text: United States Patent: 5171680 ( 1 of 1 ) United States Patent 5,171,680 Mullenbach , et al. December 15, 1992 Superoxide dismutase analogs having novel binding properties Abstract Superoxide dismutase (SOD) analogs whose amino acid sequence includes a heterologous peptide domain such as the RGDX tetrapeptide found in fibronectin or the LGGAKQAGDV decapeptide found in fibrinogen that enables the analog to bind to a moiety that is normally present at sites of desired SOD therapy. The domain is incorporated into the SOD sequence in a manner in which it is available to interact with such moieties but does not destroy the enzymatic activity of the molecule. The inclusion of the domain enables the analog to more readily access the target tissue upon which it is to act and/or increase the corporeal half-life of the molecule. Inventors: Mullenbach; Guy T. (Oakland, CA), Hallewell; Robert A. (San Francisco, CA), Valenzuela; Pablo (San Francisco, CA) Assignee: Chiron Corporation (Emeryville, CA) Appl. No.: 07/561,442 Filed: August 1, 1990 Related U.S. Patent Documents Application NumberFiling DatePatent NumberIssue Date 206513Jun., 1988 Current U.S. Class: 424/94.4 ; 435/189; 435/252.3; 435/254.21; 435/320.1 Current International Class: C07K 14/75 (20060101); C07K 14/435 (20060101); C07K 14/78 (20060101); C12N 9/02 (20060101); A61K 38/00 (20060101); C12N 009/02 (); C12N 001/21 (); C12N 001/14 (); C12N 015/53 () Field of Search: 435/189,320.1,252.3,254 424/94.4 536/27 References Cited [Referenced By] U.S. Patent Documents 4391749 July 1983 Ruoslahti et al. 4517685 May 1985 Ruoslahti et al. 4578079 March 1986 Ruoslahti et al. 4589881 May 1986 Pierschbacher 4614517 September 1986 Ruoslahti et al. 4661111 April 1987 Ruoslahti et al. Foreign Patent Documents 0138111 Apr., 1985 EP 84/00540 Feb., 1985 WO Other References Barra et al., J. Biol. Chem. (1984) 259(20):12595-12601. . Hjalmarsson et al., (1987) Proc. Natl. Acad. Sci., USA 84, 6340-6344. . Santoro, S. A., et al. (1987) Cell 48, 867-873. . Ruoslahti, E. et al. (1986) Cell 44, 517-518. . Pierschabacher, M. D., et al. (1984) Nature 309, 30-33. . Abstract Nos. 564, 1140-1141, 649, 15-17, 715, 901, 908, 1043, 1587 from Thrombosis and Haemostasis 58:Abstract "Eleventh International Congress", Brussels, Belgium, Jul. 1987. . Betsholtz, Nature (1986) 320:695-699. . Bock et al. Biochem. J. (1980) 191:769-776. . Hong et al., Proc. Natl. Acad. Sci. (1987) 84:7962-7966. . Iwamoto, Science (1987) 238:1132-699. . Jabusch et al., Biochemistry (1980) 19:2310-2316. . Kaplan et al., Blood (1979) 53:604-618. . Luster et al., Nature (1985) 315:672-676. . Naccache et al., Science (1979) 203461-463. . Peterson et al., J. Biol. Chem. (1987) 262(17):8061-8065. . Petrone et al., Proc. Natl. Acad. Sci. (1980)77(2):1159-1163. . Pyatak et al., Res. Comm. Chem. Path. & Pharm. (1980) 29:113-120. . Timmons et al., Proc. Natl. Acad. Sci. (1984) 81:4935-4935. . Turrens et al., J. Clin. Invest. (1984) 73:87-95. . Yoshimura et al., Proc. Natl. Acad. Sci. (1987)84:9233-9237. . Zamir et al., Proc. Natl. Acad. Sci. (1987) 84:541-545. . Carlsson et al., Proc. Natl. Acad. Sci. (1981) 78:2403-2406. . Daly et al., Tetrahedron Letters (1988) 29(46):5859-5862. . Hynes, Cell (1987) 48:549-554. . Karlsson et al., Biochem. J. (1987) 242:55-59. . Lui et al., J. Bio. Chem. (1987) 262(36):17356-17361. . Ny et al., Proc. Natl. Acad. Sco. (1984) 81:5355-5359. . Pierschbacher et al., J. Biol. Chem. (1982) 257:9593-9597. . Plow et al., J. Biol. Chem. (1984) 259:5388-5391. . Ruoslahti et al., Science (1987) 238:491-497. . Roberts et al., J. Biol. Chem. (1986) 261:6872-6877. . Smith et al., J. Biol. Chem. (1987) 262(25):11964-11972. . Pierschbacher, M. D., et al. (1981) Cell 26, 259-267. . Marklund, S. L. (1982) Proc. Natl. Acad. Sci., USA 79, 7634-7638.. Primary Examiner: Patterson, Jr.; Charles L. Attorney, Agent or Firm: Morrison & Foerster Parent Case Text This application is a continuation of application Ser. No. 07/206,513 filed, Jun. 14, 1988 now abandoned. Claims We claim: 1. A superoxide dismutase analog having dismutase activity wherein the superoxide dismutase is human Cu/Zn superoxide dismutase, whose amino acid sequence includes a heterologous peptide domain that comprises a RGDX tetrapeptide, said domain providing the analog with an ability to bind to a moiety that localizes at or is local to a body site at which SOD therapy is desired, wherein amino acids 23 to 28 of the native sequence of Cu/Zn superoxide dismutase is modified as follows to include said tetrapeptide: where - represents an amino acid deletion, said analog being SOD-AS-T-2 and having increased binding to a platelet. 2. A pharmaceutical composition for providing superoxide dismutase therapy comprising the analog of claim 1 admixed with a pharmaceutically acceptable parenteral vehicle. 3. DNA encoding the superoxide dismutase analog of claim 1. 4. An expression vector for expressing the DNA of claim 3 in an organism comprising the DNA of claim 17 operably connected to DNA that enables the expression of the DNA in the organism. 5. A host organism containing the vector of claim 4 which permits the expression of the analog by the organism. 6. A method of producing a superoxide dismutase analog having dismutase activity and whose amino acid sequence includes a heterologous peptide domain that provides the analog with an ability to bind to a moiety that localizes at or is local to a body site at which superoxide dismutase therapy is desired comprising growing the organism of claim 5 in a suitable growth medium under conditions that result in the expression of said DNA encoding the analog and production of said analog. 7. Superoxide dismutase analog SOD-AS-T-2. Description TECHNICAL FIELD This invention is in the fields of protein chemistry, genetic engineering, and pharmaceuticals. More particularly, it relates to superoxide dismutase (SOD) analogs that are modified in a manner in which they have binding properties that enable them to be localized at sites where superoxide dismutase therapy is required and/or extend their corporeal lifetimes. BACKGROUND ART SODs are a family of enzymes that catalyze the destruction of superoxide ions. SODs are metalloproteins that are individually characterized by their respective metal ions--which can be iron, manganese, or copper and zinc. The ability of SODs to catalyze the destruction of superoxide ions renders them useful in a variety of therapeutic settings such as in reducing reperfusion injury and in treating inflammation. The amino acid sequence of human Cu/Zn SOD is described in Jabusch et al, Biochemistry (1980) 19:2310-2316. The cloning and sequencing of human Cu/Zn SOD and the production of human Cu/Zn SOD in bacteria and yeast are described in EPA 84111416.8 (published Apr. 24, 1985 under number 0138111). Human Cu/Zn SOD is normally a homodimer of two chains bound together by hydrophobic interaction. The homodimer has a molecular weight of approximately 32 kd. The primary structure of human Mn SOD is described by Barra et al, J.B.C. (1984) 259:12595-12601. The cloning and sequencing of human Mn SOD and the production of human Mn SOD in yeast is described in copending U.S. application Ser. No. 918,534, filed Oct. 14, 1986. In achieving its therapeutic potential SOD must (1) achieve access to the target tissue upon which it is to act (2) maintain its molecular integrity while in transit and at the site of action and (3) not be cleared too rapidly from circulation. Prior modifications of SOD have focused on only the latter two of these requirements. For example, commonly owned copending U.S. application Ser. No. 026,143, filed Mar. 16, 1987 describes SOD polymers composed of covalently coupled SOD dimers which are not cleared as rapidly from circulation as native SOD. Res Commun. in Chem. Path. & Pharmacol. (1980) 29:113-120 and Proc. Nat'l Acad. Sci. U.S.A. (1980) 77:1159-1163 describe conjugates of SOD and macromolecules such as polyethylene glycol that also have increased circulatory half-lives relative to wild-type SOD. J. Clin. Invest. (1984) 73:87-95 describes SOD encapsulated in liposomes to protect the SOD from proteolysis and extend its clearance time. In contrast, the present invention is primarily directed to modifying SOD in a manner to enable it to more readily access the target tissue upon which it is to act and/or to extend its corporeal lifetime. This is achieved by modifying the amino acid sequence of SOD to include a heterologous peptide domain that binds to a moiety that localizes at the site where the superoxide dismutase therapy is desired or binds to the site itself. Such domains are sometimes referred to as "adhesive peptide signals" herein. Prior workers have identified adhesive peptide signals of various proteins that bind to cells, bodies, or molecules that are real to or commonly localize at sites at which SOD therapy may be desirable. The signals for fibrinogen, fibronectin, and von Willebrand factor are described in Nature (1984) 309:30-33; Proc. Nat'l Acad. Sci. U.S.A. (1984) 81:4935-4939; Cell (1986) 44:517-518 and Cell (1987) 48:867-873. Signals for laminin are described in Science 1987) 238:1132, for extracellular superoxide dismutase (EC-SOD) in PNAS (1987) 84:6340, for platelet-derived growth factor (PDGF) in Nature (1986) 320:695, for tissue plasminogen activator (tPA) in Abstracts 1141, 1144, 1043, and 1587 in "Thrombosis and Haemostasis, Volume 58, Abstracts", Eleventh International Congress, Brussels, Belgium, July 1987, and chemotactic factor in PNAS (1987) 84:9233. Those for Antithrombin III are described in Abstracts 543-545, ibid, and in J. Biol. Chem. (1987) 262:8061, 11964, 17356. The adhesive peptide signals for anti-platelet GPIIb/IIIa receptor and anti-endothelial cell GPIIb/IIIa receptor antibodies are discussed in Abstracts 15, 715, 901 and 908 of "Thrombosis and Haemostasis, Volume 58, Abstracts", supra. Those for vitronectin appear in Abstracts 15-17 and 564, ibid., for urokinase in Abstract 1140, ibid., for thrombin inhibitor in Abstract 649, ibid. The signal for chemotactic inhibitor is disclosed in Science (1979) 203:461, and for chemotactic agonists in PNAS (1987) 84:7964. The signals for platelet factor-4 appear in Blood (1979) 53:604 and Biochem. J. (1980) 191:769 and those for Gamma IP10 in Nature (1985) 315:672. Applicants are unaware of any prior efforts to incorporate any of these adhesive domains or signals into other polypeptides to impart binding activity thereto. DISCLOSURE OF THE INVENTION One aspect of this invention is a SOD analog having dismutase activity and whose amino acid sequence includes a heterologous peptide domain that provides the analog with an ability to bind to a moiety that localizes at or is local to a body site at which SOD therapy is desired. DNA sequences encoding such SOD analogs, expression vectors containing such DNA sequences, cells transformed with such vectors, and processes for making the analogs by growing such transformed cells are another aspect of the invention. Still other aspects of the invention are pharmaceutical compositions which contain the analogs and therapeutic methods which employ the analogs. BRIEF DESCRIPTION OF THE DRAWINGS In the drawings: FIG. 1 is the nucleotide sequence of a partially synthetic human Cu/Zn SOD cDNA and the deduced amino acid sequence of human Cu/Zn SOD. FIG. 2 is a schematic illustration of the tertiary structure of human Cu/Zn SOD. FIG. 3 is a flow diagram depicting the scheme used to construct the yeast expression vector pYSOD-AS-T-2. FIG. 4 shows the DNA