text:
|A chelate comprising : a general formula I : wherein Rχ_4 is CH2COOH ; wherein n is an integer from 1 to 5; X is a member selected from the group consisting of N02, NH2, NCS, NHCOCH2Z with Z being a member selected from the group consisting of Br and I OCH2COOH; COOH; and M is a metal ion being a member selected from the group of elements consisting of Bi, Pb, Y, Cd, Hg, Al, Th, Sr, and Lanthanides.
|The chelate of claim 1 wherein n is 1 to 2 and X is a member selected from the group consisting of NO2, NCS, and NHCOCH2Z with Z being a member selected from the group consisting of Br and I.
|The chelate of claim 2 wherein M is a member selected from the group consisting of Bi, Pb, Y, Th, Sr, Gd, Eu, and Tb.
|The chelate of claim 1 herein n is 2, X is NCS, and M is a member selected from the group consisting of Pb212, Pb203, Bi212, γ90, Th224, and Sr90.
|The chelate of claim 4 wherein M is a member selected from the group consisting of Pb212 and Bi212.
|The chelate of claim 2 wherein n is 2, X is NCS, and M is a member selected from the group consisting of Eu and Tb.
|A chelate comprising: a general formula I: wherein Rχ4 is CH2COOH; wherein n is an integer from 2 to 5; X is a member selected from the group consisting of , NH2, NCS, NHC0CH2 Z with Z being a member selected from the group consisting of Br and I COOH; 0CH2C00H > and M is Cu.
|The chelate of claim 7 wherein n is 2 and X is a member selected from the group consisting of NO2, NCS and NCOCH2Z with Z being a member selected from the group consisting of Br and I.
|The chelate of claim 8 wherein X is NCS.
|A ligandhapten conjugate comprising: a general formula II: wherein Rχ4 is CH2COOH; n is an integer from 1 to 5; X' is a member selected from the group consisting of NHQ, NCQ, I II H S H NCOCH2Q, OCH2COOQ3 and O COQ with Q being a hapten selected from the group o hormones, steroids, enzymes, and proteins.
|The ligand conjugate of claim 10 wherein n is 2 and Xr is NHCQ. II S .
|The ligand conjugate of claim 11 wherein Q is a protein, said protein being a monoclonal antibody.
|The chelate conjugate of claim 14 wherein M is a member selected from the group of Bi, Pb, Y, Th, Sr, G.d, Eu, and Tb.
|The chelate conjugate of claim 15 wherein n is 2 and M is a member selected from the group consisting of Pb212, Pb203} Bi2!2, γ90, Th224, and Sr90.
|The chelate conjugate of claim 16 wherein M is a member selected from the group consisting of Pb2!2 and Bi212.
|The chelate conjugate of claim 15 wherein n is 2 and M is a member selected from the group consisting of Eu and Tb.
|A process for treating cellular disorders comprising: introducing into body fluid a solution of metal chelate of a general formula I: wherein Rχ_4 is CH2COOH; n is an integer from 1 to 5; X is a member selected from the group consisting of NHQ, NHCQ, y NHCOCH2Q, OCH COOQ, 0 COQ with Q being a hapten selected from the group consisting of hormones, steroids, enzymes, and proteins; M is a metal ion being a member selected from the group of elements consisting of Bi, Pb, Y, and Gd.
|The process of claim 19 wherein n is 2, X is NHCQ, and M is Gd. S.
|The process of claim 19 wherein M is Pb2123 said Pb212 converts to Bi ! and daughters thereof, said Bi !2 emits an alpha particle to treat said cellular disorders.
|The process of claim 21 wherein n is 2 and X is NHCQ. S.
|The process of claim 22 wherein at least 70 percent of said B1212 remains in said chelate.
|The process of claim 23 wherein at least 80 percent of said Bi212 remains in said chelate.
|The process of claim 24 wherein at least 90 percent of said Bi212 remains in said chelate.
