zinc binding sites in the hydrophobic core of thioredoxin by structure-based design.

    PubMed

    Wisz, M S; Garrett, C Z; Hellinga, H W

    1998-06-01

    A semi-automated, rational design strategy has been used to introduce a family of seven single, mononuclear Cys2His2 zinc sites at various locations in the hydrophobic core of Escherichia colithioredoxin, a protein that is normally devoid of metal centers. The electronic absorption spectra of the CoII complexes show that five of these designed proteins bind metal with the intended tetrahedral geometry. The designed sites differ in their metal-binding constants and effects on protein stability. Since these designs are constructed within the same host protein framework, comparison of their behavior allows a qualitative evaluation of dominant factors that contribute to metal-binding and metal-mediated protein stabilization. Metal-binding constants are dominated by steric interactions between the buried, designed coordination sphere and the surrounding protein matrix. Metal-mediated stability is the consequence of differential binding to the native and unfolded states. Increased interactions with the unfolded state decrease the stabilizing effect of metal binding. The affinity for the unfolded state is dependent on the placement of the primary coordination sphere residues within the linear protein sequence. These results indicate that a protein fold can have a remarkably broad potential for accommodating metal-mediated cross-links and suggest strategies for engineering protein stability by constructing metal sites that maximize metal binding to the native state and minimize binding to the unfolded state.

  3. Environmental design criteria for the 1/3 scale OTEC (Ocean Thermal Energy Conversion) cold water pipe At-Sea Test Site off Honolulu, Hawaii

    SciTech Connect

    Not Available

    1982-01-01

    A fully instrumented At-Sea Test of a 1/3 scale OTEC cold water pipe (CWP) will be carried out. The future prototype for this 1/3 scale model is envisioned to be the OTEC Pilot Plant design in the 10 to 40 megawatt-electric size range with an estimated CWP diameter of about 30 ft and an overall vertical length of about 3000 ft. Thus the 1/3 scale CWP consists of a pipe about 10 ft in diameter and 1000 ft long. The selected At-Sea Test site is located at 21/sup 0/15.5'N latitude and 157/sup 0/54.6'W longitude off Honolulu, Hawaii. In order to expedite development of the design of the 1/3 scale At-Sea Test CWP/Platform/Mooring System the report provides environmental design criteria data at the proposed At-Sea Test site evaluated from available historic data.

  4. Areal power density: A preliminary examination of underground heat transfer in a potential Yucca Mountain repository and recommendations for thermal design approaches; Yucca Mountain Site Characterization Project

    SciTech Connect

    Hertel, E.S. Jr.; Ryder, E.E.

    1991-11-01

    The design of the potential Yucca Mountain repository is subject to many thermal goals related to the compliance of the site with federal regulations. This report summarizes a series of sensitivity studies that determined the expected temperatures near the potential repository. These sensitivity studies were used to establish an efficient loading scheme for the spent fuel canisters and a maximum areal power density based strictly on thermal goals. Given the current knowledge of the site, a design-basis areal power density of 80 kW/acre can be justified based on thermal goals only. Further analyses to investigate the impacts of this design-basis APD on mechanical and operational aspects of the potential repository must be undertaken before a final decision is made.

  5. Mycobacterium tuberculosis class II apurinic/apyrimidinic-endonuclease/3'-5' exonuclease III exhibits DNA regulated modes of interaction with the sliding DNA β-clamp.

    PubMed

    Khanam, Taran; Rai, Niyati; Ramachandran, Ravishankar

    2015-10-01

    The class-II AP-endonuclease (XthA) acts on abasic sites of damaged DNA in bacterial base excision repair. We identified that the sliding DNA β-clamp forms in vivo and in vitro complexes with XthA in Mycobacterium tuberculosis. A novel 239 QLRFPKK245 motif in the DNA-binding domain of XthA was found to be important for the interactions. Likewise, the peptide binding-groove (PBG) and the C-terminal of β-clamp located on different domains interact with XthA. The β-clamp-XthA complex can be disrupted by clamp binding peptides and also by a specific bacterial clamp inhibitor that binds at the PBG. We also identified that β-clamp stimulates the activities of XthA primarily by increasing its affinity for the substrate and its processivity. Additionally, loading of the β-clamp onto DNA is required for activity stimulation. A reduction in XthA activity stimulation was observed in the presence of β-clamp binding peptides supporting that direct interactions between the proteins are necessary to cause stimulation. Finally, we found that in the absence of DNA, the PBG located on the second domain of the β-clamp is important for interactions with XthA, while the C-terminal domain predominantly mediates functional interactions in the substrate's presence.

  6. Remedial action plan and site design for stabilization of the inactive uranium processing site at Naturita, Colorado. Remedial Action Selection Report, Appendix B of Attachment 2: Geology report, Final

    SciTech Connect

    Not Available

    1994-03-01

    The uranium processing site near Naturita, Colorado, is one of 24 inactive uranium mill sites designated to be cleaned up by the US Department of Energy (DOE) under the Uranium Mill Tailings Radiation Control Act of 1978 (UMTRCA), 42 USC {section} 7901 et seq. Part of the UMTRCA requires that the US Nuclear Regulatory Commission (NRC) concur with the DOE`s remedial action plan (RAP) and certify that the remedial action conducted at the site complies with the standards promulgated by the US Environmental Protection Agency (EPA). Included in the RAP is this Remedial Action Selection Report (RAS), which describes the proposed remedial action for the Naturita site. An extensive amount of data and supporting information has been generated and evaluated for this remedial action. These data and supporting information are not incorporated into this single document but are included or referenced in the supporting documents. The RAP consists of this RAS and four supporting documents or attachments. This Attachment 2, Geology Report describes the details of geologic, geomorphic, and seismic conditions at the Dry Flats disposal site.

  7. Optimizing potentiometric ionophore and electrode design for environmental on-site control of antibiotic drugs: application to sulfamethoxazole.

    PubMed

    Almeida, S A A; Truta, Liliana A A N A; Queirós, Raquel B; Montenegro, M C B S M; Cunha, Alexandre L; Sales, M G F

    2012-05-15

    Potentiometric sensors are typically unable to carry out on-site monitoring of environmental drug contaminants because of their high limits of detection (LODs). Designing a novel ligand material for the target analyte and managing the composition of the internal reference solution have been the strategies employed here to produce for the first time a potentiometric-based direct reading method for an environmental drug contaminant. This concept has been applied to sulfamethoxazole (SMX), one of the many antibiotics used in aquaculture practices that may occur in environmental waters. The novel ligand has been produced by imprinting SMX on the surface of graphitic carbon nanostructures (CN)<500 nm. The imprinted carbon nanostructures (ICN) were dispersed in plasticizer and entrapped in a PVC matrix that included (or not) a small amount of a lipophilic additive. The membrane composition was optimized on solid-contact electrodes, allowing near-Nernstian responses down to 5.2 μg/mL and detecting 1.6 μg/mL. The membranes offered good selectivity against most of the ionic compounds in environmental water. The best membrane cocktail was applied on the smaller end of a 1000 μL micropipette tip made of polypropylene. The tip was then filled with inner reference solution containing SMX and chlorate (as interfering compound). The corresponding concentrations were studied for 1 × 10(-5) to 1 × 10(-10) and 1 × 10(-3) to 1 × 10(-8)mol/L. The best condition allowed the detection of 5.92 ng/L (or 2.3 × 10(-8)mol/L) SMX for a sub-Nernstian slope of -40.3 mV/decade from 5.0 × 10(-8) to 2.4 × 10(-5)mol/L. The described sensors were found promising devices for field applications. The good selectivity of the sensory materials together with a carefully selected composition for the inner reference solution allowed LODs near the nanomolar range. Both solid-contact and "pipette tip"-based sensors were successfully applied to the analysis of aquaculture waters.

  8. The Future Through the Past: The Use of Analog Sites for Design Criteria and Long Term Performance Assessment of Evapotranspiration Landfill Covers

    SciTech Connect

    Shafer, D. S.; Miller, J. J.; Young, M. H.; Edwards, S. C.; Rawlinson, S. E.

    2002-02-26

    There is growing support for using evapotranspiration (ET) covers for closure of low-level waste (LLW) and other types of waste disposal sites, particularly in the lower latitude arid regions of the western United States. At the Nevada Test Site (NTS), monolayer ET covers are the baseline technology for closure of LLW and mixed LLW cells. To better predict the long-term performance of monolayer ET covers, as well as to identify design criteria that will potentially improve their performance, the properties of, and processes occurring on, analog sites for ET covers on the NTS are being studied. The project is funded through the Subsurface Contaminants Focus Area of the U.S. Department of Energy. Four analog sites on the NTS have been selected to predict performance of ET covers over a 1,000-year compliance period. Two sites are relatively recently disturbed (within the last 50 years) and have been selected to evaluate processes and changes on ET covers for the early period after active cover maintenance is discontinued. Two other sites, late to mid-Holocene in age, are intended as analogs for the end of the compliance period (1,000 years or more); both surfaces are abandoned alluvial/colluvial deposits. The history of the early post-institutional control analog sites are being evaluated by an archaeologist to help determine when the sites were last disturbed or modified, and the mode of disturbance to help set baseline conditions. Similar to other ''landforms,'' ET covers will evolve over time because of pedogenic, biotic, and climatic processes. Properties of analog sites that could affect ET water balance performance will be evaluated to help understand ET cover performance over time.

  9. Improved design of hammerhead ribozyme for selective digestion of target RNA through recognition of site-specific adenosine-to-inosine RNA editing

    PubMed Central

    Fukuda, Masatora; Kurihara, Kei; Yamaguchi, Shota; Oyama, Yui; Deshimaru, Masanobu

    2014-01-01

    Adenosine-to-inosine (A-to-I) RNA editing is an endogenous regulatory mechanism involved in various biological processes. Site-specific, editing-state–dependent degradation of target RNA may be a powerful tool both for analyzing the mechanism of RNA editing and for regulating biological processes. Previously, we designed an artificial hammerhead ribozyme (HHR) for selective, site-specific RNA cleavage dependent on the A-to-I RNA editing state. In the present work, we developed an improved strategy for constructing a trans-acting HHR that specifically cleaves target editing sites in the adenosine but not the inosine state. Specificity for unedited sites was achieved by utilizing a sequence encoding the intrinsic cleavage specificity of a natural HHR. We used in vitro selection methods in an HHR library to select for an extended HHR containing a tertiary stabilization motif that facilitates HHR folding into an active conformation. By using this method, we successfully constructed highly active HHRs with unedited-specific cleavage. Moreover, using HHR cleavage followed by direct sequencing, we demonstrated that this ribozyme could cleave serotonin 2C receptor (HTR2C) mRNA extracted from mouse brain, depending on the site-specific editing state. This unedited-specific cleavage also enabled us to analyze the effect of editing state at the E and C sites on editing at other sites by using direct sequencing for the simultaneous quantification of the editing ratio at multiple sites. Our approach has the potential to elucidate the mechanism underlying the interdependencies of different editing states in substrate RNA with multiple editing sites. PMID:24448449

  10. Improved design of hammerhead ribozyme for selective digestion of target RNA through recognition of site-specific adenosine-to-inosine RNA editing.

    PubMed

    Fukuda, Masatora; Kurihara, Kei; Yamaguchi, Shota; Oyama, Yui; Deshimaru, Masanobu

    2014-03-01

    Adenosine-to-inosine (A-to-I) RNA editing is an endogenous regulatory mechanism involved in various biological processes. Site-specific, editing-state-dependent degradation of target RNA may be a powerful tool both for analyzing the mechanism of RNA editing and for regulating biological processes. Previously, we designed an artificial hammerhead ribozyme (HHR) for selective, site-specific RNA cleavage dependent on the A-to-I RNA editing state. In the present work, we developed an improved strategy for constructing a trans-acting HHR that specifically cleaves target editing sites in the adenosine but not the inosine state. Specificity for unedited sites was achieved by utilizing a sequence encoding the intrinsic cleavage specificity of a natural HHR. We used in vitro selection methods in an HHR library to select for an extended HHR containing a tertiary stabilization motif that facilitates HHR folding into an active conformation. By using this method, we successfully constructed highly active HHRs with unedited-specific cleavage. Moreover, using HHR cleavage followed by direct sequencing, we demonstrated that this ribozyme could cleave serotonin 2C receptor (HTR2C) mRNA extracted from mouse brain, depending on the site-specific editing state. This unedited-specific cleavage also enabled us to analyze the effect of editing state at the E and C sites on editing at other sites by using direct sequencing for the simultaneous quantification of the editing ratio at multiple sites. Our approach has the potential to elucidate the mechanism underlying the interdependencies of different editing states in substrate RNA with multiple editing sites.

  11. 77 FR 67399 - Hewlett-Packard Company, Design Delivery Organization (DDO), Including On-Site Leased Workers...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-09

    ... Employment and Training Administration Hewlett-Packard Company, Design Delivery Organization (DDO), Including...; Hewlett-Packard Company, Ink Jet & Web Services, World Wide Design Group, Vancouver, WA; Amended... workers of Hewlett-Packard Company, Design Delivery Organization (DDO), Corvallis, Oregon. The...