sequence of the insert used in the construction of pYSOD-AS-T-2. FIG. 5 is a flow diagram depicting the scheme used to construct the yeast expression vector pYSOD-AS-T-8. FIG. 6 shows the DNA sequence of an insert used in the construction of pYSOD-AS-T-8. FIG. 7 is a flow diagram depicting the scheme used to construct the yeast expression vector pYSOD-H-T8. MODES FOR CARRYING OUT THE INVENTION A. Definitions The term "SOD" intends a polypeptide having the amino acid sequence of a native intracellular superoxide dismutase and fragments, analogs, or muteins thereof having substantially homologous amino acid sequences thereto which may differ in one or more amino acid substitutions, additions or deletions (other than those directed by the present invention) but still retain the enzymatic activity of the native superoxide dismutase. Examples of such analogs are those described in commonly owned copending U.S. application Ser. No. 003578, filed Jan. 15, 1987. Polymers of SOD, such as those described in said U.S. Ser. No. 026,143, the disclosure of which is incorporated herein by reference, are intended to be included within the term. The term also encompasses SOD of various mammalian species. Human SOD is preferred for use in humans. Human Cu/Zn SOD and human Mn SOD are preferred species of SOD for modification in accordance with the present invention. The term "substantially homologous", as used above, intends at least about 75% identity, more usually at least about 85% identity, in amino acid sequence. A "replicon" is any genetic element (e.g., a plasmid, a chromosome, a virus) that behaves as an autonomous unit of polynucleotide replication within a cell; i.e., capable of replication under its own control. A "vector" is a replicon in which another polynucleotide segment is attached, so as to bring about the replication and/or expression of the attached segment. An "expression vector" refers to a vector capable of autonomous replication or integration and contains control sequences which direct the transcription and translation of the SOD analog DNA in an appropriate host. A "coding sequence" is a polynucleotide sequence which is transcribed and/or translated into a polypeptide. A "promoter sequence" is a DNA regulatory region capable of binding RNA polymerase and initiating transcription of a downstream (i.e., in the 3' direction) coding sequence. A coding sequence is "under the control" of the promoter sequence in a cell when transcription of the coding sequence results from the binding of RNA polymerase to the promoter sequence; translation of the resulting mRNA then results in the polypeptide encoded within the coding sequence. "Operably linked" refers to a juxtaposition wherein the components are configured so as to perform their usual function. Thus, control sequences operably linked to a coding sequence are capable of effecting the expression of the coding sequence. "Control sequences" refers to those sequences which control the transcription and/or translation of the coding sequence(s); these may include, but are not limited to, promoter sequences, transcriptional initiation and termination sequences, and translational initiation and termination sequences. In addition, "control sequences" refers to sequences which control the processing of the polypeptide encoded within the coding sequence; these may include, but are not limited to sequences controlling secretion, protease cleavage, and glycosylation of the polypeptide. "Transformation" is the insertion of an exogenous polynucleotide into a host cell. The exogenous polynucleotide may be maintained as a plasmid, or alternatively, may be integrated within the host genome. B. Characterization of SOD Analogs The amino acid sequence of the SOD analogs of this invention comprise the amino acid sequence of SOD altered via amino acid substitution, deletion, addition, or combinations thereof to include one or more heterologous peptide domains that provide the analog with the ability to bind to a moiety that localizes at or is local to a body site (e.g., the endothelial wall to which a hemostatic fibrin plug adheres) at which SOD therapy is desired. The binding activity of these analogs lessens the likelihood of their being cleared from circulation. Accordingly the corporeal half-lives of the analogs will typically be greater than native SOD and the concentration of analog at the desired site maintained at higher levels relative to native SOD. The moiety to which the analog is capable of binding via the domain(s) depends upon the nature of the domains and maybe, for example, cells such as phagocytes (macrophages, neutrophils), fibroblasts and endothelial cells, noncellular bodies such as platelets, or other proteinaceous or nonproteinaceous molecules such as glycosaminoglycans (heparin), fibrin, and thrombin. In some instances these moieties localize at sites of desired SOD therapy (e.g., platelets, neutrophils) or are cells that are local to such a site (e.g., endothelial cells). The nature and location of the alteration is such that the domain(s) is(are) available to interact with and bind to such moieties but not destroy the superoxide dismutase activity of the analog. Accordingly, the domains will be positioned at a location that is exposed in the tertiary structure of native SOD, such as a hydrophilic loop or the amino or carboxy termini, and their size, charge, hydrophilicity/hydrophobicity, will be such as to not alter the molecule (e.g., by changing its tertiary structure or charge distribution) in a manner that eliminates superoxide dismutase activity. The domain may include innocuous additional amino acid modifications beyond those that are crucial for binding activity. These additional modifications may serve a spacer function or otherwise serve to enhance the accessibility of the domain to the moiety or maintain the enzymatic activity of the analog. Normally the number of amino acid alterations directed by the invention will not exceed about 40, usually not more than about 30, and preferably not more than about 20. Representative domains are those described in the Background section, supra. In addition, suitable domains that provide binding activity may be identified by making random amino acid alterations at selected sites (e.g, the hydrophilic loops or amino or carboxy termini) in the native SOD sequence and then screening the resulting analogs for enzymatic activity and binding activity. Preferred domains are the RGDX tetrapeptide (Nature (1984) 309:30 and U.S. Pat. No. 4,578,079), the RGDX tetrapeptide with up to about a total of 15 to 20 flanking residues (on the carboxy and/or amino terminal side of the tetrapeptide), the decapeptide LGGAKQAGDV which is found at the carboxy terminus of fibrinogen, and that decapeptide with up to a total of about 10 flanking residues (on the carboxy and/or amino terminal side) of the decapeptide found in the native fibrinogen sequence. "X" in RGDX represents an amino acid that does not eliminate the binding properties of the domain. It should be appreciated that many of the possible analogs that may be made by incorporating the domains described in the Background section into SOD or by making random alterations in the SOD sequence will either lack enzymatic activity and/or lack the desired binding activity and thus not be within the invention. Those analogs falling within the invention may be identified by routine screening for enzymatic activity and binding activity. Enzymatic activity may be assayed by the pyrogallol assay and binding activity (depending upon the target moiety) according to the various art assays used to identify the domains described in the Background section (e.g., PNAS (1981) 78:2403-2406 and Nature (1984) 309:30-33). The N-terminus of the analog may be acetylated (as in native human Cu/Zn SOD) or lack acetylation depending upon the organism in which the analog is produced. Bacterially produced analog will lack such acetylation whereas analog produced in yeast using the procedures described in EPA 0138111 are so acetylated. Analogs made in mammalian cells will also be acetylated. Analogs having such acetylation are preferred. Similarly, the analog may be glycosylated or unglycosylated depending upon the organism and signaling sequence with which it is produced. C. Synthesis of SOD Analogs Genes encoding the analogs of human Cu/Zn SOD may be made via oligonucleotide synthesis and ligation, site directed mutagenesis of the DNA sequences shown in FIG. 1 and/or by insertion of synthetic DNA fragments that encode the desired amino acid modifications into a DNA sequence encoding human Cu/Zn SOD. Genes encoding analogs of other SODs, such as Mn SOD, may be made by similar procedures. Site directed mutagenesis techniques are well known in the art. See for instance, Smith and Gilliam in Genetic Engineering Principles and Methods, Plenum press (1981) 3:1-32; Zoller and Smith, Nucleic Acids Res. (1982) 10:6487-6500; and Brake et al, Proc. Natl. Acad. Sci. U.S.A. (1984) 81:4642-4646. The mutant genes may be inserted into suitable prokaryotic or eukaryotic vectors, the resulting expression vectors incorporated into suitable host organisms or cells, the recombinant organism or cell grown under conditions that result in expression of the mutant gene, and the resulting analog isolated from the host or, if secreted, from the growth medium using the same techniques as are described in said EPA 0138111 to produce recombinant human Cu/Zn SOD. The disclosure of that EPA is incorporated herein by reference. The metal ions required for enzymatic activity may be provided by growing the recombinant hosts in medium supplemented with the ion(s) or by dialyzing a solution of the analog against a solution containing the ions. In creating an expression vector, the mutant sequence is located in the vector with the appropriate control DNA sequences, which include a promoter, a ribosomal binding site, and transcriptional and translational stop codons. The positioning and orientation of the coding sequence with respect to the control sequences is such that the coding sequence is transcribed under the control of the control sequences. In addition to control sequence, it may be desirable to add regulatory sequences which allow for regulation of the expression of the hSOD analog gene relative to the growth of the host cell. D. Formulation and Use of SOD Analogs The SOD analogs of the invention may be used for the same purposes as SOD. The analogs may be used in human or veterinary medicine to treat (i.e., cure, alleviate or prevent) a variety of conditions. They are useful as antiinflammatory agents, chemopreventive agents to prevent oncogenesis and tumor promotion, protective agents to reduce cytotoxic and cardiotoxic effects of anticancer drugs or protect ischemic tissue. The treatment of medical conditions with SOD is referred to as "SOD therapy" Like native SOD, the analogs catalyze the dismutation of superoxide radicals to hydrogen peroxide and molecular oxygen and may thus be used to reduce perfusion injury following ischemia, prolong the viability of excised isolated organ transplants, reduce injury on reperfusion following organ transplant or spinal cord ischemia, reduce cardiac infarct size, reduce spinal cord injury and treat bronchial pulmonary dysplasia. For therapeutic medical applications the analogs may be administered orally or parenterally to individuals in various dosage forms such as tablets, capsules and injectables. When used to treat tissues in vitro the analog will be added to the perfusion or culture