|e process o c a m w ere n at east percent of said Bi2!2 remains in said chelate.
|A process for diagnostic testing comprising: introducing into a test medium a solution of metal chelate of a general formula I: wherein Rx_4 is CH2COOH; n is an integer from 1 to 5; X' is a member selected from the group consisting of NHQ, NCQ, S NHCOCH2Q, 0CH2C00Q, and 0 11 COQ with Q being a hapten selected from the group consisting of hormones, steroids, enzymes, and proteins; M is a metal ion being a member selected from the group consisting of Pb203, Tc99m} ιnlH, Ga6?, Ga6^, Sc43, Sc44? Fe52} Fe5 , Te>6 , Fe57, Fe^S, and Co55.
|The process of claim 27 wherein n is 2, X is NCSQ, and Q is a monoclonal antibody.
|The process of claim 28 wherein M is Pb203.
1. Field of the Invention
This invention relates to macrocyclic chelates and methods of use thereof. ϊ * _ore specifically, this invention relates to 2-substituted 1, 4, 7, 10-Tetraaza cyclododecane -N, N 1 ,, N' 1 N' ' ' -tetraacetic acid, and 2-substituted 1, 4, 7, 10-Tetraazacyclododecane, and analog maci'ocycles and their uses.
2. Description of the Background Art
Macrocycles have been studied for their usefulness as chelates for numerous metal ions that have therapeutic diagnostic, or other uses. A macrocycle of particular usefulness as a chelate is the 1, 4, 7, 10-Tetra- azacyclododecane -N, N, N, N-tetraacetic acid (DOTA) . DOTA compounds have been linked to biomolecules to form delivery systems for the chelated metal ion to specific sites within an organism.
U.S. Patent Number 4,678,667 to Meares et al. , discloses a macrocyclic bifunctional chelating agent The chelating agents of this disclosure can include DOTA compound that is a Cu(II) chelate. The usefulness of the chelating agent is limited to the effects of the copper metal ion. The synthesis of this disclosure gives low and not always reproducible results.
An earlier U.S. Patent No. U.S. 4,622,420 to Meares et al. disclosed bifunctional chelating agents of the acyclic ligand ethylene diamene N, N 1 N : ' , N ! ' ' tetraacetic acid (EDTA) useful for binding metals other than copper such as Indium. These compounds are useful for imaging of tumors.
U.S. Patent Number 4,652,519 to arshawsky et al., discloses bifunctional chelating agents and process for their production. The compounds disclosed in this patent are analogues of EDTA. These compounds are used to chelate metal ions and are linked to haptens to provide specific site selection within an organism. The compounds of this patent are offered to provide an improved substitutent for the EDTA compounds such as those disclosed in the Meares et al. patent discussed above.
U.S. Patent Numbers 4,454,106 and 4,472,509 to Gansow et al. , respectively disclose the use of metal chelate conjugated monoclonal antibodies and the specific metal chelate conjugated monoclonal antibodies. These disclosures provide compounds and methods for treating cellular disorders. Radiometal chelate conjugated monoclonal antibodies specific to a target cell are used to deliver alpha, beta, or Auger electron emitting metal ions. These disclosures are not related to DOTA compounds.
The value of having a ligand conjugate to chelate metal ions for therapeutic, diagnostic, or other uses is of commercial importance. This commercial importance is created by the fact that many metal ions have desirable characteristics for these various uses, but the delivery systems for the metal ions lack specificity to target cells or do not adequately bind the metal ions. Examples of the usefulness of specific metal ions are as follows.