  12. A Team-Based Process for Designing Comprehensive, Integrated, Three-Tiered (CI3T) Models of Prevention: How Does My School-Site Leadership Team Design a CI3T Model?

    ERIC Educational Resources Information Center

    Lane, Kathleen Lynne; Oakes, Wendy Peia; Jenkins, Abbie; Menzies, Holly Mariah; Kalberg, Jemma Robertson

    2014-01-01

    Comprehensive, integrated, three-tiered models are context specific and developed by school-site teams according to the core values held by the school community. In this article, the authors provide a step-by-step, team-based process for designing comprehensive, integrated, three-tiered models of prevention that integrate academic, behavioral, and…

  13. A design study for the isolation of the 281-3H retention basin at the Savannah River Site using the viscous liquid barrier technology

    SciTech Connect

    Moridis, G.J.; Persoff, P.; Apps, J.; James, A.; Oldenburg, C.; McGrath, A.; Myer, L.; Pellerin, L.; Pruess, K.

    1996-11-01

    This report is a description of the design study for a pilot-scale field demonstration of the Viscous Liquid Barrier (VLB) technology, a new subsurface containment technology for waste isolation using a new generation of barrier liquids. The demonstration site was Retention Basin 281-3H, a shallow catchment basin at the Savannah River Site, which is contaminated mainly by radionuclides ({sup 137}Cs, {sup 90}Sr, and {sup 238}Pu). The goals of the field demonstration were (a) to demonstrate the ability to create a continuous subsurface barrier in order to isolate the contaminants, and (b) to demonstrate the continuity, performance, and integrity of the barrier. The site was characterized, and preliminary hydraulic conductivity data were obtained from core samples. Based on the site characteristics and the functional requirements, a conceptual model was developed, the barrier specifications were defined, and lance injection was selected as the emplacement method. The injection strategy for the subsurface conditions at the site was determined using numerical simulations. An appropriate variant of Colloidal Silica (CS) was selected as the barrier liquid based on its relative insensitivity to interactions with the site soils, and the formulation for optimum site performance was determined. A barrier verification strategy, including hydraulic, pneumatic, tracer, and geophysical methods, was developed. A lance water injection test was conducted in order to obtain representative estimates of the hydraulic conductivity and its distribution for the design of the barrier emplacement. The water injection test demonstrated the lack of permeable zones for CS injection, and a decision not to proceed with the barrier emplacement was reached.

  14. VS30 – A site-characterization parameter for use in building Codes, simplified earthquake resistant design, GMPEs, and ShakeMaps

    USGS Publications Warehouse

    Borcherdt, Roger D.

    2012-01-01

    VS30, defined as the average seismic shear-wave velocity from the surface to a depth of 30 meters, has found wide-spread use as a parameter to characterize site response for simplified earthquake resistant design as implemented in building codes worldwide. VS30 , as initially introduced by the author for the US 1994 NEHRP Building Code, provides unambiguous definitions of site classes and site coefficients for site-dependent response spectra based on correlations derived from extensive borehole logging and comparative ground-motion measurement programs in California. Subsequent use of VS30 for development of strong ground motion prediction equations (GMPEs) and measurement of extensive sets of VS borehole data have confirmed the previous empirical correlations and established correlations of SVS30 with VSZ at other depths. These correlations provide closed form expressions to predict S30 V at a large number of additional sites and further justify S30 V as a parameter to characterize site response for simplified building codes, GMPEs, ShakeMap, and seismic hazard mapping.

  15. Comparison of the active-site design of molybdenum oxo-transfer enzymes by quantum mechanical calculations.

    PubMed

    Li, Jilai; Ryde, Ulf

    2014-11-17

    There are three families of mononuclear molybdenum enzymes that catalyze oxygen atom transfer (OAT) reactions, named after a typical example from each family, viz., dimethyl sulfoxide reductase (DMSOR), sulfite oxidase (SO), and xanthine oxidase (XO). These families differ in the construction of their active sites, with two molybdopterin groups in the DMSOR family, two oxy groups in the SO family, and a sulfido group in the XO family. We have employed density functional theory calculations on cluster models of the active sites to understand the selection of molybdenum ligands in the three enzyme families. Our calculations show that the DMSOR active site has a much stronger oxidative power than the other two sites, owing to the extra molybdopterin ligand. However, the active sites do not seem to have been constructed to make the OAT reaction as exergonic as possible, but instead to keep the reaction free energy close to zero (to avoid excessive loss of energy), thereby making the reoxidation (SO and XO) or rereduction of the active sites (DMSOR) after the OAT reaction facile. We also show that active-site models of the three enzyme families can all catalyze the reduction of DMSO and that the DMSOR model does not give the lowest activation barrier. Likewise, all three models can catalyze the oxidation of sulfite, provided that the Coulombic repulsion between the substrate and the enzyme model can be overcome, but for this harder reaction, the SO model gives the lowest activation barrier, although the differences are not large. However, only the XO model can catalyze the oxidation of xanthine, owing to its sulfido ligand.

  16. Remedial Action Plan and site design for stabilization of the inactive uranium mill tailings site at Falls City, Texas. Remedial action selection report: Attachment 2, Geology report; Attachment 3, Groundwater hydrology report; Attachment 4, Water resources protection strategy: Final report

    SciTech Connect

    Chernoff, A.R.; Lacker, D.K.

    1992-09-01

    The uranium processing site near Falls City, Texas, was one of 24 inactive uranium mill sites designated to be remediated by the US Department of Energy (DOE) under Title I of the Uranium Mill Tailings Radiation Control Act of 1978 (UMTRCA). The UMTRCA requires that the US Nuclear Regulatory Commission (NRC) concur with the DOE`s remedial action plan (RAP) and certify that the remedial action conducted at the site complies with the standards promulgated by the US Environmental Protection Agency (EPA). The RAP, which includes this summary remedial action selection report (RAS), serves a two-fold purpose. First, it describes the activities proposed by the DOE to accomplish long-term stabilization and control of the residual radioactive materials at the inactive uranium processing site near Falls City, Texas. Second, this document and the remainder of the RAP, upon concurrence and execution by the DOE, the State of Texas, and the NRC, becomes Appendix B of the Cooperative Agreement between the DOE and the State of Texas.

  17. Design of a hairpin polyamide, ZT65B, for targeting the inverted CCAAT box (ICB) site in the multidrug resistant (MDR1) gene.

    PubMed

    Buchmueller, Karen L; Taherbhai, Zarmeen; Howard, Cameron M; Bailey, Suzanna L; Nguyen, Binh; O'Hare, Caroline; Hochhauser, Daniel; Hartley, John A; Wilson, W David; Lee, Moses

    2005-12-01

    A novel hairpin polyamide, ZT65B, containing a 3-methylpicolinate moiety was designed to target the inverted CCAAT box (ICB) of the human multidrug resistance 1 gene (MDR1) promoter. Binding of nuclear factor-Y (NF-Y) to the ICB site upregulates MDR1 gene expression and is, therefore, a good target for anticancer therapeutic agents. However, it is important to distinguish amongst different promoter ICB sites so that only specific genes will be affected. All ICB sites have the same sequence but they differ in the sequence of the flanking base pairs, which can be exploited in the design of sequence-specific polyamides. To test this hypothesis, ten ICB-containing DNA hairpins were designed with different flanking base pairs; the sequences ICBa and ICBb were similar to the 3'-ICB site of MDR1 (TGGCT). Thermal-denaturation studies showed that ZT65B effectively targeted ICBa and ICBb (DeltaTM=6.5 and 7.0 degrees C) in preference to the other DNA hairpins (<3.5 degrees C), with the exception of ICBc (5.0 degrees C). DNase I-footprinting assays were carried out with the topoisomerase IIalpha-promoter sequence, which contains five ICB sites; of these, ICB1 and ICB5 are similar to the ICB site of MDR1. ZT65B was found to selectively bind ICB1 and ICB5; footprints were not observed with ICB2, ICB3, or ICB4. A strong, positive induced ligand band at 325 nm in CD studies confirmed that ZT65B binds in the DNA minor groove. The selectivity of ZT65B binding to hairpins that contained the MDR1 ICB site compared to one that did not (ICBd) was confirmed by surface-plasmon studies, and equilibrium constants of 5x10(6)-1x10(7) and 4.6x10(5) M-1 were obtained with ICB1, ICB5,and ICB2 respectively. ZT65B and the previously published JH37 (J. A. Henry, et al. Biochemistry 2004, 43, 12 249-12 257) serve as prototypes for the design of novel polyamides. These can be used to specifically target the subset of ubiquitous gene elements known as ICBs, and thereby affect the expression of one or

  18. P-SAMS: a web site for plant artificial microRNA and synthetic trans-acting small interfering RNA design

    PubMed Central

    Fahlgren, Noah; Hill, Steven T.; Carrington, James C.; Carbonell, Alberto

    2016-01-01

    Summary: The Plant Small RNA Maker Site (P-SAMS) is a web tool for the simple and automated design of artificial miRNAs (amiRNAs) and synthetic trans-acting small interfering RNAs (syn-tasiRNAs) for efficient and specific targeted gene silencing in plants. P-SAMS includes two applications, P-SAMS amiRNA Designer and P-SAMS syn-tasiRNA Designer. The navigation through both applications is wizard-assisted, and the job runtime is relatively short. Both applications output the sequence of designed small RNA(s), and the sequence of the two oligonucleotides required for cloning into ‘B/c’ compatible vectors. Availability and implementation: The P-SAMS website is available at http://p-sams.carringtonlab.org. Contact: acarbonell@ibmcp.upv.es or nfahlgren@danforthcenter.org PMID:26382195

  19. Application of Frequency of Detection Methods in Design and Optimization of the INL Site Ambient Air Monitoring Network

    SciTech Connect

    Rood, Arthur S.; Sondrup, A. Jeffrey

    2015-11-01

    This report presents an evaluation of a hypothetical INL Site monitoring network and the existing INL air monitoring network using frequency of detection methods. The hypothetical network was designed to address the requirement in 40 CFR Part 61, Subpart H (2006) that “emissions of radionuclides to ambient air from U.S. DOE facilities shall not exceed those amounts that would cause any member of the public to receive in any year an effective dose equivalent exceeding 10 mrem/year.” To meet the requirement for monitoring only, “radionuclide releases that would result in an effective dose of 10% of the standard shall be readily detectable and distinguishable from background.” Thus, the hypothetical network consists of air samplers placed at residence locations that surround INL and at other locations where onsite livestock grazing takes place. Two exposure scenarios were used in this evaluation: a resident scenario and a shepherd/rancher scenario. The resident was assumed to be continuously present at their residence while the shepherd/rancher was assumed to be present 24-hours at a fixed location on the grazing allotment. Important radionuclides were identified from annual INL radionuclide National Emission Standards for Hazardous Pollutants reports. Important radionuclides were defined as those that potentially contribute 1% or greater to the annual total dose at the radionuclide National Emission Standards for Hazardous Pollutants maximally exposed individual location and include H-3, Am-241, Pu-238, Pu 239, Cs-137, Sr-90, and I-131. For this evaluation, the network performance objective was set at achieving a frequency of detection greater than or equal to 95%. Results indicated that the hypothetical network for the resident scenario met all performance objectives for H-3 and I-131 and most performance objectives for Cs-137 and Sr-90. However, all actinides failed to meet the performance objectives for most sources. The shepherd/rancher scenario showed

  20. Multi-site effectiveness trials of treatments for substance abuse and co-occurring problems: Have we chosen the best designs?

    PubMed Central

    Nunes, Edward V.; Ball, Samuel; Booth, Robert; Brigham, Gregory; Calsyn, Donald A.; Carroll, Kathleen; Feaster, Daniel J.; Hien, Denise; Hubbard, Robert L.; Ling, Walter; Petry, Nancy M.; Rotrosen, John; Selzer, Jeffrey; Stitzer, Maxine; Tross, Susan; Wakim, Paul; Winhusen, Theresa; Woody, George

    2010-01-01

    Multi-site effectiveness trials such as those carried out in the National Drug Abuse Treatment Clinical Trials Network (CTN) are a critical step in the development and dissemination of evidence-based treatments, because they address how such treatments perform in real-world clinical settings. As Brigham and colleagues summarized in a recent article (Brigham, Feaster, Wakim, & Dempsey, 2009), several possible experimental designs may be chosen for such effectiveness trials. These include: 1) A new treatment intervention (Tx) is compared to an existing mode of community based treatment as usual (TAU): Tx versus TAU; 2) A new intervention is added to TAU and compared to TAU alone: Tx + TAU versus TAU; or 3) A new intervention is added to TAU and compared to a control condition added to TAU: Tx + TAU versus control + TAU. Each of these designs addresses a different question and has different potential strengths and weaknesses. As of December 2009, the primary outcome paper had been published for 16 of the multi-site randomized clinical trials conducted in the CTN, testing various treatments for drug abuse, HIV risk behavior, or related problems. This paper systematically examines, for each of the completed trials, the experimental design type chosen and its original rationale, the main findings of the trial, and the strengths and weaknesses of the design in hindsight. Based on this review, recommendations are generated to inform the design of future effectiveness trials on treatments for substance abuse, HIV risk, and other behavioral health problems. PMID:20307801

  1. X-ray structure of the ternary MTX·NADPH complex of the anthrax dihydrofolate reductase: A pharmacophore for dual-site inhibitor design

    SciTech Connect

    Bennett, Brad C.; Wan, Qun; Ahmad, Md Faiz; Langan, Paul; Dealwis, Chris G.