medium. The analog may be administered neat or admixed in effective amounts with pharmaceutically acceptable solid, semisolid or liquid vehicles such as albumins, globulins, dextran, Ficoll polymers, sugars, starches and liposomes. Preferably the SOD analog is conveniently stored lyophilized with sugar, usually sucrose, usually in a ratio of 1:2 w/w. The lyophilized enzyme is conveniently reconstituted in a suitable diluent for the particular application. For example, to treat inflammatory joint disease the SOD analog may be reconstituted in physiologic saline in a volume convenient for intraarticular administration. The dose of SOD analog administered to an individual will depend upon the nature of the individual being treated, the mode of treatment and the condition being treated. In general the amount administered must be sufficient to provide an enzymatically effective amount of the mutein at the desired site of treatment. In this regard, when the analog is administered systemically, larger doses will typically be required than when the analog is administered locally at the site that requires treatment. By way of example, human patients having inflammatory joint disease are treated by a weekly intraarticular injection into a joint afflicted with the disease of a solution having SOD analog in a suitable diluent in an amount effective to reduce inflammation, usually 1 to 10 mg, more usually 2 to 6 mg. The injections are given weekly for a period of time sufficient to reduce inflammation, usually for 2 to 8 weeks, more usually for 4 to 6 weeks. When used to minimize post-ischemic tissue damage the human patient is administered 10 mg to 1,000 mg, more usually 50 mg to 500 mg of SOD analog in a suitable diluent during the ischemic reaction. When the patient suffers ischemia due to a disease the solution is administered intravenously or intraarterially as a bolus dosage or a continuous infusion. In such situations, the SOD analog may be administered in conjunction with fibrinolytic agents such as urokinase, streptokinase or tissue plasminogen activator (tPA). When ischemia damage is due to a surgical procedure, SOD analog is administered during surgery. This application finds particular use in organ transplant surgery where SOD is preferably administered prior to reirrigation of the organ and is also useful in any other surgery where bloodflow to an organ is interrupted, such as open heart surgery. F. Examples The invention is further exemplified by the following examples. These examples are not intended to limit the invention in any manner. EXAMPLE 1: CONSTRUCTION OF EXPRESSION VECTORS FOR PRODUCING SOD-AS-T-2 This example describes the construction of expression vectors for producing a SOD analog that has four amino acid substitutions located in loop II and two amino acid deletions (see FIG. 2). The substitutions were as follows (single letter residue designations followed by residue position number (native Cu/Zn numbering); - indicates a deletion). ______________________________________ Native Sequence K23 E24 S25 N26 G27 P28 Analog Sequence R G D -- -- T ______________________________________ The analog is designated SOD-AS-T-2 and the bacterial and yeast expression vectors used to produce the analog are designated pSOD-AS-T-2 and pYSOD-AS-T-2 respectively. The constructions of plasmids pSOD-AS-T-2 and pYSOD-AS-T-2 are depicted in FIG. 3. The ampicillin-resistant plasmid p6610SC4 is prepared by inserting the gene segment shown in FIG. 1 between the NcoI and SalI sites of plasmid pNco5AHSODm, which is described in commonly owned copending U.S. patent application Ser. No. 918,534, filed Oct. 14, 1986, the disclosure of which is incorporated herein by reference. A synthetic gene segment (FIG. 4) prepared from synthetic oligomers designated T-2(u)(78) and T-2(1)(82) by phosphorylating individual oligomers and annealing them (by slow cooling of an equimolar solution from 70.degree. to 25.degree. C.), was inserted between the ApaI and StuI sites of p6610SC4 to yield plasmid pSOD-AS-T-2. Plasmid pSOD-AS-T-2 was then treated with NcoI and SalI and the resulting digest was ligated with the kanamycin-resistant, ampicillin-sensitive vector, pPGAPXSSB-bovine which had been digested with NcoI and SalI and treated with alkaline phosphatase. Following ligation and transformation, plasmid pPGAPXSSB-SOD-AS-T-2 was selected on kanamycin. (The construction of pPGAPXSSB-bovine used above had been prepared previously as follows: between the NcoI and SalI sites of pPGAPXSSHSODm [described in said U.S. Ser. No. 918,534] was inserted a segment encoding bovine Cu/Zn SOD. Kanamycin resistance was then conferred by inserting at the PstI site the approximately 1200 bp fragment carrying the kanamycin-resistance element obtained from a PstI digest of PUC-4K [Pharmacia]). A SacI digest of pPGAPXSSB-SOD-AS-T-2 was then ligated with a phosphatase-treated SacI digest of the ampicillin-resistant vector pCl/lXSS (described in said U.S. Ser. No. 918,534). The resulting plasmid, pYSOD-AS-T-2, was selected on ampicillin. EXAMPLE 2: CONSTRUCTION OF EXPRESSION VECTORS FOR PRODUCING SOD-AS-T-8 This example describes the preparation of expression vectors for producing a SOD analog that has a C-terminal fibrinogen adhesive domain extension. The sequence of the extension was as follows: ______________________________________ Native G150 I151 A152 Q153 Sequence Analog G I A Q GQQHHLGGAKQAGDV Sequence ______________________________________ In the extension GQQHH is a fibrinogen-derived spacer sequence and the remaining decapeptide is the adhesive domain. This analog is designated SOD-AS-T-8 and the expression plasmids used to produce it are designated pSOD-AS-T-8 for bacteria and pYSOD-AS-T-8 for yeast. The construction of plasmid pYSOD-AS-T-8 is depicted in FIG. 5. A gene segment (FIG. 6) prepared from synthetic oligomers designated T-8(u)(87) and T-8(1)(87) by phosphorylating individual oligomers and annealing them (by slow cooling of an equimolar solution from 70.degree. to 25.degree. C.), was inserted between the BamHI and SalI sites of p6610SC4 to yield plasmid pSOD-AS-T-8. Plasmid pSOD-AS-T-8 was then treated with NcoI and SalI and the resulting digest was ligated with the kanamycin-resistant, ampicillin-sensitive vector, pPGAPXSSB-bovine, which had first been treated with NcoI and SalI and the alkaline phosphatase. Following transformation, plasmid pPGAPXSSB-SOD-AS-T-8 was selected on kanamycin. A SacI digest of pPGAPXSSB-SOD-AS-T-8 was then ligated with phosphatase-treated SacI digest of the ampicillin-resistant vector, pC1/1XSS. The resulting plasmid pYSOD-AS-T-8 was selected on ampicillin. EXAMPLE 3: CONSTRUCTION OF EXPRESSION VECTOR FOR PRODUCING SOD-H-T8 This example describes the preparation of a yeast expression vector for producing an analog of a SOD polymer that has the fibrinogen adhesive domain extension described in Example 2. This analog is designated SOD-H-T8 and the expression plasmid used to produce it is designated pYSOD-H-T8. Plasmid pPGAPSODHA1-met (described in U.S. patent application Ser. No. 026,143, filed Mar. 16, 1987), was digested with ApaI and SalI and then treated with alkaline phosphatase. The larger vector fragment was then gel-isolated. Also prepared was an ApaI-SalI cassette, carrying a portion of the gene coding hSOD-AS-T-8, by digestion of pYSOD-AS-T-8 with ApaI and SalI, followed by gel-isolation of the ca. 500 bp fragment. This fragment was cloned into the vector described above to yield pPGAPSOD-H-T8. Plasmid pPGAPSOD-H-T8 was then partially digested with BamHI and the ca. 2443 bp gel-isolated fragment was cloned into a vector which had been derived from pC1/1 by BamHI digestion and treatment with alkaline phosphatase. Plasmid pYSOD-H-T8 was obtained. EXAMPLE 4: EXPRESSION OF SOD-AS-T2, SOD-AS-T-8 AND SOD-H-T8 E. coli strain MC1061 was transformed with plasmids pSOD-AS-T-2 or pSOD-AS-T-8 and selected on ampicillin. Transformants were then grown overnight at 37.degree. C. in 1.5 ml of L-broth containing 100 mg/ml of ampicillin and 1.0 mM CuSO.sub.4. To the cell pellet obtained by centrifugation was then added 60 ul of lysis buffer (50 mM Tris, pH 8.0, 1.0 mM phenylmethylsulfonyl fluoride, 2.0 mM CuSO.sub.4) and 50 ul of glass beads. The mixture was vortexed 10 sec and shaken (30 min, Eppendorf Mixer 5432). Twenty ul of the supernatant obtained by centrifugation (7 min) was mixed with 7 ul of 6.times.sample buffer (30% glycerol and dyes), loaded on a 10% polyacrylamide gel and electrophoresed. Gel staining for enzymatic activity was then performed according to Beauchamp and Fridovich (Analyt. Biochem. (1971) 44:276-187). Both are active. S. cerevesiae, strain PO17, was transformed with pYSOD-AS-T-2, pYSOD-AS-T-8 or pYSOD-H-T8. Transformants were grown and assayed for intracellular recombinant SOD activity as described in EPA 0138111. Each analog exhibited enzymatic activity. Ten liters of cell culture of the above yeast transformants were grown. Cells were lysed, and SOD-AS-T-2, SOD-AS-T-8 and SOD-H-T8 were purified as described for recombinant Cu/Zn SOD in said EPA 0131811. EXAMPLE 5: IN VITRO PLATELET BINDING ASSAY The ability of an analog to bind to platelets may be determined as follows. Three-tenths mg to 30 mg of test SOD analog or rhSOD (recombinant human Cu/Zn SOD) is added to 1.0 ml of heparinized or unheparinized blood and to 1.0 ml of plasma fractions prepared from heparinized and unheparinized blood. After 15 min incubation, the whole blood is centrifuged and SOD activity of the supernatant is determined (pyrogallol assay). Enzymatic activity is also determined for plasma fractions to which SOD or its analogs is similarly added. A decrease in the ratio of enzymatic activity in the whole blood supernatant vs treated plasma compared to the ratio derived from rhSOD-treated fractions (i.e., the control) reflects an increase in platelet binding of the test analog over that of rhSOD. In preliminary tests using this technique, SOD-AS-T-2 exhibited a decrease in said ratio relative to rhSOD, whereas SOD-AS-T-8 exhibited a ratio approximately the same as rhSOD. In addition to SOD-AS-T-2, SOD-AS-T-8, and SOD-H-T8 applicants have attempted to prepare or have prepared other SOD analogs in bacteria that included adhesive peptide signals but did not exhibit enzymatic activity. Some of these analogs are reported in the table below. __________________________________________________________________________ Modification Location Sequence __________________________________________________________________________ Loop III Wild: G37 L38 T39 E40 G41 L42 Analog: RGD (fibronectin insertion) Analog: GRGDS (fibronectin insertion) Greek key Loop Wild: L106 S107 G108 D109 H110 C111 Analog: R C-Terminus Wild: G150 I151 A152 Q153 Analog: " " " " GQQHHL-GYAVTGRGDSPASSKPIS (fibronectin extension using its GRGDS complete loop and a tolerated fibrinogen spacer) C-Terminus Wild: G150 I151 A152 Q153 Analog: " V C G PGLWERQAREHSERKKRRRESECKAA (C-terminal extension with EC-SOD tail and 3 "internal" Cu/Zn SOD residues altered) Analog: " I A Q GQQHHLCVVGVCGPGLWERQAR- EHSERKKRRRESECKAA (a longer EC-SOD tail including all 3 Cys with a fibrinogen spacer; "internal" amino acids unaltered) __________________________________________________________________________ Modifications of the above-described modes for carrying out the invention that are obvious to those of skill in the fields of protein chemistry, genetic engineering, pharmaceuticals, medicine and related fields are intended to be within the scope of the following claims. * * * * *


text:
Dutch bank ING is to cut 1700 jobs and spend EUR200 million to simplify and upgrade its IT systems over the next three years.
Swipp, a mobile payments service owned by a consortium of Danish banks, has acquired Paii, a rival outfit formed by a group of telcos.
In its latest foray into the commerce sphere, Twitter is testing a feature that lets users add discounts from advertisers on the social network to their payment cards.
Paylib, a PayPal-style online payment system set up last year by French banks, is extending its reach thanks to the addition of Crédit Agricole as a member and a deal with MasterCard that will let people use the service abroad.
The FIX trading community has agreed a set of best practices for use of the messaging protocol for the exchange of pre-trade information in the bond market, as banks and asset managers work together to overcome a liquidity shortage in fixed income trading.
NAB has decommissioned 37 legacy servers that supported its old credit risk engine, following the successful roll-out of a new analytics layer as part of the Australian bank's NextGen programme.
Half of Silicon Valley may be bidding to make it a relic of the past, but the old fashioned leather wallet is getting a new lease of life through a high-tech makeover.
A man spent nearly five hours trapped inside a bank branch yesterday after a technology failure locked the door on him.
The Bank of England has appointed Deloitte to conduct an independent review of the ten-hour breakdown in the operation of the UK's high value payments system, Chaps, last month.
Goldman Sachs has led a $15 million investment round in Kensho, a startup that is seeking to supplant human equity analysts with intelligent big data mining bots.
£300K + package with no upper limitLondon based with substantial travel in the Region
Competitive base, bonus, full benefitsAnywhere, UK (Europe Considered)
to £85k base, double OTE, benefitsLondon, UK
© Finextra Research 2014