    2009-11-18

    For reasons of bioterrorism and drug resistance, it is imperative to identify and develop new molecular points of intervention against anthrax. Dihydrofolate reductase (DHFR) is a highly conserved enzyme and an established target in a number of species for a variety of chemotherapeutic programs. Recently, the crystal structure of B. anthracis DHFR (baDHFR) in complex with methotrexate (MTX) was determined and, based on the structure, proposals were made for drug design strategies directed against the substrate binding site. However, little is gleaned about the binding site for NADPH, the cofactor responsible for hydride transfer in the catalytic mechanism. In the present study, X-ray crystallography at 100 K was used to determine the structure of baDHFR in complex with MTX and NADPH. Although the NADPH binding mode is nearly identical to that seen in other DHFR ternary complex structures, the adenine moiety adopts an off-plane tilt of nearly 90 deg. and this orientation is stabilized by hydrogen bonds to functionally conserved Arg residues. A comparison of the binding site, focusing on this region, between baDHFR and the human enzyme is discussed, with an aim at designing species-selective therapeutics. Indeed, the ternary model, refined to 2.3{angstrom} resolution, provides an accurate template for testing the feasibility of identifying dual-site inhibitors, compounds that target both the substrate and cofactor binding site. With the ternary model in hand, using in silico methods, several compounds were identified which could potentially form key bonding contacts in the substrate and cofactor binding sites. Ultimately, two structurally distinct compounds were verified that inhibit baDHFR at low {mu}M concentrations. The apparent K{sub d} for one of these, (2-(3-(2-(hydroxyimino)-2-(pyridine-4-yl)-6,7-dimethylquinoxalin-2-yl)-1-(pyridine-4-yl)ethanone oxime), was measured by fluorescence spectroscopy to be 5.3 {mu}M.

  2. Enhanced Thermostability of Lipoxygenase from Anabaena sp. PCC 7120 by Site-Directed Mutagenesis Based on Computer-Aided Rational Design.

    PubMed

    Diao, Hanwen; Zhang, Chong; Wang, Shuicheng; Lu, Fengxia; Lu, Zhaoxin

    2016-04-01

    Lipoxygenase from Anabaena sp. PCC 7120 (Ana-LOX) was thermally unstable. So, improving the thermostability of the enzyme was quite essential. The target site of Ana-LOX selected for site-directed mutagenesis was based on computer-aided rational design. The thermostability and specific activity of Ana-LOX were improved with replacing valine with alanine at the target site 421 and the site 40. Compared to the wild-type enzyme which has a half-life (T 1/2) of inactivation of 3.8 min at 50 °C, the T 1/2 of mutant enzymes with V421A and V40A substitution increased to 4.4 and 7.0 min, respectively. The double mutant V421A/V40A showed a synergistic effect with a T 1/2 value of 8.3 min, resulting in a 1.18-fold improvement compared to the original Ana-LOX. V421A, V40A, and V421A/V40A also obtained 4.83, 41.58, and 80.07 % increase in specific activity, respectively. This study provides useful theoretical reference for enzyme molecular modification and computer-aided rational design.

  3. Reversible supramolecular assembly at specific DNA sites: nickel-promoted bivalent DNA binding with designed peptide and bipyridyl-bis(benzamidine) components.

    PubMed

    Sánchez, Mateo I; Mosquera, Jesús; Vázquez, M Eugenio; Mascareñas, José L

    2014-09-01

    At specific DNA sites, nickel(II) salts promote the assembly of designed components, namely a bis(histidine)-modified peptide that is derived from a bZIP transcription factor and a bis(benzamidine) unit that is equipped with a bipyridine. This programmed supramolecular system with emergent properties reproduces some key characteristics of naturally occurring DNA-binding proteins, such as bivalence, selectivity, responsiveness to external agents, and reversibility.

  4. A Grounded Theory Approach to Examining Design and Usability Guidelines for Four-Year Tribal College Web Sites

    ERIC Educational Resources Information Center

    Broberg, Loretta L.

    2011-01-01

    With the increasing awareness of design and usability issues in regards to websites, in this case tribal college websites, there is an increasing desire to have a set of guidelines to assist in determining design and usability for academic websites. Though there is an overwhelming amount of information available to researchers in this subject area…

  5. ONWI (Office of Nuclear Waste Isolation) 30% design review findings report for Exploratory Shaft Facility, Deaf Smith site

    SciTech Connect

    Not Available

    1987-05-08

    Based on the performance of a TMP-05 Design Review with integration into the review, via TMP-22, of comments by SRP contractors other than ONWI, the Design Review Board has developed conclusions and recommendations with respect to the 30% design effort submitted by PB/PB-KBB for interim design review. A number of comments were submitted on the design basis criteria and requirements furnished as guidance to PB/PB-KBB. These comments are forwarded to SRPO for disposition and resolution. Additionally, comments whose resolution by PB/PB-KBB require input from other SRP contractors are included. All comments forwarded to SRPO are compiled and subdivided by appropriate category in Section 11.0 of this Findings Report.

  6. 77 FR 46439 - Decision To Evaluate a Petition To Designate a Class of Employees From the Baker Brothers Site in...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-03

    ... Site in Toledo, Ohio, To Be Included in the Special Exposure Cohort AGENCY: National Institute for..., Ohio, to be included in the Special Exposure Cohort under the Energy Employees Occupational Illness..., MS C-46, Cincinnati, OH 45226, Telephone 877-222-7570. Information requests can also be submitted...

  7. Recognizing critical mine spoil health characteristics to design biochars for site improvement to promote stabilizing plant growth

    EPA Science Inventory

    Biochar can be used as an amendment to remediate metal-contaminated mine spoils for improved site phytostabilization. For successful phytostabilization to occur, biochar amendments must improve mine spoil health with respect to plant rooting plus uptake of water and nutrients. ...

  8. Do Cross-circle Designs, the Mayan World Tree, Chitto Tustenuggee's, and Miami's Tequesta, Sites have Analogs in Brazil as they have in Peru, Europe, and Africa?

    NASA Astrophysics Data System (ADS)

    Ataide, Jade; Mc Leod, Roger; Mc Leod, David

    2007-04-01

    Florida's Miami Tequesta site conveys information about potential tornadoes, hurricanes, and even earthquakes. It is visually analogous to cross-circle designs, like other equivalent sites we have located, as in Maine, New Hampshire, in Medicine Wheels, and elsewhere. We focus on the detectable effects of time-and-place dependent electromagnetic signals. Non-technologic societies, and individuals, still find and use them, even today, especially in places like Cuzco, Peru. Modes of detection involve senses, such as sensitive, observant eyesight, and electromagnetically induced nerve signals interpreted as tinnitus, as traditionally indicated by ``Kokopelli's'' flute-playing, ``pins and needles,'' or even odor sensations. Recorded events show that youthful children are sometimes involved, as by Pacal's Classic-Mayan-era son, who became Kan Balum, Serpent Jaguar. Our intent is to check whether similar signals can be technologically identified in Brazil and New England. Site information investigated by us seems to be driven by the electromagnetic field. Enigmatic Brazilian locations should be technologically investigated with site correlations to other possible analogs, such as Florida's Chitto Tustenuggee site at Miramar. To cite this abstract, use the following reference: http://meetings.aps.org/link/BAPS.2007.NES07.C2.6

  9. Digital mapping of the Mars Pathfinder landing site: Design, acquisition, and derivation of cartographic products for science applications

    USGS Publications Warehouse

    Gaddis, L.R.; Kirk, R.L.; Johnson, J. R.; Soderblom, L.A.; Ward, A.W.; Barrett, J.; Becker, K.; Decker, T.; Blue, J.; Cook, D.; Eliason, E.; Hare, T.; Howington-Kraus, E.; Isbell, C.; Lee, E.M.; Redding, B.; Sucharski, R.; Sucharski, T.; Smith, P.H.; Britt, D.T.

    1999-01-01

    The Imager for Mars Pathfinder (IMP) acquired more than 16,000 images and provided panoramic views of the surface of Mars at the Mars Pathfinder landing site in Ares Vallis. This paper describes the stereoscopic, multispectral IMP imaging sequences and focuses on their use for digital mapping of the landing site and for deriving cartographic products to support science applications of these data. Two-dimensional cartographic processing of IMP data, as performed via techniques and specialized software developed for ISIS (the U.S.Geological Survey image processing software package), is emphasized. Cartographic processing of IMP data includes ingestion, radiometric correction, establishment of geometric control, coregistration of multiple bands, reprojection, and mosaicking. Photogrammetric processing, an integral part of this cartographic work which utilizes the three-dimensional character of the IMP data, supplements standard processing with geometric control and topographic information [Kirk et al., this issue]. Both cartographic and photogrammetric processing are required for producing seamless image mosaics and for coregistering the multispectral IMP data. Final, controlled IMP cartographic products include spectral cubes, panoramic (360?? azimuthal coverage) and planimetric (top view) maps, and topographic data, to be archived on four CD-ROM volumes. Uncontrolled and semicontrolled versions of these products were used to support geologic characterization of the landing site during the nominal and extended missions. Controlled products have allowed determination of the topography of the landing site and environs out to ???60 m, and these data have been used to unravel the history of large- and small-scale geologic processes which shaped the observed landing site. We conclude by summarizing several lessons learned from cartographic processing of IMP data. Copyright 1999 by the American Geophysical Union.

  10. Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site.

    PubMed

    Manos-Turvey, Alexandra; Cergol, Katie M; Salam, Noeris K; Bulloch, Esther M M; Chi, Gamma; Pang, Angel; Britton, Warwick J; West, Nicholas P; Baker, Edward N; Lott, J Shaun; Payne, Richard J

    2012-12-14

    Mycobacterium tuberculosis salicylate synthase (MbtI) catalyses the first committed step in the biosynthesis of mycobactin T, an iron-chelating siderophore essential for the virulence and survival of M. tuberculosis. Co-crystal structures of MbtI with members of a first generation inhibitor library revealed large inhibitor-induced rearrangements within the active site of the enzyme. This plasticity of the MbtI active site was probed via the preparation of a library of inhibitors based on a 2,3-dihydroxybenzoate scaffold with a range of substituted phenylacrylate side chains appended to the C3 position. Most compounds exhibited moderate inhibitory activity against the enzyme, with inhibition constants in the micromolar range, while several dimethyl ester variants possessed promising anti-tubercular activity in vitro. PMID:23108268

  11. Small Molecule Inhibitors of the LEDGF Site of Human Immunodeficiency Virus Integrase Identified by Fragment Screening and Structure Based Design

    PubMed Central

    Peat, Thomas S.; Rhodes, David I.; Vandegraaff, Nick; Le, Giang; Smith, Jessica A.; Clark, Lisa J.; Jones, Eric D.; Coates, Jonathan A. V.; Thienthong, Neeranat; Newman, Janet; Dolezal, Olan; Mulder, Roger; Ryan, John H.; Savage, G. Paul; Francis, Craig L.; Deadman, John J.

    2012-01-01

    A fragment-based screen against human immunodeficiency virus type 1 (HIV) integrase led to a number of compounds that bound to the lens epithelium derived growth factor (LEDGF) binding site of the integrase catalytic core domain. We determined the crystallographic structures of complexes of the HIV integrase catalytic core domain for 10 of these compounds and quantitated the binding by surface plasmon resonance. We demonstrate that the compounds inhibit the interaction of LEDGF with HIV integrase in a proximity AlphaScreen assay, an assay for the LEDGF enhancement of HIV integrase strand transfer and in a cell based assay. The compounds identified represent a potential framework for the development of a new series of HIV integrase inhibitors that do not bind to the catalytic site of the enzyme. PMID:22808106

  12. Comparison of in silico tools for binding site prediction applied for structure-based design of autolysin inhibitors.