subset: commoncrawl


text:
2.4GHz Aircraft Receivers
Great Planes TR624 2.4GHZ 6 ch. Rx
No. 705981$19.99
Out of stock
This is a Great Planes Tactic TR624 6-Channel SLT 2.4GHz Receiver. This 2.4GHz receiver is compatible with Tactic TTX404 and TTX600 stick transmitters. Features FHSS 2.4GHz technology and built-in bind button with red LED status indicator.Learn More
Airtronics RX60 6-ch 2.4G Park Flyer Receiver - FHSS-1 Short Range
No. 468516$29.99
The RX60 (92664) 6-Channel 2.4GHz FHSS-1 Park Flyer Receiver is a small, lightweight, short-range receiver that is compatible with Airtronics RDS and SD series transmitters. Also compatible with the Stylus 2.4GHz FHSS-1 Module. This receiver is specifically designed for lightweight foamies and small 180 to 250 size helicopters. It's perfect for indoor flyers and small park flyers!Learn More
Hitec/RCD Minima 6E 6-Ch 2.4G Parkflyer Rx
No. 759865$29.99
Out of stock
This is a Hitec Minima 6S 6-Channel 2.4GHz AFHSS Park-Flyer Receiver. The new Minima's wide range operation from 4.8 to 8.4 volts along with the low current consumption makes this receiver a must have for park flying.Learn More
Hobby People Receiver - MR-600 2.4G 6-Ch (For MT600 tx)
No. 117205$34.99
Out of stock
This is an HP Model MR-600 6-Channel 2.4GHz Receiver. The MR-600 is used with the HP Model's MT-600 transmitterLearn More
HP-PRT Receiver Board - Micro SuperCub
No. 161829$34.99
Out of stock
Hitec/RCD Maxima 6 Receiver 2.4G
No. 759187
Regular Price: $44.99
Special Price: $36.99
This is a Hitec Maxima 6 6-Channel 2.4GHz Full-Range AFHSS Micro Receiver. The Maxima 6 is our 6-channel, high response, low latency micro receiver, designed to work with all Hitec Generation 2 Adaptive Frequency Hopping Spread Spectrum Technology radios and our digital servo line.Learn More
Hitec/RCD Minima 6T 6-Ch Top Port 2.4G Micro Rx
No. 759870$38.99
This is a Hitec Minima 6T 6-Channel 2.4GHz AFHSS Micro Receiver. Utilizing Hitec's advanced 2.4GHz AFHSS technology, the Minima 6T full-range micro receiver is an excellent choice for modelers flying smaller aircraft.Learn More
HP-PRT Receiver - P-51D & Others 2.4G (see 117205)
No. 161703$39.99This is the HP-PRT 2.4G Receiver replacement part for Hobby People P-51D Learn More
Hitec/RCD Minima 6E 6-Ch End Port 2.4G Micro Rx
No. 759862$42.99
This is a Hitec Minima 6E 6-Channel 2.4GHz AFHSS Micro Receiver. Utilizing our advanced 2.4GHz AFHSS technology, our new full-range micro receiver, the 6E is the excellent choice for modelers flying smaller aircraft.Learn More


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Deutsch Aktuell will engage your students and launch them on a path to life-long fluency. This 3-level German program focuses on experiences and activities involving German, Austrian, and Swiss teenagers and adults. We created Deutsch Aktuell with the most up-to-date research in teaching and learning German, and our program is intended for students with varying abilities, backgrounds, interests, and learning styles. Multiplatform eBooks that work on any device, video-based teaching tools, authentic cultural videos, ACTFL-aligned proficiency assessments, and much more—it's all here waiting to be discovered!Buy It Now!
Through a long-term collaborative partnership with the University of Minnesota's Institute for Design Innovation (IDI) we are building, integrating, and researching the future of fluency. Passport® builds upon and extends research-based language learning platforms created by the IDI, leveraging EMC Publishing's world language instructional content in an easy-to-use environment designed to drive educator effectiveness and student fluency. Students will discover languages and cultures, expand their knowledge beyond the textbook and written test, and perform what they've learned within a portfolio-style environment to achieve lasting proficiency.
Through our partnership with the University of Minnesota's Institute for Design Innovation (IDI), we are now offering award-winning, research-based learning platforms that enhance your face-to-face, blended, or online classroom.
Avenue™ is a simple, yet powerful e-assessment platform where your students build portfolios of their spoken performances. Educators can create custom tasks or build tasks based on EMC's rich, pre-loaded library of media.Learn more about Avenue
Flipgrid™ is a video-based discussion environment where students respond to short, teacher-created questions. Flipgrid brings the back row to the front in your classroom.Learn more about Flipgrid
Our eBooks connect students with the language in and out of the classroom. With a touch of the finger, students access every page as well as all of the audio (vocabulary presentations, dialogues and activities). Students also have all of the video resources at their fingertips, both dialogue and continuous storyline videos.
Our eBooks are available for delivery on all laptops, desktops, and mobile devices including the iPad®. The best part is that you can have our multiplatform eBook for one low price!
Watch authentic culture come alive for your students as they immerse themselves in engaging and varied media: videos, news articles, and songs. i-Passport, i-Videos, and i-Songs bring cultural experiences into the classroom and into your students' lives.
Filmed on location in Berlin with professional actors and actresses, Treffpunkt Berlin features a continuous, intriguing story line woven throughout the three-level video series. Your students will cling to the edge of their seats as each episode of this unique video series unfolds! Can love blossom at the hottest café in Berlin? Stay tuned…
The series of ten episodes (Folgen) feature various locations within the capital city of Berlin with professional actors. In each five- to six-minute episode, students follow the everyday lives of four German teens.Watch an episode
Use EMC Language Proficiency Assessments (ELPAC) to measure your students' German language proficiency. Choose from multi-level online assessments in Reading, Listening, Writing, and Speaking that can be administered individually or as a battery. Developed with input from language teachers and school administrators, ELPAC assessments meet the highest standards for reliability while offering flexibility and ease in delivery.Learn more
EMC Publishing Launches Online Platform to Teach World Languages
Article via THE Journal
"EMC Publishing has launched Passport, an online environment for teaching and learning world languages. Passport (formerly EMCL) is designed to tap into the learning technologies that digital natives embrace and to increase students' fluency by allowing them to fully experience the language they are learning."
Click here to read the entire aricle.
EMC Publishing unveils immersive Spanish education program
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"EMC Publishing, a leader in print and online educational programs and a division of New Mountain Learning, announced the launch of its new immersive Spanish language proficiency program, ¡Qué chévere!. The new series, which offers five levels of Spanish instruction for middle school through high school students is available in print and digital format. It continues EMC Publishing's mission to increase world language fluency for the 21st century student."
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Most businesses have three things they can offer: price, product and service. It's rare that one business consistently offers all three. After more...Read More ->
I placed an order on the 8th of November and I'm a resident of Québec, and I received my order on the 14th! Just 6 days! I'm very Impressed...Read More ->


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Archived Content
The content on this page is provided for reference purposes only. This content has not been altered or updated since it was archived.
About FDA
2011-NCTR Research Highlights
January-March 2011
International Scientist Exchange Program 2011
Joint NCTR and CBER Workshop
NTP Pathology
NTP Technical Report Review Meeting
Long-Lasting Effects of Pediatric Use of Ketamine Anesthesia
Tobacco Products Workshop
Next-Generation Sequencing (NGS)
On-Site Training
Microbes and Oil Spills
NCTR Strategic Planning
Posting of NCTR Studies with Potential Regulatory Impact and Questions from Public
Combinatorial Therapy Approach to Pancreatic Cancer Treatment
Society for Toxicology (SOT) Annual Meeting
OECD Genotoxicity Test Guidelines
MAQC-I Highlighted
Similarities in S. Heidelberg Isolates from Human and Food/Animal Sources
Multi-Scale Toxicology Initiative—March 15, 2011
Hepatotoxicity Special Interest Group Meeting—March 23-24, 2011
April-June 2011
Medical Countermeasures Workshop—March 29-30, 2011
MCBIOS 2011—April 1-2, 2011
Congratulations to NCTR scientist and MCBIOS Post Doc Award Winner Dr. Yan Li—April 2, 2011
Novel Algorithm to Identify Biomarkers of Susceptibility
National Toxicology Program (NTP) Technical Report Review—April 5, 2011
Glucosamine Efficacy and Toxicity
Nanotechnology and Health Care—April 6-9, 2011
NTP Board of Scientific Counselors—April 13, 2011
Epigenetics in Cancer Risk Assessment
American Society for Pharmacology and Experimental Therapeutics Scientific Program on Pharmacogenomics—April 13, 2011
National Institutes of Health (NIH)-Industry Roundtable—April 21-22, 2011
Urinary microRNAs as Biomarkers of Drug-Induced Liver Injury
Human Microbiome Conference—April 27-28, 2011
Antimicrobial Resistance in Salmonella enterica serovar Dublin
Technology Invented at NCTR for Rapid Bacterial Detection Being Further Validated at Local University
Leflunomide-Induced Hepatotoxicity
Detection of Rare Cancer Gene Mutations
Biomarkers of Nephrotoxicity—May 13, 2011
Regulatory Science Research Studies Reviewed—May 17-18, 2011
SmartTots and Pediatric Anesthesia Research—May 23, 2011
American Society for Microbiology Meeting—May 21-24, 2011
Bitter Orange Extracts and Developmental Toxicity
European Food Safety Assessments—May 30 to June 1, 2011
Toxicogenomic Models in Predictive Toxicology
Drug-Induced Hepatotoxicity in Pediatric Patients—June 8
Identification of Nephrotoxicity Biomarkers Using Toxicoproteomics—June 9
Meta-Analysis for Biomarker Identification
NCTR Article Selected as Editor's Choice
NIEHS Director Visits NCTR—June 21, 2011
July-September 2011
Public Health Impact Award—June 21-22
Antimicrobial Resistant Pseudomonas in Imported Retail Shrimp
Pig-a Genotoxicity Assay Validation
Strategic Planning for NIEHS—July 12-14
Detection of Mitochondrial Toxicity
Pediatric Inhalation Anesthetic-Induced Neuronal Damage
Identification of Biomarkers of Idiosyncratic Liver Toxicity
Genomic Biomarkers of Kidney Toxicity From Melamine and Cyanuric Acid Co-Exposure
Global Summit on Regulatory Science—August 11
NCTR Celebrates 40 Years of Service—August 12
Women's Health Research at NCTR—August 10
Science Advisory Board Site Visit—August 16-17
Reducing Salmonella in Egg and Poultry Production
Drugs of Abuse and Addiction—August 23-26
Surface Coating of Single-Walled Carbon Nanotubes Reduces Toxicity
EUROTOX 2011—August 28-31, 2011
The 13th Meeting of the MicroArray Quality Control (MAQC) Project—September 13-14
Medical Countermeasures Lecture
Visiting Speakers
Visiting Speakers-September 26-30
October-December 2011
Titanium Dioxide Exposure Induces Proteomic Alterations in Lymph Nodes
Mechanism for Combinatorial Therapy in Pancreatic Cancer Treatment
Metabolic Network for Bioremediation Applications
Environmental Mutagen Society Meeting—October 15-19
Fluoroquinolone-Resistant Salmonella Schwarzengrund from Imported Foods
South Central Chapter of the Society of Toxicology—October 27-29
NCTR Science Advisory Board Meeting—November 8-9
Regulatory Science Research Studies Reviewed—November 15-16
Rapid, High-Sensitivity Detection of E. coli O157
Urinary MicroRNA Profiles as Biomarkers for Hepatotoxicity
Joint FAO/WHO Expert Committee on Food Additives—November 7-17
Pharmacoproteomics and Toxicoproteomics
Scientific Panel on Contaminants in the Food Chain—November 29 - December 1
Improved Culture Method for Human Intestinal Microbiota
NTP Board of Scientific Counselors—December 15