    PubMed

    Tibaut, T; Borišek, J; Novič, M; Turk, D

    2016-07-01

    Autolysin E (AtlE) is a bacteriolytic enzyme which plays an important role in division and growth of bacterial cells and therefore represents a promising potential drug target. Its 3D structure has been recently elucidated. We used in silico prediction tools to study substrate or ligand (inhibitor) binding regions of AtlE. We applied several freely available tools and a commercial tool for binding site identification and compared results of the prediction. Calculation time, number of predictions and output data provided by specific software vary according to the different approaches utilized by specific method categories. Despite different approaches, binding sites in similar locations on the protein were predicted. Specific amino acid residues that form these binding sites were predicted as binding residues. The predicted residues, especially those with predicted highest conservation score, could theoretically have catalytic and binding properties. According to our results, we assume that E138, which has the highest conservation score, is the catalytic residue and F161, G162 and Y224, which are also highly conserved, are responsible for substrate binding. Ligands developed with binding specificity towards these residues could inhibit the catalysis and binding of the substrate of AtlE. The molecules with inhibitory potency could therefore represent potential new antibacterial agents. PMID:27686112

  13. Remedial action plan and site design for stabilization of the inactive uranium mill tailings sites at Rifle, Colorado: Final report. Volume 4, Addenda D1--D5 to Appendix D

    SciTech Connect

    Allen, James W.

    1990-02-01

    This radiologic characterization of tho two inactive uranium millsites at Rifle, Colorado, was conducted by Bendix Field Engineering Corporation (Bendix) for the US Department of Energy (DOE), Grand Junction Projects Office, in accord with a Statement of Work prepared by the DOE Uranium Mill Tailings Remedial Action (UMTRA) Project Technical Assistance Contractor, Jacobs Engineering Group, Inc. (Jacobs). The purpose of this project is to define the extent of radioactive contamination at the Rifle sites that exceeds US Environmental Protection Agency, (EPA) standards for UMTRA sites. The data presented in this report are required for characterization of the areas adjacent to the tailings piles and for the subsequent design of cleanup activities. An orientation visit to the study area was conducted on 31 July--1 August 1984, in conjunction with Jacobs, to determine the approximate extent of contaminated area surrounding tho piles. During that visit, survey control points were located and baselines were defined from which survey grids would later be established; drilling requirements were assessed; and radiologic and geochemical data were collected for use in planning the radiologic fieldwork. The information gained from this visit was used by Jacobs, with cooperation by Bendix, to determine the scope of work required for the radiologic characterization of the Rifle sites. Fieldwork at Rifle was conducted from 1 October through 16 November 1984.

  14. Hydration properties of ligands and drugs in protein binding sites: tightly-bound, bridging water molecules and their effects and consequences on molecular design strategies.

    PubMed

    García-Sosa, Alfonso T

    2013-06-24

    Some water molecules in binding sites are important for intermolecular interactions and stability. The way binding site explicit water molecules are dealt with affects the diversity and nature of designed ligand chemical structures and properties. The strategies commonly employed frequently assume that a gain in binding affinity will be achieved by their targeting or neglect. However, in the present work, 2332 high-resolution X-ray crystal structures of hydrated and nonhydrated, drug and nondrug compounds in biomolecular complexes with reported Ki or Kd show that compounds that use tightly bound, bridging water molecules are as potent as those that do not. The distribution of their energies, physicochemical properties, and ligand efficiency indices were compared for statistical significance, and the results were confirmed using 2000 permutation runs. Ligand cases were also split into agonists and antagonists, and crystal structure pairs with differing tightly bound water molecules were also compared. In addition, agonists and antagonists that use tightly bound water bridges are smaller, less lipophilic, and less planar; have deeper ligand efficiency indices; and in general, possess better physicochemical properties for further development. Therefore, tightly bound, bridging water molecules may in some cases be replaced and targeted as a strategy, though sometimes keeping them as bridges may be better from a pharmacodynamic perspective. The results suggest general indications on tightly hydrated and nontightly hydrated compounds in binding sites and practical considerations to adopt a strategy in drug and molecular design when faced with this special type of water molecules. There are also benefits of lower log P and better developability for tightly hydrated compounds, while stronger potency is not always required or beneficial. The hydrated binding site may be one of the many structure conformations available to the receptor, and different ligands will have a

  15. Design of a three-dimensional site-scale model for the unsaturated zone at Yucca Mountain, Nevada

    SciTech Connect

    Wittwer, C.S.; Bodvarsson, G.S.; Chornack, M.P.; Flint, A.L.; Lewis, B.D.; Spengler, R.W.; Flint, L.E.; Rautman, C.A.

    1992-01-01

    A three-dimensional model of moisture flow within the unsaturated zone at Yucca Mountain is being developed. This site-scale model covers an area of about 30 km{sup 2} and is bounded by major faults to the east and west. A detailed numerical grid has been developed based on location of boreholes, different infiltration zones, hydrogeological units and their outcrops, major faults, and water level data. Different maps, such as contour maps and isopachs maps, are presented for the different infiltration zones, and for the base of the Tiva Canyon, the Paintbrush, and the Topopah Spring hydrogeological units.

  16. Design of a three-dimensional site scale model for the unsaturated zone at Yucca Mountain, Nevada

    SciTech Connect

    Wittwer, C.S.; Bodvarsson, G.S.; Chornack, M.P.; Flint, A.L.; Lewis, B.D.; Spengler, R.W.; Flint, L.E.; Rautman, C.A.

    1992-10-01

    This paper discusses a three-dimensional model of moisture flow within the unsaturated zone at Yucca Mountain which is being developed. The site-scale model covers an area of about 30 km{sup 2} and is bounded by major faults to the east and west. A detailed numerical grid has been developed based on locations of boreholes, different infiltration zones, hydrogeological units and their outcrops, major faults, and water level data. Different maps, such as contour maps and isopachs maps, are presented for the different infiltration zones, and for the base of the Tiva Canyon, the Paintbrush, and the Topopah Spring hydrogeological units.

  17. A Playground for All Children. Book 1: User Groups and Site Selection. Book 2: Design Competition Program.

    ERIC Educational Resources Information Center

    New York City Dept. of City Planning, NY.

    These booklets, parts I and II of a three-part series, describe in detail issues related to the future development of an innovative outdoor public playground especially designed for integrated play between handicapped and able-bodied children. The first booklet describes potential user groups--the types of children who are expected to use the…

  18. Designing a Site to Embed and to Interact with Wolfram Alpha Widgets in Math and Sciences Courses

    ERIC Educational Resources Information Center

    Cepeda, Francisco Javier Delgado; Acosta, Ruben Dario Santiago

    2014-01-01

    This paper reports design and implementation outcomes at middle development advance of an educative program based on use and construction of widgets on Wolfram Alpha platform at higher education level for engineering and sciences areas. Widgets were based on Physics and Mathematics curricula under Project Oriented Learning and Blended Learning…

  19. Hybrid Placemaking in the Library: Designing Digital Technology to Enhance Users' On-Site Experience

    ERIC Educational Resources Information Center

    Bilandzic, Mark; Johnson, Daniel

    2013-01-01

    This paper presents research findings and design strategies that illustrate how digital technology can be applied as a tool for "hybrid" placemaking in ways that would not be possible in purely digital or physical spaces. Digital technology has revolutionised the way people learn and gather new information. This trend has challenged the…

  20. Design of a Fluorescent Ligand Targeting the S-adenosylmethioine Binding Site of the Histone Methyltransferase MLL1

    PubMed Central

    Luan, Yepeng; Blazer, Levi L.; Hu, Hao; Hajian, Taraneh; Zhang, Jing; Wu, Hong; Houliston, Scott; Arrowsmith, Cheryl H.; Vedadi, Masoud; Zheng, Yujun George

    2015-01-01

    The histone methyltransferase MLL1 has been linked to translocation-associated gene fusion in childhood leukemias and is an attractive drug target. High-throughput biochemical analysis of MLL1 methyltransferase activity requires the production of at least a trimeric complex of MLL1, RbBP5 and WDR5 to elicit robust activity. Production of trimeric and higher order MLL1 complexes in the quantities and reproducibility required for high-throughput screening presents a significant impediment to MLL1 drug discovery efforts. We present here a small molecule fluorescent ligand (FL-NAH, 6) that is able to bind to the S-adenosylmethionine (SAM) binding site of MLL1 in a manner independent of the associated complex members. We have used FL-NAH to develop a fluorescence polarization-based SAM displacement assay in a 384-well format targeting the MLL1 SET domain in the absence of associated complex members. FL-NAH competes with SAM and is displaced from the MLL1 SET domain by other SAM-binding site ligands with Kdisp values similar to the higher-order complexes, but is unaffected by the H3 peptide substrate. This assay enables screening for SAM-competitive MLL1 inhibitors without requiring the use of trimeric or higher order MLL1 complexes, significantly reducing screening time and cost. PMID:26541578

  1. Sequence, structure, and active site analyses of p38 MAP kinase: exploiting DFG-out conformation as a strategy to design new type II leads.

    PubMed

    Badrinarayan, Preethi; Sastry, G Narahari

    2011-01-24

    A new knowledge, structure, and sequence based strategy involving the effective exploitation of the DFG-out conformation is delineated. A comprehensive analysis of the structure, sequence, cocrystals, and active sites of p38 MAP kinase crystal structures present in Protein Data Bank (PDB) and the FDA approved MAP kinase drugs has been done, and the information is used for the design of type II leads. The 98 crystal structures, 138 cocrystals, and 31 FDA drugs comprise of 7 different sequences of 2 organisms viz., Homo sapiens and Mus musculus differing in sequence length, constituting both homo- and heterochains. Multiple sequence alignment with ClustalW showed >95% sequence similarity with highly conserved domains and a high propensity for mutations in the activation loop. The bound ligands were extracted, and their interactions with DFG in and out conformations were studied. These cocrystals and FDA drugs were fragmented on the basis of their binding interactions and their affinity to ATP and allosteric sites. The fragment library thus generated contains 106 fragments with overlapping drug fragments. A blue print constituting three main parts viz., head (ATP region), linker (DFG region), and tail (allosteric region) has thus been formulated and used to design 64 type II p38 MAP kinase inhibitors. The above strategy has been employed to design potent type II p38 MAP kinase inhibitors, which are shown to be very promising. PMID:21141877

  2. Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75.

    PubMed

    Li, Bo-Wen; Zhang, Feng-Hua; Serrao, Erik; Chen, Huan; Sanchez, Tino W; Yang, Liu-Meng; Neamati, Nouri; Zheng, Yong-Tang; Wang, Hui; Long, Ya-Qiu

    2014-06-15

    HIV integrase (IN) is an essential enzyme for the viral replication. Currently, three IN inhibitors have been approved for treating HIV-1 infection. All three drugs selectively inhibit the strand transfer reaction by chelating a divalent metal ion in the enzyme active site. Flavonoids are a well-known class of natural products endowed with versatile biological activities. Their β-ketoenol or catechol structures can serve as a metal chelation motif and be exploited for the design of novel IN inhibitors. Using the metal chelation as a common pharmacophore, we introduced appropriate hydrophobic moieties into the flavonol core to design natural product-based novel IN inhibitors. We developed selective and efficient syntheses to generate a series of mono 3/5/7/3'/4'-substituted flavonoid derivatives. Most of these new compounds showed excellent HIV-1 IN inhibitory activity in enzyme-based assays and protected against HIV-1 infection in cell-based assays. The 7-morpholino substituted 7c showed effective antiviral activity (EC50=0.826 μg/mL) and high therapeutic index (TI>242). More significantly, these hydroxyflavones block the IN-LEDGF/p75 interaction with low- to sub-micromolar IC50 values and represent a novel scaffold to design new generation of drugs simultaneously targeting the catalytic site as well as protein-protein interaction domains.

  3. Conceptual designs for waste packages for horizontal or vertical emplacement in a repository in salt for reference in the site characterization plan

    SciTech Connect

    Not Available

    1987-06-01

    This report includes the options of horizontal and vertical emplacement, the addition of a phased repository, an additional waste form (intact spent fuel), revised geotechnical data appropriate for the Deaf Smith County site, new corrosion data for the container, and new repository design data. The waste package consists of waste form and canister within a thick-walled, low-carbon steel container surrounded by packing. The container is a hollow cylinder with a flat head welded to each end. The design concepts for the waste container or vertical and horizontal emplacement are identical. This report discusses the results of analyses of aspects of the reference waste package concept needing changes because of new data and information believed applicable to the Deaf Smith County site. Included are waste package conceptual designs or (1) the reference defense high-level waste form from the Savannah River Plant; (2) intact spent fuel with our pressurized-water-reactor or nine boiling-water-reactor assemblies per package for emplacement during Phase 1 of repository operation; and (3) spent fuel which has been disassembled and consolidated into a segmented cylindrical canister with rods from either 12 pressurized-water-reactor or 30 boiling-water-reactor assemblies per package for emplacement during Phase 2. 30 refs., 61 figs., 30 tabs.

  4. New Computational Approaches for NMR-based Drug Design: A Protocol for Ligand Docking to Flexible Target Sites

    SciTech Connect

    Gracia, Luis; Speidel, Joshua A.; Weinstein, Harel

    2006-08-24

    NMR-based drug design has met with some success in the last decade, as illustrated in numerous instances by Fesik's ''ligand screening by NMR'' approach. Ongoing efforts to generalize this success have led us to the development of a new paradigm in which quantitative computational approaches are being integrated with NMR derived data and biological assays. The key component of this work is the inclusion of the intrinsic dynamic quality of NMR structures in theoretical models and its use in docking. A new computational protocol is introduced here, designed to dock small molecule ligands to flexible proteins derived from NMR structures. The algorithm makes use of a combination of simulated annealing monte carlo simulations (SA/MC) and a mean field potential informed by the NMR data. The new protocol is illustrated in the context of an ongoing project aimed at developing new selective inhibitors for the PCAF bromodomains that interact with HIV Tat.