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Have you ever substituted butter for shortening in your peanut blossoms?
Find a Conversation
Have you ever substituted butter for shortening in your peanut blossoms?
|Tue, 12-20-2011 - 11:04am
Anyone know if this will affect them? I googled the question and the answer I got was some recipes it's okay and some it's not.
|Tue, 12-20-2011 - 11:30am
I think it would be fine. I would chill the dough first or try to keep the butter very cold like when you make biscuits so it melts slower (should help everything rise better and be tender).
|Tue, 12-20-2011 - 2:02pm
I made peanut butter blossoms for the first time yesterday, and my recipe called for butter... maybe because I got it off the Land o' Lakes website? ;-) I don't mind using a little shortening sometimes, but butter is always better!
They turned out great!
|Tue, 12-20-2011 - 2:19pm
I've not made them in years.... if they're the ones I'm thinking of... peanut butter cookie with a chocolate kiss mashed in the middle? I don't care for that big hunk of chocolate so I used red and green peanut M&M's to mash down into them.... they were very festive! So... sorry candice, I'm no help.... I don't know that I'd give you advice about baking anyway since I suck at it!
|Tue, 12-20-2011 - 2:49pm
good idea about the m&m's Daisy!! I think they're cute and easy, but I don't care to eat them either! lol
|Tue, 12-20-2011 - 4:02pm
I did get a lot of compliments on them ... They were a perfect size to fill in a cookie plate for the neighbors too... Made the whole pile look very festive. I think I remember cutting down the baking time and making them smaller .... like bite-sized.
|Tue, 12-20-2011 - 4:22pm
My recipe doesn't call for shortening either. I use butter in almost all of my cookies.
|Tue, 12-20-2011 - 4:48pm
Okay, I checked the land o lakes website and the only difference is 2 T milk in my shortening recipe. Which makes sense since butter has water in it. I'm going with the butter recipe. I think what oil your recipe calls for depends on how old your recipe is. This is the only recipe I have that calls for shortening and I usually buy it and throw the rest away because I don't use shortening for anything else all year. Thanks for the help, guys!


text:
2 Tickets to BBC music awards.. SOLD OUT first time event. One Direction, Calvin Harris, Coldplay..
2 Tickets to this incredible event. Many huge acts playing, including One Direction, Coldplay, Ed Sheeran, Clean Bandit, Paloma Faith and Calvin Harris. Presented by Chris Evens and Fearne Cotton at Earls Court London. Please call if you are in
8 miles | Wantage, Oxfordshire£195 7 days ago


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atmos x Ewing 33 Hi – Preview by John Kim 0 Comments
How much when dey drop on da 30th?
January 4, 2013 BY Brendan Dunne / 12
It looks like the Ewing 33 Hi will really run the gamut as far as paying tribute to Patrick Ewings various stops on his way to the NBA. Along with the 'Jamaica' pair that's planned, there is also an Ewing 33 Hi 'Georgetown' colorway in the works that should satisfy the fans looking for a tie in to his NCAA days. The Hoyas look goes heavy on the suede and ends up as perhaps the most muted of releases we've seen from the revived Ewing Athletics to date. Click through for the full look and watch for these soon at spots like Titolo.
Filed under: Basketball Upcoming Sneakers
How much when dey drop on da 30th?
I like em. Haven't been able to find any of the cw's in a 13 so far though =/
Ya'll dont get so excited..its cool I guess,bt dont have nuthin on the question georgetown cw 2be honest
colors to boring
stupid sexy. please take me now, my body is ready.
I'm in love, these are amazing
Tooooo dope
Crazy dope! Must have-So OG.
the Jamaica ones are nice these are overdoing it imo
@NewSneakerScent Peeped the Georgetown Questions... no new ground there and kind boring.. in my eyes, these are better. Ewing Athletics definitely doing its thing. Got me thinking about the Jamaica joints and I ain't even Jamaican. LOL
@IgotthatFIRE True dat jamaican joints r dope
atmos x Ewing 33 Hi – Preview by John Kim 0 Comments
Ewing 33 Hi "Dandelion" Releasing In December by Darren Griffin 0 Comments
Ewing Athletics Rogue – Release Date by Patrick Johnson 0 Comments
Ewing Athletics Brings Back A 1991 PE by Brendan Dunne 1 Comments
Ewing 33 Hi – Black – White – Gum by Brendan Dunne 0 Comments


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Gifts for Golfers
From the hottest new clubs to game-improvement technology, we've selected outstanding new products that will warm the hearts – and fill the bags – of every golfer on your list.Launch Gallery » – Nicholas Hegel McClelland
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Cars > Events > ENWICC Meeting
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About ENWICC Meeting
Regular meertings are held on the thrid Wednesday of every month alternating between Omaha and Lincoln. Officers and representatives of member organizations are asked to sign in before the meeting, guests are always welcome. Meeting begin at 7:30 PM, many arrive early for dinner.
Date and Time
Wed Dec 19, 2007 from 7:30 pm – 8:30 pm (CST)
Location and MapTangier Temple
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G.O.O.D. Music's Kid Cudi recently discussed his close-knit bond with Kanye West's star-studded team and why he feels the most comfortable around the regional crew.
Cudder credited G.O.O.D. Music artists like Big Sean and Q-Tip for helping him get into his comfort zone.
"It's the only time where I feel like I'm around people that understand me. I felt like an orphan before then. It's good for me, man. I don't really click well with people. I don't know what it is, but everybody in this family, I click with. From 2 Chainz to Big Sean to Q-Tip. I've been seeing Q-Tip since I've started in this business and he's always had my back. You can look online and check. I'm just really happy that everybody embraced me and they don't think I'm too much of a nut job. When you work with your family, it's love behind every record and you want everybody to win. I love hearing Pusha rap. I love hearing his raps, man. It will never get old. I've told him that. And that's the exciting thing. I'm around people that I'm a fan of, that I grew up on and shit, and I can watch them create and do what they do and I can contribute and be a part of history. It's wild." (Complex)
Last May, R&B singer Teyana Taylor credited G.O.O.D. Music's team for inspiring her decision to ink a deal.
"This is the second go 'round for me, and hopefully, the second time's the charm," the 21-year-old continued. "I signed to Star Trak with Pharrell when I was 15, and now I'm at a new chapter in my life where I'm signed to G.O.O.D. Music, and I'm blessed and happy to be part of the team." The rapper, singer, writer and actress said the new deal will definitely improve her worth ethic. "Being signed to G.O.O.D. Music/Def Jam has opened more doors now that I finally have a team behind me that can push me to work harder," she said. (MTV)
G.O.O.D. Music's Cyhi The Prynce recently discussed his role in the growing crew.
"A lot of people don't know my role. A lot of people don't know that Big Sean was signed five years before he actually broke. But what we do is build on foundation organically because it doesn't matter if [Kanye] is on our song or not, we can still promote our music. I can still put out a mixtape and everybody receives it. That's the foundation I built so… And at the same time I do a lot of creative work that people don't see. I play my position, then when it's time for me to do what I do, then I do." (The Juice)
Despite his association, 2 Chainz recently denied reports which claimed he inked to G.O.O.D. Music.
"He just said I'm good, like I'm ill. But we was talking and I think I was jeopardizing my brand sometimes by doing the homeboy special," Chainz said, referring to his knack for hooking artists up with guest features. "So I think he felt like we should just put that out there that we ain't doing no more of that — I would have done almost anything a couple months ago, and it was all about really reaching out because I still will, I'm still grounded, but it made sense for me to slow down a little bit being that I got an album coming out August 14th. I'm still working on that — I'm just trying to focus on 2 Chainz a little more." (Bootleg Kev)