  5. New Computational Approaches for NMR-based Drug Design: A Protocol for Ligand Docking to Flexible Target Sites

    NASA Astrophysics Data System (ADS)

    Gracia, Luis; Speidel, Joshua A.; Weinstein, Harel

    2006-08-01

    NMR-based drug design has met with some success in the last decade, as illustrated in numerous instances by Fesik's "ligand screening by NMR" approach. Ongoing efforts to generalize this success have led us to the development of a new paradigm in which quantitative computational approaches are being integrated with NMR derived data and biological assays. The key component of this work is the inclusion of the intrinsic dynamic quality of NMR structures in theoretical models and its use in docking. A new computational protocol is introduced here, designed to dock small molecule ligands to flexible proteins derived from NMR structures. The algorithm makes use of a combination of simulated annealing monte carlo simulations (SA/MC) and a mean field potential informed by the NMR data. The new protocol is illustrated in the context of an ongoing project aimed at developing new selective inhibitors for the PCAF bromodomains that interact with HIV Tat.

  6. Rapid Deployment Drilling System for on-site inspections under a Comprehensive Test Ban Preliminary Engineering Design

    SciTech Connect

    Maurer, W.C.; Deskins, W.G.; McDonald, W.J.; Cohen, J.H.; Heuze, F.E.; Butler, M.W.

    1996-09-01

    While not a new drilling technology, coiled-tubing (CT) drilling continues to undergo rapid development and expansion, with new equipment, tools and procedures developed almost daily. This project was undertaken to: analyze available technological options for a Rapid Deployment Drilling System (RDDS) CT drilling system: recommend specific technologies that best match the requirements for the RDDS; and highlight any areas where adequate technological solutions are not currently available. Postshot drilling is a well established technique at the Nevada Test Site (NTS). Drilling provides essential data on the results of underground tests including obtaining samples for the shot zone, information on cavity size, chimney dimensions, effects of the event on surrounding material, and distribution of radioactivity.

  7. Bone microarchitecture at muscle attachment sites: The relationship between macroscopic scores of entheses and their cortical and trabecular microstructural design.

    PubMed

    Djukic, Ksenija; Milovanovic, Petar; Hahn, Michael; Busse, Björn; Amling, Michael; Djuric, Marija

    2015-05-01

    The studies of entheses in bioarchaeology attempted to reconstruct the habitual physical activities of past populations. However, the studies of microarchitecture of the underlying bone are still lacking despite well-known potential of bone internal microarchitecture to reflect mechanical loading. It is unknown whether different morphological expressions of entheseal changes (ECs) correlate with the microstructural characteristics of the underlining bone. This study analyzed bone microstructural characteristics at the entheses. Our focus was on examining the possible successive nature of the three-stage scale of entheseal macroscopic changes by comparing EC scores with the microarchitectural features at the attachment sites. The study was based on the hypothesis that mechanical loading influences the microarchitecture of the bone at the attachment site. The bone samples were taken from 24 adult male skeletons from medieval cemeteries in Serbia, with different macroscopic expression score of EC. We evaluated the macroscopic and microscopic appearance of four entheses of the lower limbs (origin of the soleus muscle and the insertions of the adductor magnus, gluteus maximus, and iliopsoas muscles). The specimens were scanned using microcomputed tomography (Scanco µCT 40). Our data showed a lack of consistent correlation between stages of the macroscopic scoring systems with microarchitecture at the entheses, only cortical thickness was significantly different between EC stages. Analyzing relationship between trabecular and cortical bone microstructure we found correlations between cortical and trabecular variables only in Stage C. Results of our study suggest that macroscopic EC might not represent distinct successive phases in bone adaptation to mechanical loading. PMID:25546406

  8. Active Site and Loop 4 Movements with Human Glycolate Oxidase: Implications for Substrate Specificity and Drug Design

    SciTech Connect

    Murray,M.; Holmes, R.; Lowther, W.

    2008-01-01

    Human glycolate oxidase (GO) catalyzes the FMN-dependent oxidation of glycolate to glyoxylate and glyoxylate to oxalate, a key metabolite in kidney stone formation. We report herein the structures of recombinant GO complexed with sulfate, glyoxylate, and an inhibitor, 4-carboxy-5-dodecylsulfanyl-1, 2,3-triazole (CDST), determined by X-ray crystallography. In contrast to most {alpha}-hydroxy acid oxidases including spinach glycolate oxidase, a loop region, known as loop 4, is completely visible when the GO active site contains a small ligand. The lack of electron density for this loop in the GO-CDST complex, which mimics a large substrate, suggests that a disordered to ordered transition may occur with the binding of substrates. The conformational flexibility of Trp110 appears to be responsible for enabling GO to react with a-hydroxy acids of various chain lengths. Moreover, the movement of Trp110 disrupts a hydrogen-bonding network between Trp110, Leu191, Tyr134, and Tyr208. This loss of interactions is the first indication that active site movements are directly linked to changes in the conformation of loop 4. The kinetic parameters for the oxidation of glycolate, glyoxylate, and 2-hydroxy octanoate indicate that the oxidation of glycolate to glyoxylate is the primary reaction catalyzed by GO, while the oxidation of glyoxylate to oxalate is most likely not relevant under normal conditions. However, drugs that exploit the unique structural features of GO may ultimately prove to be useful for decreasing glycolate and glyoxylate levels in primary hyperoxaluria type 1 patients who have the inability to convert peroxisomal glyoxylate to glycine.

  9. miR-Synth: a computational resource for the design of multi-site multi-target synthetic miRNAs

    PubMed Central

    Laganà, Alessandro; Acunzo, Mario; Romano, Giulia; Pulvirenti, Alfredo; Veneziano, Dario; Cascione, Luciano; Giugno, Rosalba; Gasparini, Pierluigi; Shasha, Dennis; Ferro, Alfredo; Croce, Carlo Maria

    2014-01-01

    RNAi is a powerful tool for the regulation of gene expression. It is widely and successfully employed in functional studies and is now emerging as a promising therapeutic approach. Several RNAi-based clinical trials suggest encouraging results in the treatment of a variety of diseases, including cancer. Here we present miR-Synth, a computational resource for the design of synthetic microRNAs able to target multiple genes in multiple sites. The proposed strategy constitutes a valid alternative to the use of siRNA, allowing the employment of a fewer number of molecules for the inhibition of multiple targets. This may represent a great advantage in designing therapies for diseases caused by crucial cellular pathways altered by multiple dysregulated genes. The system has been successfully validated on two of the most prominent genes associated to lung cancer, c-MET and Epidermal Growth Factor Receptor (EGFR). (See http://microrna.osumc.edu/mir-synth). PMID:24627222

  10. Structure of the endonuclease IV homologue from Thermotoga maritima in the presence of active-site divalent metal ions

    SciTech Connect

    Tomanicek, Stephen J.; Hughes, Ronny C.; Ng, Joseph D.; Coates, Leighton

    2010-10-05

    The most frequent lesion in DNA is at apurinic/apyrimidinic (AP) sites resulting from DNA-base losses. These AP-site lesions can stall DNA replication and lead to genome instability if left unrepaired. The AP endonucleases are an important class of enzymes that are involved in the repair of AP-site intermediates during damage-general DNA base-excision repair pathways. These enzymes hydrolytically cleave the 5{prime}-phosphodiester bond at an AP site to generate a free 3{prime}-hydroxyl group and a 5{prime}-terminal sugar phosphate using their AP nuclease activity. Specifically, Thermotoga maritima endonuclease IV is a member of the second conserved AP endonuclease family that includes Escherichia coli endonuclease IV, which is the archetype of the AP endonuclease superfamily. In order to more fully characterize the AP endonuclease family of enzymes, two X-ray crystal structures of the T. maritima endonuclease IV homologue were determined in the presence of divalent metal ions bound in the active-site region. These structures of the T. maritima endonuclease IV homologue further revealed the use of the TIM-barrel fold and the trinuclear metal binding site as important highly conserved structural elements that are involved in DNA-binding and AP-site repair processes in the AP endonuclease superfamily.

  11. Remedial Action Plan and Site Design for Stabilization of the Inactive Uranium Mill Tailings Sites at Slick Rock, Colorado: Appendix B to Attachment 3, Lithologic logs and monitor well construction information. Final report

    SciTech Connect

    1995-09-01

    This volume contains lithology logs and monitor well construction information for: NC processing site; UC processing site; and Burro Canyon disposal site. This information pertains to the ground water hydrology investigations which is attachment 3 of this series of reports.

  12. Modification to the Remedial Action Plan and site design for stabilization of the inactive uranium mill tailings site at Mexican Hat, Utah: Volume 1, Text, Attachments 1--6. Final report

    SciTech Connect

    1989-01-01

    This document provides the modifications to the 1988 Remedial Action Plan (RAP) of the contaminated materials at the Monument Valley, Arizona, and Mexican Hat, Utah. The text detailing the modifications and attachments 1 through 6 are provided with this document. The RAP was developed to serve a two-fold purpose. It presents the activities proposed by the Department of Energy (DOE) to accomplish long-term stabilization and control of the residual radioactive materials (RRM) from Monument Valley, Arizona, and Mexican Hat, Utah, at the Mexican Hat disposal site. It also serves to document the concurrence of both the Navajo Nation and the Nuclear Regulatory Commission (NRC) in the remedial action. This agreement, upon execution by DOE and the Navajo Nation and concurrence by the NRC, becomes Appendix B of the Cooperative Agreement. This document has been structured to provide a comprehensive understanding of the remedial action proposed for the Monument Valley and Mexican Hat sites. It includes specific design and construction requirements for the remedial action. Pertinent information and data are included with reference given to the supporting documents.

  13. Rational design, biophysical and biological characterization of site-specific antibody-tubulysin conjugates with improved stability, efficacy and pharmacokinetics.

    PubMed

    Thompson, Pamela; Fleming, Ryan; Bezabeh, Binyam; Huang, Fengying; Mao, Shenlan; Chen, Cui; Harper, Jay; Zhong, Haihong; Gao, Xizhe; Yu, Xiang-Qing; Hinrichs, Mary Jane; Reed, Molly; Kamal, Adeela; Strout, Patrick; Cho, Song; Woods, Rob; Hollingsworth, Robert E; Dixit, Rakesh; Wu, Herren; Gao, Changshou; Dimasi, Nazzareno

    2016-08-28

    Antibody-drug conjugates (ADCs) are among the most promising empowered biologics for cancer treatment. ADCs are commonly prepared by chemical conjugation of small molecule cytotoxic anti-cancer drugs to antibodies through either lysine side chains or cysteine thiols generated by the reduction of interchain disulfide bonds. Both methods yield heterogeneous conjugates with complex biophysical properties and suboptimal serum stability, efficacy, and pharmacokinetics. To limit the complexity of cysteine-based ADCs, we have engineered and characterized in vitro and in vivo antibody cysteine variants that allow precise control of both site of conjugation and drug load per antibody molecule. We demonstrate that the chemically-defined cysteine-engineered antibody-tubulysin conjugates have improved ex vivo and in vivo stability, efficacy, and pharmacokinetics when compared to conventional cysteine-based ADCs with similar drug-to-antibody ratios. In addition, to limit the non-target FcγRs mediated uptake of the ADCs by cells of the innate immune system, which may result in off-target toxicities, the ADCs have been engineered to lack Fc-receptor binding. The strategies described herein are broadly applicable to any full-length IgG or Fc-based ADC and have been incorporated into an ADC that is in phase I clinical development.

  14. Geological and Geotechnical Site Investigation for the Design of a CO2 Rich Flue Gas Direct Injection and Storage Facility

    SciTech Connect

    Metz, Paul; Bolz, Patricia

    2013-03-25

    With international efforts to limit anthropogenic carbon in the atmosphere, various CO{sub 2} sequestration methods have been studied by various facilities worldwide. Basalt rock in general has been referred to as potential host material for mineral carbonation by various authors, without much regard for compositional variations due to depositional environment, subsequent metamorphism, or hydrothermal alteration. Since mineral carbonation relies on the presence of certain magnesium, calcium, or iron silicates, it is necessary to study the texture, mineralogy, petrology, and geochemistry of specific basalts before implying potential for mineral carbonation. The development of a methodology for the characterization of basalts with respect to their susceptibility for mineral carbonation is proposed to be developed as part of this research. The methodology will be developed based on whole rock data, petrography and microprobe analyses for samples from the Caledonia Mine in Michigan, which is the site for a proposed small-scale demonstration project on mineral carbonation in basalt. Samples from the Keweenaw Peninsula will be used to determine general compositional trends using whole rock data and petrography. Basalts in the Keweenaw Peninsula have been subjected to zeolite and prehnite-pumpellyite facies metamorphism with concurrent native copper deposition. Alteration was likely due to the circulation of CO{sub 2}-rich fluids at slightly elevated temperatures and pressures, which is the process that is attempted to be duplicated by mineral carbonation.