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New Wild pre-deadline Master Plan
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Registered User
Join Date: Aug 2009
Posts: 3,627
vCash: 500
Originally Posted by
I wonder if Yeo's system is wearing down forwards not just over the game but through the season. Early on the Wild would be flying and aggressive and doing fine with scrubs on D, but later in the year the forwards just aren't winning those battles and being aggressive. Then the team gets stuck in their end, takes bad penalties, and gives up goals far more often.
Getting younger next year should help quite a bit, but I'd have to think adding a stud defenseman in addition to Brodin would be a huge help for the team. To be able to get the puck out as well as defend properly under pressure rather than taking penalties and/or icing the puck.
i think our D has been the biggest issue in wearing down our forwards. when we were flying our D did a good job of getting the puck out thus focusing the attack in the offensive zone and letting our guys be the attackers. on our long losing slid (minus the few games we looked good) we've had trouble getting the puck out of the zone leaving our guys chasing after the puck and getting gassed, when you have a few of those shifts in a row it takes a lot out of you, when you combine that with some penalty filled games and being on the road a ton it all adds up and leaves a worn hockey player.
having some dman who can break up the play in our zone and get it out will help and Brodin is the guy who can do that, but it will take more then him to get it done.
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Quality, Affordable Web Design
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I have been proud to be involved with this project and seen it develop from idea to reality. Well done to all those involved - well deserving of Heritage Lottery funding. Kate Baugh, Gloucestershire Rural Community Council
If the number of enquiries we have had lately are anything to go by, the recession ha...
A New Member Joins The Voodoochilli Team
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El Regalo de Ícaro
New doors, new rituals.
On 10 and 11 of July at the Palacio de Carlos V+
On 15th, 16th and 17th of july in Teatre Principal.+
New doors, new rituals.
La Fura has designed 'Turn on the lights' to open the season of De Bijenkorf's Christmas on Dam Square
Turn on the Lights is an eminent visual and poetic act that combines kinetic images and vibrant sounds. It will represent the process of the inner search within the human being, the awareness about the process that, day after day, will help the human being to conceive the world with a
The mysterious structure of 'M.U.R.S.' will be erected by the promenade in West Kowloon, inviting the audience of Hong Kong to an amazing digital world.
The show, directed by Miki Espuma, will be based on a human net with around a hundred actors.
The first smartshow in history arrives in Molina de Segura on the 18th of October and in November will perform 3 shows in hong Kong
Director Àlex Ollé returns to the Opera de Lyon with the great challenge of the stage direction of his second adaptation of Wagner
Return the legend and the realism of this opera to the public through a few emotions that have been transformed since the time of Wagner, preserving the romantic feeling of the absolute as the composer saw in the sea.
The film will be subtitled in Italian and will take approximately 2 hours and 20 minutes, including an interval of 15 minutes.
The first smartshow history illustrates the most prominent features of the cities of the future, the coveted smart cities.
A video installation related to success and failure. Free electronic version based on The Soldier's Tale. Music from Igor Stravinsky. Texts by Charles-Ferdinand Ramuz.


text: 1000 pts How Can You Receive A Free Month Of Tanning? [QUIZ] <KVKI VIP Club Take the quiz to find out how you can receive a free month of dating! Sign in to Participate Category: Q & A Tags: local-expert-endless-summer-tanning Share on Facebook Share on Twitter More Leave a comment Send to a friend! Print this page Pin it! Reddit This! Share on Tumblr! More Ways To Get and Use Points Win a Trip To See Trans-Siberian Orchestra Live in Washington, DCKeurig Brewing SystemThanksgiving Gift CardToy Store Shopping Spree$100 GameStop Gift Card$100 Bass Pro Shops Gift Card


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At the upcoming LDI 2014 exhibition in Las Vegas, Clear-Com® will demonstrate its continued commitment in linking communication groups together with its latest intercom, signal transport and intercom connectivity (ICON) solutions. These new solutions can save users time and money, while making their workflows much more efficient.
Clear-Com will present the new LQ⢠Series, a new family of ICON devices for linking intercom and audio systems over IP networks. Visitors will also see the new FreeSpeak II⢠wireless intercom system, a DECT-based offering that operates in the license-free band 1.92 to 1.93 GHz. In addition, we will be showing ProGridâ¢, the synchronous, optical fiber transport solution for audio, intercom, video, and data.
As a low audio latency communication link, LQ Series can be used for natural intercom conversation, networked music performances and for audio signals that are transported between different facilities. Based on Clear-Com's patented I.V.Core® technology, the compact LQ throw-down devices enable connections of 2-wire partyline with call signaling and 4-wire audio over LAN, WAN or Internet IP infrastructures. LQ Series has a 2-wire (LQ-2W2) or 4-wire (LQ-4W2) option. The LQ-2W2 is both Clear-Com and RTS TW compatible. A maximum of six LQ IP interfaces can be linked together in any 2- or 4-wire combination.
The recent release of FreeSpeak II⢠places it as the preferred DECT-based, all-roaming wireless communication solution in the United States and Canada for live event, broadcast, sport production, industrial, military and government applications. Operating in the license-free 1.92 to 1.93 GHz band, FreeSpeak II has been demonstrating its advanced roaming capabilities across large-scale, multi-zone production areas.
The system supports up to 20 full-duplex wireless beltpacks and 10 antennas connected to one base station or fully integrated into the Clear-Com Eclipse HX digital matrix system. The base station has connections for two partylines and four 4-wires, including a dedicated SA output and program audio input. With the full-duplex 7kHz bandwidth, the digital âClear-Com Soundâ reduces ear fatigue after extended usage and delivers clear intelligibility of every word said into the system.
Clear-Com will also highlight ProGridâ¢, the highly resilient and scalable platform for carrying, distributing, and routing high capacity of audio, intercom and video signals, as well as control data, across long distances without compromising its performance, speed, or quality. ProGrid is based on the open AES3 and AES10 (MADI) standards, providing fiber-based transport, routing and format conversion with full management and diagnostic capabilities using the Optocore® and SANE technologies.
âWe are excited to confirm our commitment to the live event and live entertainment markets by showing off our latest innovations at LDI 2014,â said Michael Rucker, Director of SalesâNorth and South America at Clear-Com. âClear-Com has been a part of this vibrant market since the beginning. We are pleased to show our latest wired and wireless intercom systems as well as our innovative connectivity and infrastructure solutions. Setting up, managing and using our communication and transport products is quicker and easier than ever before, which allows users to concentrate on providing the best performance possible.â
The complete line of Clear-Comâs new and enhanced products will be available for demonstration at LDI 2014 on booth 1752.
Related Topics: Events, Government, Houses of Worship, Large Venue, New Products, News, Product Updates, Tradeshow News |


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It is November 12, and the off-season is young. Where does the Brewers' roster stand compared to their divisional competition? The only…
2014 NL SP Rankings: Brewers Improvement
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text:
POS & Payment Processing Articles
Global Online Purchase Intentions Have Doubled Since 2011
A Nielsen report states online purchase intentions around the world have doubled since 2011 for many durable and entertainment-related categories. Nearly half of global respondents intend to make an online purchase in the next six months in high-prominence categories including clothing (46 percent), and airline (48 percent) and hotel (44 percent) reservations.
EMV: Challenges And Opportunities For VARs
It's no surprise the "View From The Top: Leadership Panel" at this year's Retail Solutions Providers Association's RetailNOW included a discussion of EMV.
What MSPs Can Learn From Chick-fil-A
I love coming across quick, easy-to-follow advice for solutions providers. During a short presentation at the recently-held GFI MAX Customer Conference in Orlando, Tony Hayden, president of Sabre Networks, shared his thoughts on why an MSP should adopt many of the practices of restaurant chain Chick-fil-A. He believes the result would be a highly successful business. Here's what the restaurant does that can be applied to your business.
Retail, Grocery, And Hospitality IT News For VARs — September 15, 2014
In the news, The EMV Migration Forum launches a new online resource and plans a one-day workshop for VARs and other solutions providers. Also, card issuers are signing on to work with Apple Pay. In other news, OTAs will begin listing Wi-Fi speeds along with other information travelers can consider before they book, and the Payment Card Industry Security Standards Council (PCI SSC) has issued updated guidance on card-skimming prevention.
2015 Retail IT Spending Predicted to Surpass $190 Billion
IHL Report Foresees Unprecedented IT Growth For 2015.
Business Advice: Exhibit "Technology Humility"
It's easy for solutions providers to get caught thinking they're smarter and better than their customers. However, just because you have more IT knowledge than your customers, doesn't mean you're better. Have some humility. That was the advice of Jason Etheridge, president and CEO of Logic Speak, who spoke at the recently held GFI MAX Customer Conference in Orlando. During his presentation on technology humility, he provided a handful of tips for solutions providers...
Point Of Sale, Payment Processing, And Data Collection News From August 2014
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A new study released by RetailMeNot demonstrates how digital coupons are adapting to mobile and omni-channel commerce.


text:
You don't *have* to use RM - some network managers like it because it makes their day-to-day tasks easier (or so I'm led to believe).
Personally you can't beat a vanilla setup
Hello Everyone.
I would like to know if there is any training or any way i can test RM software on a network.
I have worked in a college for 5 years as a senior technician, and i am now working in the industry. I am thinking about getting a job back in the education sector, but most of the ones i see use RM on the computers and servers, i have not used this so it puts me at a disadvantaged as i am used to doing everything manually.
you someone point me to some good training info.
You don't *have* to use RM - some network managers like it because it makes their day-to-day tasks easier (or so I'm led to believe).
Personally you can't beat a vanilla setup
Where abouts you based as sure I can find someone for you to visit to talk about it.
Arguments about RM will go on for ever all I can say is my view and experience. Reasons we choose RM is mainly it free my time up to deal with what me a network manager should be doing which is strategic stuff, dealing with various external orgs I have to deal with and work associated, advising school how technology can be integrated into education environment. We havn't got time to implement a vanilla network.
imho it takes 8 weeks (approx a summer hols) for a vanilla network to embed and working. I have better use of my time than to do that.
But as said this my view and my experience.
As said let me know where abouts you are?
My argument to the LG was that a RM network would improve my golf handicap. They weren't impressed :-(
you pays your money you makes your choice!!
Nuff said i think.
so bossman what do you think of RM.
I have started as a technician in a school and we have CC3. I think its great and if you follow instructions and do things how you should without trying shortcuts then it seems to work fine for us. I love it.
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Dawes Discovery 201 bike, 21 shimano gears, 1 year old, minimum use, Kryptonite lock included
Dawes Discovery 201, graphite grey, 16 inch frame. 1 year old from new, minimum use. Side handles bars added for comfort (can be removed) New mud guards & pannier rack. Gears may need some fine tuning. Kryptonite series 2 lock included. Availabl


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"Think twice before working here "
- Comp & Benefits
- Work/Life Balance
- Senior Management
- Culture & Values
- Career Opportunities
I worked at TASER full-time (more than an year)
Hans Marrero is a great person if you get to meet him
All of the smart employees don't stay around very long. No loyalty between employees. No loyalty between employees and managers.. Mass lay-offs, weekly firings. Not to mention working with a product that by nature has many safety concerns.. that you will have to spin positive.. and it will leave you with many sleepless nights wondering..
find new gigs
49 Other Employee Reviews for TASER (View Most Recent)Sort: Rating Date
2 people found this helpful
"Great place to work, great leadership, but keep your nose to the grind stone. "
- Comp & Benefits
- Work/Life Balance
- Senior Management
- Career Opportunities
I worked at TASERPros
Good mission statement, the company really has a strong place in this world. The people who work there are very amicable, and stick together as a family. The work environment is relatively casual. You are on the cutting edge of emerging technologyCons
Compensation is way below market rate.Advice to ManagementAdvice
To pay better, you can afford it. And listen to your employees when they want to move.RecommendsApproves of CEO
"Mission "
- Comp & Benefits
- Work/Life Balance
- Senior Management
- Culture & Values
- Career Opportunities
I have been working at TASER full-time (more than an year)Pros
"TASER's mission is the end user, the law enforcement officer. TASER has effectively changed law enforcement by adding intermediate weapons, cameras, and technology that protects them, allows them to save more lives, and positively enhance the delivery of police service in their community. I'm proud to be a part of this mission," –Andy, Sales OpsCons
Well if you don't like technology, career opportunity, talent, innovation, individualism, motivation, excitement, sci-fi, self-management, open communication, working for an industry leader, educational opportunities, positive motivation, then you may not enjoy this employer.RecommendsPositive OutlookApproves of CEO


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Rosenbuschite rich pegmatite
Rosenbuschite rich pegmatite
Photo Copyright © Peter Andresen  - This image is copyrighted. Unauthorized reproduction prohibited.
Nepheline-syenite pegmatite vein rich in rosenbuschite. 3. May 2008.
This photo has been shown 655 times
Photo added: 3rd May 2008
This photo has been shown 655 times
Photo added: 3rd May 2008
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Locality Updated: Toluca meteorite, Jiquipilco (Xiquipilco), Mexico, MexicoFrom Lon Clay Hill, 27th Nov 2014 15:51:17


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Search results
No Easy Way to Figure a Shop's Sales Price
to back-up his reasoning. For 10 years, he owned and ran the Sports Garage in Boulder, Colorado, before ...
Posted February 1, 2010 in Retail News
Slashed Orders Hurt Mavic's Q1
sporting goods business entered 2009 under the same cloud of uncertainty that is oppressing almost all ...
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Paceline Products to Distribute AquaJoe
sports drink powder," Ohring said. "Our product will work with any powder and easily attaches to any cycling jersey, hydration pack, sports bottle, hydration belt as well as working with bottled ...
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Delta 7 Bike Working OT at OR
for the Mion Footwear booth," said Lester Muranaka, vice president of marketing for Delta 7 Sports ...
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The new web pages can be viewed at www.mtborahcustom.com (click on link), simply choose your sport ...
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Thule Recalls Select Podium Fit Kits
on the roadway. There have been no reported injuries. The Fit Kits involved were sold at bicycle, sporting ...
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women's participation in the sport and support grassroots programs like Velo Bella," said founder and CEO ...
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OR Winter Show Online Registration Open
attendees including CEOs, industry leaders, outdoor and winter sports manufacturers, 5,000+ retailers, ...
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The Bike Cooperative Hires Kevin Wren
Sports where he was responsible for the Blackburn, Rhode Gear and Vista Lite brands. Before that role, he ...
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Berghoff Oktoberfest (In Store Only)
Back to Products
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12 Pack of 12oz Bottles $27.98
Case of 2
12 Pack of 12oz Bottles $27.98
Case of 2
Item #810299
Size: 12oz
Type: Lager
Varietal: Oktoberfest
Country: United States
Region: Indiana
"...Sweet caramel malt aroma with hints of vanilla. Nice malty hit at the beginning, sweetness lingers, vanilla tones carry over from aroma...Finishes with a nice crisp hop snap. Decent velvety creamy mouthfeel..."
Reviewed by: Beeradvocate.com
Prices, promotions and availability may vary by store and online.
Point Amber Classic
"Pretty nice tasting beer from Stevens Point Brewery...There is a nice color and aroma to this and the mouthfeel is very balanced...Nothing amazing, but a nice session beer."
$12.99 / 12 Pack of 12oz Bottles
$25.98 / Case of 2
$25.98 / Case of 2
Point Octoberfest 12pk cans
"...Nice flavor that seems spot on for style. Malty, not exceedingly rich, yet heavy and bold enough. Good toastiness...Great with a lot of different types of food...Well done."
$12.99 / 12 Pack of 12oz Cans
$25.98 / Case of 2
$25.98 / Case of 2
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text: celebrity twitter Comments 7 You Won't Believe Who Was Mistaken for Daniel Radcliffe By Aislinn Shevlin Jun 13, 2013 Back 1 of 14 Next More More Slideshows On-Set Selfies, a Haircut, and a Wedding! WHAM, BAM, ALL-OUT GLAM: The Latest Looks From KStew, JLaw, & the Entire Mockingjay Cast! I Journeyed Into Snow's Great White Bathroom to Meet JLaw, Josh, Liam, Willow, Sam and All the Mockingjay Stars THAT YOU MIGHT LIVE FOREVER! Back Next more > Back Next more > Celebrity Monitor/MS_imageSPACE/Splash NewsCredit: You Won't Believe Who Was Mistaken for Daniel Radcliffe Topics: Celebs & Stuff Tags: twitter, slideshows, daniel radcliffe, celebs, tweets, celebrity tweets, celebrity twitter, celebrity twitter slideshow, jake johnson It's Raining Boys: Bracket Round 2 It's Raining Boys: Bracket Round 2 What's Your Psych Name? What's Your Psych Name? Related Posts twitter Who's Pregnant, and Who's Mad About Tabloid Lies? celebrity tweets Who Caused the Fight Between Drake and Chris? celebrity twitter On-Set Selfies, a Haircut, and a Wedding! Write your own comment! Hold up there partner! Before you comment on a post there's one more step. You'll have to choose a nickname to be displayed on your comment. Give 'er a shot below! Write your own comment! OR OR Please log in first Email Password Remember me Log in Create an account | Lost password ...or log in using


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If you own an existing business or are looking to start one, we can help. With over 7,875 businesses in the borough, our experienced advisors can provide support, advice, training and much more.
Contracts for a wide variety of works, services and supplies are available for tender each year in Lewisham Council.
In Lewisham you will find a wide range of office, retail and commercial space to suit your company's needs.
Readers of Time Out magazine have named their favourite shops, bars, cafes and restaurants in Lewisham.
Saturday 6, 13, 20 December
Be aware of bogus fundraisers