  15. Rational design, biophysical and biological characterization of site-specific antibody-tubulysin conjugates with improved stability, efficacy and pharmacokinetics.

    PubMed

    Thompson, Pamela; Fleming, Ryan; Bezabeh, Binyam; Huang, Fengying; Mao, Shenlan; Chen, Cui; Harper, Jay; Zhong, Haihong; Gao, Xizhe; Yu, Xiang-Qing; Hinrichs, Mary Jane; Reed, Molly; Kamal, Adeela; Strout, Patrick; Cho, Song; Woods, Rob; Hollingsworth, Robert E; Dixit, Rakesh; Wu, Herren; Gao, Changshou; Dimasi, Nazzareno

    2016-08-28

    Antibody-drug conjugates (ADCs) are among the most promising empowered biologics for cancer treatment. ADCs are commonly prepared by chemical conjugation of small molecule cytotoxic anti-cancer drugs to antibodies through either lysine side chains or cysteine thiols generated by the reduction of interchain disulfide bonds. Both methods yield heterogeneous conjugates with complex biophysical properties and suboptimal serum stability, efficacy, and pharmacokinetics. To limit the complexity of cysteine-based ADCs, we have engineered and characterized in vitro and in vivo antibody cysteine variants that allow precise control of both site of conjugation and drug load per antibody molecule. We demonstrate that the chemically-defined cysteine-engineered antibody-tubulysin conjugates have improved ex vivo and in vivo stability, efficacy, and pharmacokinetics when compared to conventional cysteine-based ADCs with similar drug-to-antibody ratios. In addition, to limit the non-target FcγRs mediated uptake of the ADCs by cells of the innate immune system, which may result in off-target toxicities, the ADCs have been engineered to lack Fc-receptor binding. The strategies described herein are broadly applicable to any full-length IgG or Fc-based ADC and have been incorporated into an ADC that is in phase I clinical development. PMID:27327768

  16. Design and installation of deep multilevel piezometer nests in Columbia River basalts at the Hanford Site, Washington. [Measurement of head in different rock zones sealed from each other

    SciTech Connect

    Jackson, R.L.; Veatch, M.D.

    1985-04-01

    The Basalt Waste Isolation Project (BWIP) was established in 1976 as part of the National Waste Terminal Storage Program, now the Office of Civilian Radioactive Waste Management. The BWIP objective is to assess the suitability of basalt as a repository medium for the long-term storage of commercial high-level radioactive waste. As part of the hydrogeologic characterization activities, BWIP designed and installed multilevel piezometer nests at three borehole cluster sites within and adjacent to the 18-square-mile reference repository location. These borehole cluster sites will provide multilevel piezometric baseline data across the reference repository location prior to, during, and after drilling a large-diameter exploratory shaft. They will also be used to monitor future hydraulic stress tests on a large scale. Three series of piezometer nests (A-, C-, and D-series) were installed at three borehole cluster sites in nine hydrogeologic units from a depth of about 500 to 3700 feet within the Columbia River Basalt Group. These multilevel monitoring zones are isolated from each other and the next overlying hydrogeologic unit by high-density cement seals. The A-series piezometer nests monitor two shallow sedimentary units. The C-series piezometer nests monitor basalt flow tops in the six deepest zones. The D-series piezometer monitors an intermediate sedimentary unit. Each piezometer tube was developed by air-lift pumping to complete the installtion prior to installing downhole pressure transducers. 23 refs., 10 figs., 1 tab.

  17. Preliminary design of a solar central receiver for a site-specific repowering application (Saguaro Power Plant). Volume 1. Executive summary. Final report, October 1982-September 1983

    SciTech Connect

    Weber, E.R.

    1983-09-01

    The preliminary design of a solar central receiver repowered gas/oil fired steam-Rankine cycle electric power generation plant was completed. The design is based on a central receiver technology using molten salt (60% NaNO/sub 3/, 40% KNO/sub 3/, by weight) for the heat transport and thermal storage fluid. Unit One of APS's Saguaro power plant located 43 km (27 mi) northwest of Tucson, AZ, is to be repowered. The selection of both the site and the molten salt central receiver promotes a near-term feasibility demonstration and cost-effective power production from an advanced solar thermal technology. The recommended system concept is to repower the existing electric power generating system at the minimum useful level (66 MW/sub e/ gross) using a field of 4850 Martin Marietta second-generation (58.5 m/sup 2/) heliostats and a storage capacity of 4.0 hours. The storage capacity will be used to optimize dispatch of power to the utility system. The preliminary design was based on the use of the systems approach to design where the overall project was divided into systems, each of which is clearly bounded, and performs specific functions. The total project construction cost was estimated to be 213 million in 1983 dollars. The plant will be capable of displacing fossil energy equivalent to 2.4 million barrels of No. 6 oil in its first 10 years of operation.

  18. Design

    ERIC Educational Resources Information Center

    Buchanan, Richard; Cross, Nigel; Durling, David; Nelson, Harold; Owen, Charles; Valtonen, Anna; Boling, Elizabeth; Gibbons, Andrew; Visscher-Voerman, Irene

    2013-01-01

    Scholars representing the field of design were asked to identify what they considered to be the most exciting and imaginative work currently being done in their field, as well as how that work might change our understanding. The scholars included Richard Buchanan, Nigel Cross, David Durling, Harold Nelson, Charles Owen, and Anna Valtonen. Scholars…

  19. Groundwater contamination from waste management sites: The interaction between risk-based engineering design and regulatory policy: 1. Methodology

    NASA Astrophysics Data System (ADS)

    Massmann, Joel; Freeze, R. Allan

    1987-02-01

    This paper puts in place a risk-cost-benefit analysis for waste management facilities that explicitly recognizes the adversarial relationship that exists in a regulated market economy between the owner/operator of a waste management facility and the government regulatory agency under whose terms the facility must be licensed. The risk-cost-benefit analysis is set up from the perspective of the owner/operator. It can be used directly by the owner/operator to assess alternative design strategies. It can also be used by the regulatory agency to assess alternative regulatory policy, but only in an indirect manner, by examining the response of an owner/operator to the stimuli of various policies. The objective function is couched in terms of a discounted stream of benefits, costs, and risks over an engineering time horizon. Benefits are in the form of revenues for services provided; costs are those of construction and operation of the facility. Risk is defined as the cost associated with the probability of failure, with failure defined as the occurrence of a groundwater contamination event that violates the licensing requirements established for the facility. Failure requires a breach of the containment structure and contaminant migration through the hydrogeological environment to a compliance surface. The probability of failure can be estimated on the basis of reliability theory for the breach of containment and with a Monte-Carlo finite-element simulation for the advective contaminant transport. In the hydrogeological environment the hydraulic conductivity values are defined stochastically. The probability of failure is reduced by the presence of a monitoring network operated by the owner/operator and located between the source and the regulatory compliance surface. The level of reduction in the probability of failure depends on the probability of detection of the monitoring network, which can be calculated from the stochastic contaminant transport simulations. While

  20. Design and Methods of a Multi-Site, Multi-Behavioral Treatment Trial for Menopausal Symptoms: The MsFLASH Experience

    PubMed Central

    Sternfeld, Barbara; LaCroix, Andrea; Caan, Bette J.; Dunn, Andrea L.; Newton, Katherine M.; Reed, Susan D.; Guthrie, Katherine A; Booth-LaForce, Cathryn; Sherman, Karen J; Cohen, Lee; Freeman, Marlene P.; Carpenter, Janet S.; Hunt, Julie R.; Roberts, Melanie; Ensrud, Kristine E.

    2013-01-01

    Background Behavioral strategies are recommended for menopausal symptoms, but little evidence exists regarding efficacy. Purpose Describe design and methodology of a randomized controlled 3 by 2 factorial trial of yoga, exercise and omega-3 fatty acids. Methods Women from three geographic areas with a weekly average of ≥14 hot flashes/night sweats, who met exclusion/inclusion criteria, were randomized to 12 weeks of: 1) yoga classes and daily home practice; 2) supervised, facility-based aerobic exercise training; or 3) usual activity. Women in each arm were further randomized to either omega-3 supplement or placebo. Standardized training, on-going monitoring, and site visits were adopted to ensure consistency across sites and fidelity to the intervention. Participant adherence to the intervention protocol was monitored continuously, and retention was actively encouraged by staff. Information on adverse events was systematically collected. Results Of 7,377 women who responded to mass mailings, 355 (4.8%) were randomized; mean age was 54.7 (sd=3.7), 26.2% were African American, 81.7% were post-menopausal, and mean baseline frequency of daily hot flashes/night sweats was 7.6 (sd=3.8). Adherence of ≥ 80% was 59% for yoga, 77% for exercise training, and 80% for study pills. Final week 12 data were collected from 95.2% Conclusions Conducting a multi-site, multi-behavioral randomized trial for menopausal symptoms is challenging but feasible. Benefits included cost-effective study design, centralized recruitment, and methodologic standardization. PMID:23462342

  1. Designing Surface Monitoring Meshes for Geologic Carbon Capture and Storage Sites: Accurate Emissions Accounting for an Essential 2°C Mitigation Technology

    NASA Astrophysics Data System (ADS)

    Augustin, C. M.; Swart, P. K.; Broad, K.

    2014-12-01

    Geologic carbon capture and storage (CCS) is a feasible solution to the international greenhouse gas (GHG) emissions problem and it has recently been called a "vital" mitigation tool by the International Energy Agency. However, there exists uncertainty concerning the terminal fate of stored carbon dioxide (CO2.) In this regard, reliable monitoring, verification and accounting (MVA) technologies are essential for making CCS publicly acceptable. Chiefly, MVA addresses safety and environmental concerns by providing a warning system to prevent or alleviate CO2 leakages. A secondary purpose of MVA technologies is to prove compliance with CO2 reduction standards through inventory verification. A key MVA tool for tracking CO2 leakages is surface (atmospheric) monitoring. Demonstrating its value, industry actors feel an impetus to invest in surface monitoring as a low-risk, high-value technology to mitigate liability in cases of potential leakages. Despite how necessary this tool is, to date, all surface monitoring mesh designs and best practices have been proposed locally, without discussion of standardization or optimization on a regional, national or international level. We identify the fundamental problem of surface monitoring mesh design as locating the monitoring sites to record CO2 levels over the designated geographic area at lowest cost with maximum impact. We approach this problem from both an operations research (OR) perspective and atmospheric dispersion perspective. From an OR perspective, we approach mesh design using multiobjective optimization models - we specify the relative placement of candidate sites, observation time interval, and optimality criteria. In the second approach, we model CO2 leakage scenarios to test the effectiveness of proposed mesh design from the first approach. We use atmospheric dispersion modeling softwares AERMOD and SCREEN3 - both tools developed by the United States Environmental Protection Agency and codified into law - for

  2. Site-specific thermodynamic stability and unfolding of a de novo designed protein structural motif mapped by 13C isotopically edited IR spectroscopy.

    PubMed

    Kubelka, Ginka S; Kubelka, Jan

    2014-04-23

    The mechanism of protein folding remains poorly understood, in part due to limited experimental information available about partially folded states. Isotopically edited infrared (IR) spectroscopy has emerged as a promising method for studying protein structural changes with site-specific resolution, but its full potential to systematically probe folding at multiple protein sites has not yet been realized. We have used (13)C isotopically edited IR spectroscopy to investigate the site-specific thermal unfolding at seven different locations in the de novo designed helix-turn-helix protein αtα. As one of the few stable helix-turn-helix motifs, αtα is an excellent model for studying the roles of secondary and tertiary interactions in folding. Circular dichroism (CD) experiments on the full αtα motif and its two peptide fragments show that interhelical tertiary contacts are critical for stabilization of the secondary structure. The site-specific thermal unfolding probed by (13)C isotopically edited IR is likewise consistent with primarily tertiary stabilization of the local structure. The least thermally stable part of the αtα motif is near the turn where the interhelical contacts are rather loose, while the motif's center with best established core packing has the highest stability. Similar correlation between the local thermal stability and tertiary contacts was found previously for a naturally occurring helix-turn-helix motif. These results underline the importance of native-like tertiary stabilizing interactions in folding, in agreement with recent state-of-the art folding simulations as well as simplified, native-centric models.

  3. Compressed air energy storage: preliminary design and site development program in an aquifer. Final draft, Task 2: Volume 2 of 3. Characterize and explore potential sites and prepare research and development plan

    SciTech Connect

    1980-12-01

    The characteristics of sites in Indiana and Illinois which are being investigated as potential sites for compressed air energy storage power plants are documented. These characteristics include geological considerations, economic factors, and environmental considerations. Extensive data are presented for 14 specific sites and a relative rating on the desirability of each site is derived. (LCL)

  4. USDA-ARS Southeast Watershed Laboratory at Tifton, GA:Index Site Design for the Suwannee Basin

    NASA Astrophysics Data System (ADS)

    Bosch, D.; Strickland, T.; Sheridan, J.; Lowrance, R.; Truman, C.; Hubbard, R.; Potter, T.; Wauchope, D.; Vellidis, G.; Thomas, D.

    2001-12-01

    The Southeast Watershed Hydrology Research Center (SEWHRC) was established in 1966 by order of the U.S. Senate "to identify and characterize those elements that control the flow of water from watersheds in the southeast". A 129 sq.mi. area within the headwaters of Little River Watershed (LRW) in central south Georgia was instrumented to provide data for evaluating and characterizing Coastal Plain hydrologic processes and for development and testing of prediction methodologies for use in ungaged watersheds in regions of low topographic relief. Pesticide analytical capabilities were added in 1976, and inorganic chemistry and sediment transport research were expanded. In 1980, the Center was renamed as the Southeast Watershed Research Laboratory (SEWRL), and laboratories were constructed for nutrient analysis and soil physics. A pesticide analysis laboratory was constructed in 1987. In the early 1990s, a hydraulics laboratory was established for sediment and chemical transport studies, and research on riparian buffers was expanded. The SEWRL research program continues to focus on hydrologic and environmental concerns. Major components of the program are hydrology, pesticides behavior, buffer systems, animal waste management, erosion, remote sensing of watershed condition, and relationships between site-specific agricultural management (BMPs) and small-to-large watershed response. SEWRL's program will be expanded over the next five years to include two additional watersheds comparable in size and instrumentation to the LRW; nesting the LRW within the full Little River drainage and subsequently...all three watersheds within the full Suwannee Basin; and mapping and quantifying irrigation water removals within the Suwannee Basin. We will instrument the three intensive study watersheds and the full Suwannee Basin to provide real-time characterization of precipitation, soil moisture, hydrologic flow, and water quality at a range of spatial and temporal scales. We will

  5. Recombinant plasmepsin 1 from the human malaria parasite Plasmodium falciparum: Enzymatic characterization, active site inhibitor design, and structural analysis

    PubMed Central

    Liu, Peng; Marzahn, Melissa R.; Robbins, Arthur H.; Gutiérrez-de-Terán, Hugo; Rodríguez, David; McClung, Scott; Stevens, Stanley M.; Yowell, Charles A.; Dame, John B.; McKenna, Robert; Dunn, Ben M.

    2009-01-01

    A mutated form of truncated proplasmepsin 1 (proPfPM1) from the human malaria parasite Plasmodium falciparum, proPfPM1 K110pN, was generated and overexpressed in E. coli. The auto-maturation process was carried out at pH 4.0 and 4.5, and the optimal catalytic pH of the resulting mature PfPM1 was determined to be pH 5.5. This mature PfPM1 showed comparable binding affinity to peptide substrates and inhibitors with the naturally-occurring form isolated from parasites. The S3-S3’ subsite preferences of the recombinant mature PfPM1 were explored using combinatorial chemistry based peptide libraries. Based on the results, a peptidomimetic inhibitor (compound 1) was designed and yielded 5-fold selectivity for binding to PfPM1 versus the homologous human cathepsin D (hcatD). The 2.8 Å structure of the PfPMP2-compound 1 complex is reported. Modeling studies were conducted using a series of peptidomimetic inhibitors (compounds 1–6, Table 3) and three plasmepsins: the crystal structure of PfPM2, and homology derived models of PfPM1 and PfPM4. PMID:19271776

  6. Self-catalyzed site-specific depurination of guanine residues within gene sequences.

    PubMed

    Amosova, Olga; Coulter, Richard; Fresco, Jacques R

    2006-03-21

    A self-catalyzed, site-specific guanine-depurination activity has been found to occur in short gene sequences with a potential to form a stem-loop structure. The critical features of that catalytic intermediate are a 5'-G-T-G-G-3' loop and an adjacent 5'-T.A-3' base pair of a short duplex stem stable enough to fix the loop structure required for depurination of its 5'-G residue. That residue is uniquely depurinated with a rate some 5 orders of magnitude faster than that of random "spontaneous" depurination. In contrast, all other purine residues in the sequence depurinate at the spontaneous background rate. The reaction requires no divalent cations or other cofactors and occurs under essentially physiological conditions. Such stem-loops can form in duplex DNA under superhelical stress, and their critical sequence features have been found at numerous sites in the human genome. Self-catalyzed stem-loop-mediated depurination leading to flexible apurinic sites may therefore serve some important biological role, e.g., in nucleosome positioning, genetic recombination, or chromosome superfolding.

  7. Reservoir High's TE Site Wins Web Site of the Month

    ERIC Educational Resources Information Center

    Tech Directions, 2008

    2008-01-01

    This article features "Mr. Rhine's Technology Education Web Site," a winner of the Web Site of the Month. This Web site was designed by Luke Rhine, a teacher at the Reservoir High School in Fulton, Maryland. Rhine's Web site offers course descriptions and syllabuses, class calendars, lectures and presentations, design briefs and other course…

  8. Remote engineering for a cheese whey biorefinery: an Internet-based application for process design, economic analysis, monitoring, and control of multiple plant sites.

    PubMed

    Pinto, Gilson A; Giordano, Raquel L C; Giordano, Roberto C

    2009-01-01

    The proteolysis of cheese whey with the aid of immobilized enzymes is an attractive alternative for this by-product of the dairy industry. Among some possible applications for whey protein hydrolysates, one may cite their use as protein source for individuals with reduced capacity of digestion, or with genetic metabolic disorders (phenylketonuria patients, for instance). The multipurpose plant that processes whey is named here as a cheese whey biorefinery. This work presents the remote control and monitoring of the whey biorefineries using the Internet. In an integrated environment, the web application also enables simulation and economic analyses of the process. This technology might allow small companies to access a remote "engineering centre", with know-how on plant design and advanced control techniques. The idea can also be extended to large dairy companies, providing the remote control of geographically spread sites of production. PMID:18431600

  9. Remote engineering for a cheese whey biorefinery: an Internet-based application for process design, economic analysis, monitoring, and control of multiple plant sites.

    PubMed

    Pinto, Gilson A; Giordano, Raquel L C; Giordano, Roberto C

    2009-01-01

    The proteolysis of cheese whey with the aid of immobilized enzymes is an attractive alternative for this by-product of the dairy industry. Among some possible applications for whey protein hydrolysates, one may cite their use as protein source for individuals with reduced capacity of digestion, or with genetic metabolic disorders (phenylketonuria patients, for instance). The multipurpose plant that processes whey is named here as a cheese whey biorefinery. This work presents the remote control and monitoring of the whey biorefineries using the Internet. In an integrated environment, the web application also enables simulation and economic analyses of the process. This technology might allow small companies to access a remote "engineering centre", with know-how on plant design and advanced control techniques. The idea can also be extended to large dairy companies, providing the remote control of geographically spread sites of production.

  10. A new design for a green calcium indicator with a smaller size and a reduced number of calcium-binding sites

    PubMed Central

    Barykina, Natalia V.; Subach, Oksana M.; Doronin, Danila A.; Sotskov, Vladimir P.; Roshchina, Marina A.; Kunitsyna, Tatiana A.; Malyshev, Aleksey Y.; Smirnov, Ivan V.; Azieva, Asya M.; Sokolov, Ilya S.; Piatkevich, Kiryl D.; Burtsev, Mikhail S.; Varizhuk, Anna M.; Pozmogova, Galina E.; Anokhin, Konstantin V.; Subach, Fedor V.; Enikolopov, Grigori N.

    2016-01-01

    Genetically encoded calcium indicators (GECIs) are mainly represented by two- or one-fluorophore-based sensors. One type of two-fluorophore-based sensor, carrying Opsanus troponin C (TnC) as the Ca2+-binding moiety, has two binding sites for calcium ions, providing a linear response to calcium ions. One-fluorophore-based sensors have four Ca2+-binding sites but are better suited for in vivo experiments. Herein, we describe a novel design for a one-fluorophore-based GECI with two Ca2+-binding sites. The engineered sensor, called NTnC, uses TnC as the Ca2+-binding moiety, inserted in the mNeonGreen fluorescent protein. Monomeric NTnC has higher brightness and pH-stability in vitro compared with the standard GECI GCaMP6s. In addition, NTnC shows an inverted fluorescence response to Ca2+. Using NTnC, we have visualized Ca2+ dynamics during spontaneous activity of neuronal cultures as confirmed by control NTnC and its mutant, in which the affinity to Ca2+ is eliminated. Using whole-cell patch clamp, we have demonstrated that NTnC dynamics in neurons are similar to those of GCaMP6s and allow robust detection of single action potentials. Finally, we have used NTnC to visualize Ca2+ neuronal activity in vivo in the V1 cortical area in awake and freely moving mice using two-photon microscopy or an nVista miniaturized microscope. PMID:27677952

  11. Max-E47, a Designed Minimalist Protein that Targets the E-Box DNA Site In Vivo and In Vitro

    PubMed Central

    Xu, Jing; Chen, Gang; De Jong, Antonia T.; Shahravan, S. Hesam; Shin, Jumi A.

    2009-01-01

    Max-E47 is a designed hybrid protein comprising the Max DNA-binding basic region and E47 HLH dimerization subdomain. In the yeast one-hybrid system (Y1H), Max-E47 shows strong transcriptional activation from the E-box site, 5'-CACGTG, targeted by the Myc/Max/Mad network of transcription factors; two mutants, Max-E47Y and Max-E47YF, activate more weakly from the E-box in the Y1H. Quantitative fluorescence anisotropy titrations to gain free energies of protein:DNA binding gave low nM Kd values for the native MaxbHLHZ, Max-E47, and the Y and YF mutants binding to the E-box site (14 nM, 15 nM, 9 nM, and 6 nM, respectively), with no detectable binding to a nonspecific control duplex. Because these minimalist, E-box-binding hybrids have no activation domain and no interactions with the c-MycbHLHZ, as shown by the yeast two-hybrid assay, they can potentially serve as dominant-negative inhibitors that suppress activation of E-box-responsive genes targeted by transcription factors including the c-Myc/Max complex. As proof-of-principle, we used our modified Y1H, which allows direct competition between two proteins vying for a DNA target, to show that Max-E47 effectively outcompetes the native MaxbHLHZ for the E-box; weaker competition is observed from the two mutants, consistent with Y1H results. These hybrids provide a minimalist scaffold for further exploration of the relationship between protein structure and DNA-binding function and may have applications as protein therapeutics or biochemical probes capable of targeting the E-box site. PMID:19449889

  12. Binding of 3,4,5,6-Tetrahydroxyazepanes to the Acid-[beta]-glucosidase Active Site: Implications for Pharmacological Chaperone Design for Gaucher Disease

    SciTech Connect

    Orwig, Susan D.; Tan, Yun Lei; Grimster, Neil P.; Yu, Zhanqian; Powers, Evan T.; Kelly, Jeffery W.; Lieberman, Raquel L.

    2013-03-07

    Pharmacologic chaperoning is a therapeutic strategy being developed to improve the cellular folding and trafficking defects associated with Gaucher disease, a lysosomal storage disorder caused by point mutations in the gene encoding acid-{beta}-glucosidase (GCase). In this approach, small molecules bind to and stabilize mutant folded or nearly folded GCase in the endoplasmic reticulum (ER), increasing the concentration of folded, functional GCase trafficked to the lysosome where the mutant enzyme can hydrolyze the accumulated substrate. To date, the pharmacologic chaperone (PC) candidates that have been investigated largely have been active site-directed inhibitors of GCase, usually containing five- or six-membered rings, such as modified azasugars. Here we show that a seven-membered, nitrogen-containing heterocycle (3,4,5,6-tetrahydroxyazepane) scaffold is also promising for generating PCs for GCase. Crystal structures reveal that the core azepane stabilizes GCase in a variation of its proposed active conformation, whereas binding of an analogue with an N-linked hydroxyethyl tail stabilizes GCase in a conformation in which the active site is covered, also utilizing a loop conformation not seen previously. Although both compounds preferentially stabilize GCase to thermal denaturation at pH 7.4, reflective of the pH in the ER, only the core azepane, which is a mid-micromolar competitive inhibitor, elicits a modest increase in enzyme activity for the neuronopathic G202R and the non-neuronopathic N370S mutant GCase in an intact cell assay. Our results emphasize the importance of the conformational variability of the GCase active site in the design of competitive inhibitors as PCs for Gaucher disease.

  13. Computational fragment-based drug design to explore the hydrophobic sub-pocket of the mitotic kinesin Eg5 allosteric binding site.

    PubMed

    Oguievetskaia, Ksenia; Martin-Chanas, Laetitia; Vorotyntsev, Artem; Doppelt-Azeroual, Olivia; Brotel, Xavier; Adcock, Stewart A; de Brevern, Alexandre G; Delfaud, Francois; Moriaud, Fabrice

    2009-08-01

    Eg5, a mitotic kinesin exclusively involved in the formation and function of the mitotic spindle has attracted interest as an anticancer drug target. Eg5 is co-crystallized with several inhibitors bound to its allosteric binding pocket. Each of these occupies a pocket formed by loop 5/helix alpha2 (L5/alpha2). Recently designed inhibitors additionally occupy a hydrophobic pocket of this site. The goal of the present study was to explore this hydrophobic pocket with our MED-SuMo fragment-based protocol, and thus discover novel chemical structures that might bind as inhibitors. The MED-SuMo software is able to compare and superimpose similar interaction surfaces upon the whole protein data bank (PDB). In a fragment-based protocol, MED-SuMo retrieves MED-Portions that encode protein-fragment binding sites and are derived from cross-mining protein-ligand structures with libraries of small molecules. Furthermore we have excluded intra-family MED-Portions derived from Eg5 ligands that occupy the hydrophobic pocket and predicted new potential ligands by hybridization that would fill simultaneously both pockets. Some of the latter having original scaffolds and substituents in the hydrophobic pocket are identified in libraries of synthetically accessible molecules by the MED-Search software.

  14. Design, Synthesis, and Biological Evaluation of 1-Methyl-1,4-dihydroindeno[1,2-c]pyrazole Analogues as Potential Anticancer Agents Targeting Tubulin Colchicine Binding Site.

    PubMed

    Liu, Yan-Na; Wang, Jing-Jing; Ji, Ya-Ting; Zhao, Guo-Dong; Tang, Long-Qian; Zhang, Cheng-Mei; Guo, Xiu-Li; Liu, Zhao-Peng

    2016-06-01

    By targeting a new binding region at the interface between αβ-tubulin heterodimers at the colchicine binding site, we designed a series of 7-substituted 1-methyl-1,4-dihydroindeno[1,2-c]pyrazoles as potential tubulin polymerization inhibitors. Among the compounds synthesized, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)acetamide 6a and 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)-N-hydroxyacetamide 6n showed noteworthy low nanomolar potency against HepG2, Hela, PC3, and MCF-7 cancer cell lines. In mechanism studies, 6a inhibited tubulin polymerization and disorganized microtubule in A549 cells by binding to tubulin colchicine binding site. 6a arrested A549 cells in G2/M phase that was related to the alterations in the expression of cyclin B1 and p-cdc2. 6a induced A549 cells apoptosis through the activation of caspase-3 and PARP. In addition, 6a inhibited capillary tube formation in a concentration-dependent manner. In nonsmall cell lung cancer xenografts mouse model, 6a suppressed tumor growth by 59.1% at a dose of 50 mg/kg (ip) without obvious toxicity, indicating its in vivo potential as anticancer agent. PMID:27172319

  15. White paper on the proposed design, development, and implementation of a monitored retrievable storage module and the siting criteria for spent nuclear fuel

    SciTech Connect

    Villarreal, B.; Knobeloch, D.

    1996-01-01

    Congress enacted the Nuclear Waste Policy (NWP) Act in 1982 as comprehensive legislation for the DOE to locate, build, and operate repositories to permanently dispose of spent nuclear fuel and other high-level wastes. In 1987, Congress amended the NWP Act and authorized the DOE to site, construct, and operate one Monitored Retrievable Storage (MRS) facility. The MRS facility was planned as a means to enhance the flexibility and reliability of the overall waste management system. This white paper presents a broad prospectus of the scientific and regulatory capabilities at Los Alamos National Laboratory and outlines the methodology to design and implement an MRS test module. This proposed module will incorporate the flexibility to store all types of spent nuclear fuel above or below ground level and will be fully monitored for the residence time of the spent fuel in the MRS module. The purpose of this test module is to define the parameters necessary to build a simple and economical MRS system. Demonstration of the proposed MRS test module will be important because it will form the basis for an integrated MRS site model.

  16. Discovery of Cyclic Acylguanidines as Highly Potent and Selective β-Site Amyloid Cleaving Enzyme (BACE) Inhibitors: Part I-Inhibitor Design and Validation

    SciTech Connect

    Zhu, Zhaoning; Sun, Zhong-Yue; Ye, Yuanzan; Voigt, Johannes; Strickland, Corey; Smith, Elizabeth M; Cumming, Jared; Wang, Lingyan; Wong, Jesse; Wang, Yu-Sen; Wyss, Daniel F; Chen, Xia; Kuvelkar, Reshma; Kennedy, Matthew E; Favreau, Leonard; Parker, Eric; McKittrick, Brian A; Stamford, Andrew; Czarniecki, Michael; Greenlee, William; Hunter, John C

    2010-10-18

    A number of novel amidine containing heterocycles were designed to reproduce the unique interaction pattern, revealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit (3), with special attention paid to maintaining the appropriate basicity and limiting the number of H-bonding donors of these scaffolds. The iminohydantoin cores (10 and 23) were examined first and found to interact with the catalytic diad in one of two binding modes (A and B), each with the iminohydantoin core flipped 180º in relation to the other. The amidine structural motif within each core forms a bidentate interaction with a different aspartic acid of the catalytic diad. Both modes reproduced a highly conserved interaction pattern between the inhibitors and the catalytic aspartates, as revealed by 3. Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the molecular design as aspartyl protease catalytic site inhibitors. Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been discovered, enabling multiple strategies for further development of these inhibitors into highly potent, selective and in vivo efficacious BACE inhibitors.

  17. Discovery of Cyclic Acylguanidines as Highly Potent and Selective β-Site Amyloid Cleaving Enzyme (BACE) Inhibitors: Part I–Inhibitor Design and Validation

    SciTech Connect

    Zhu, Zhaoning; Sun, Zhong-Yue; Ye, Yuanzan; Voigt, Johannes; Strickland, Corey; Smith, Elizabeth M.; Cumming, Jared; Wang, Lingyan; Wong, Jesse; Wang, Yu-Sen; Wyss, Daniel F.; Chen, Xia; Kuvelkar, Reshma; Kennedy, Matthew E.; Favreau, Leonard; Parker, Eric; McKittrick, Brian A.; Stamford, Andrew; Czarniecki, Michael; Greenlee, William; Hunter, John C.

    2013-11-20

    A number of novel amidine containing heterocycles were designed to reproduce the unique interaction pattern, revealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit, with special attention paid to maintaining the appropriate basicity and limiting the number of H-bonding donors of these scaffolds. The iminohydantoin cores were examined first and found to interact with the catalytic diad in one of two binding modes (A and B), each with the iminohydantoin core flipped 180° in relation to the other. The amidine structural motif within each core forms a bidentate interaction with a different aspartic acid of the catalytic diad. Both modes reproduced a highly conserved interaction pattern between the inhibitors and the catalytic aspartates. Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the molecular design as aspartyl protease catalytic site inhibitors. Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been discovered, enabling multiple strategies for further development of these inhibitors into highly potent, selective and in vivo efficacious BACE inhibitors.

  18. Design Support of an Above Cap-rock Early Detection Monitoring System using Simulated Leakage Scenarios at the FutureGen2.0 Site

    SciTech Connect

    Williams, Mark D.; USA, Richland Washington; Vermuel, Vince R.; USA, Richland Washington; Oostrom, Mart; USA, Richland Washington; Porse, Sean L.; USA, Richland Washington; Thorne, Paul D.; USA, Richland Washington; Szecsody, Jim E.; USA, Richland Washington; Horner, Jake A.; USA, Richland Washington; Gilmore, Tyler J.; USA, Richland Washington

    2014-12-31

    The FutureGen 2.0 Project will design and build a first-of-its-kind, near-zero emissions coal-fueled power plant with carbon capture and storage (CCS). To assess storage site performance and meet the regulatory requirements of the Class VI Underground Injection Control (UIC) Program for CO2 Geologic Sequestration, the FutureGen 2.0 project will implement a suite of monitoring technologies designed to evaluate CO2 mass balance and detect any unforeseen loss in CO2 containment. The monitoring program will include direct monitoring of the reservoir, and early-leak-detection monitoring directly above the primary confining zone. This preliminary modeling study described here focuses on hypothetical leakage scenarios into the first permeable unit above the primary confining zone (Ironton Sandstone) and is used to support assessment of early-leak detection capabilities. Future updates of the model will be used to assess potential impacts on the lowermost underground source of drinking water (Saint Peter Sandstone) for a range of theoretical leakage scenarios. This preliminary modeling evaluation considers both pressure response and geochemical signals in the overlying Ironton Sandstone. This model is independent of the FutureGen 2.0 reservoir model in that it does not simulate caprock discontinuities, faults, or failure scenarios. Instead this modeling effort is based on theoretical, volumetric-rate based leakage scenarios. The scenarios include leakage of 1% of the total injected CO2 mass, but spread out over different time periods (20, 100, and 500 years) with each case yielding a different mass flux (i.e., smaller mass fluxes for longer duration leakage cases]. A brine leakage scenario using a volumetric leakage similar to the 20 year 1% CO2 case was also considered. A framework for the comparison of the various cases was developed based on the exceedance of selected pressure and geochemical thresholds at different

  19. Design Support of an Above Cap-rock Early Detection Monitoring System using Simulated Leakage Scenarios at the FutureGen2.0 Site

    DOE PAGESBeta

    Williams, Mark D.; USA, Richland Washington; Vermuel, Vince R.; USA, Richland Washington; Oostrom, Mart; USA, Richland Washington; Porse, Sean L.; USA, Richland Washington; Thorne, Paul D.; USA, Richland Washington; et al

    2014-12-31

    The FutureGen 2.0 Project will design and build a first-of-its-kind, near-zero emissions coal-fueled power plant with carbon capture and storage (CCS). To assess storage site performance and meet the regulatory requirements of the Class VI Underground Injection Control (UIC) Program for CO2 Geologic Sequestration, the FutureGen 2.0 project will implement a suite of monitoring technologies designed to evaluate CO2 mass balance and detect any unforeseen loss in CO2 containment. The monitoring program will include direct monitoring of the reservoir, and early-leak-detection monitoring directly above the primary confining zone. This preliminary modeling study described here focuses on hypothetical leakage scenarios intomore » the first permeable unit above the primary confining zone (Ironton Sandstone) and is used to support assessment of early-leak detection capabilities. Future updates of the model will be used to assess potential impacts on the lowermost underground source of drinking water (Saint Peter Sandstone) for a range of theoretical leakage scenarios. This preliminary modeling evaluation considers both pressure response and geochemical signals in the overlying Ironton Sandstone. This model is independent of the FutureGen 2.0 reservoir model in that it does not simulate caprock discontinuities, faults, or failure scenarios. Instead this modeling effort is based on theoretical, volumetric-rate based leakage scenarios. The scenarios include leakage of 1% of the total injected CO2 mass, but spread out over different time periods (20, 100, and 500 years) with each case yielding a different mass flux (i.e., smaller mass fluxes for longer duration leakage cases]. A brine leakage scenario using a volumetric leakage similar to the 20 year 1% CO2 case was also considered. A framework for the comparison of the various cases was developed based on the exceedance of selected pressure and geochemical thresholds at different distances from the point of leakage and at

  20. Conceptual Design of a Simplified Skid-Mounted Caustic-Side Solvent Extraction Process for Removal of Cesium from Savannah Rive Site High-Level Waste

    SciTech Connect

    Birdwell, JR.J.F.

    2004-05-12

    This report presents the results of a conceptual design of a solvent extraction process for the selective removal of {sup 137}Cs from high-level radioactive waste currently stored in underground tanks at the U.S. Department of Energy's Savannah River Site (SRS). This study establishes the need for and feasibility of deploying a simplified version of the Caustic-Side Solvent Extraction (CSSX) process; cost/benefit ratios ranging from 33 to 55 strongly support the considered deployment. Based on projected compositions, 18 million gallons of dissolved salt cake waste has been identified as having {sup 137}Cs concentrations that are substantially lower than the worst-case design basis for the CSSX system that is to be deployed as part of the Salt Waste Processing Facility (SWPF) but that does not meet the waste acceptance criteria for immobilization as grout in the Saltstone Manufacturing and Disposal Facility at SRS. Absent deployment of an alternative cesium removal process, this material will require treatment in the SWPF CSSX system, even though the cesium decontamination factor required is far less than that provided by that system. A conceptual design of a CSSX processing system designed for rapid deployment and having reduced cesium decontamination factor capability has been performed. The proposed accelerated-deployment CSSX system (CSSX-A) has been designed to have a processing rate of 3 million gallons per year, assuming 90% availability. At a more conservative availability of 75% (reflecting the novelty of the process), the annual processing capacity is 2.5 million gallons. The primary component of the process is a 20-stage cascade of centrifugal solvent extraction contactors. The decontamination and concentration factors are 40 and 15, respectively. The solvent, scrub, strip, and wash solutions are to have the same compositions as those planned for the SWPF CSSX system. As in the SWPF CSSX system, the solvent and scrub flow rates are equal. The system is