The usefulness of radionuclide materials in cancer therapy is disclosed in the article, Kozak et al. , "Radionuclide-conjugated monoclonal antibodies: A Synthesis of Immunology, in Organic Chemistry and Nuclear Science" Trends in Biotechnology. 4(10) :259-264 (1985). This article discusses the use of antibody conjugates to deliver either alpha or beta radiation. The value of alpha radiation from bismuth-212 in radionuclide therapy is further discussed in the two articles, Kozak et al.. "Bismuth-212-labeled anti-Tac monoclonal antibody: Alpha-particle-emitting Radionuclides as Modalities for Radioimmunotherapy" Proc. Natl. Acad. Sci. U.S.A. 83:474-478 (1986) and Gansow et al., "Generator-produced Bi-212 Chelated to Chemically Modified Monoclonal Antibody for Use in Radiotherapy" Am. Chem. So. Symposium Series 15:215-227 (1984).
Examples of other uses for chelated metal ions are disclosed in the following articles. Magerstadt et al., "Gd(DOTA): An Alternative to Gd(DPTA) as a T lj2 Relaxation Agent for NMR Imaging or Spectroscopy" Magnetic Resonance in Medicine 3:808-812 (1986), discloses the usefulness of gadolinium as a relaxation agent for NMR imaging. The article, Spirlet et al., "Structural Characterization of a Terbium(III) Complex with 1, 4, 8, 11-Tetraazacyclotetradecane- 1, 4, 8,
11-tetraacetic Acid. Lanthanide Ions and the Conformation of the 14-Membered Macrocyles" Inorganic Chemistry 23(25) :4278- 283 (1984), discloses the usefulness of lanthanide chelates.
The industry is lacking a DOTA chelate that can be efficiently produced in high yields and that has desirable chelating qualities for numerous metal ions.
The invention is a chelate having a general formula I:
wherein Rχ- is -CH2COOH;
n is 1 to 5;
X is a member selected from the group consisting of -NO2, -NH 2 , -NCS, -NHCOCH2 - Z with Σ being a member selected from the group consisting of Br and I -COOH; -0CH 2 C00H and M is a metal icn being a member selected from the group of elements consisting of Bi, Pb, Y, Cd, Hg, Al, Th, Sr, and Lanthanides.
The invention can include a chelate wherein M is a copper ion and n is an integer from 2 to 5. The invention includes chelate conjugates of general formula I and ligand conjugates of general formula II:
The invention also includes methods to use these compounds for treatment of cellular disorders and for diagnostic tests.
Figure 1 illustrates a chemical pathway to produce the preferred embodiment of the invention.
The compound of this invention is a substituted DOTA represented by the general formula I shown above or specifically by compound X of Figure 1. Compound X can subsequently be converted to other substituted DOTA compounds, but compound X is the parent compound for such other compounds. The general formula is a 12 membered ring tetraaza macromolecule with the nitrogens in the 1, 4, 7, and 10 positions. Each of the nitrogens is "ribbed" by an ethylene group.
The substituted DOTA ligand represented by compound X of Figure 1 complexes metals. Metal complexes are formed by placing the DOTA into solution with an appropriate metal salt having the metal to be chelated. Metal salts
have to be selected so as to prevent the hydrolysis of the metal. Also, reaction conditions in an aqueous medium have to be chosen such that the metal it not hydrolyzed. For example, a lead nitrate complex, bismuth iodide complex, or yttrium acetate salts can be used to form a metal chelate with lead, bismuth, or yttrium, respectively. General examples of suitable salts include any soluble divalent metal complex or any trivalent metal complex that is not hydrolyzed at pH 4 or below. Thorium requires the use of iodide salt, specifically. The most desirable metal ions for chelation with general formula 1 are members from the group consisting of bismuth, lead, yttrium, cadmium, mercury, actinium, thorium, strontium, and any of the elements of the lanthanide elements. The most desirable elements of the lanthanide series are gadolinium, for use in NMR imaging and as a relaxation agent in NMR imaging, and terbium and europium because of their use as chromophores in time resolved fluorescence spectroscopy. These fluorescent compounds can be useful in an in vitro diagnostic assay where a florescent assay is used rather than a radioactive a ino assay.
The X substituent of general formula is desirably a substituent that conjugates the compound with haptans. This substituent is desirably a free-end nitro group which can be reduced to an a ine. The amine can then be activated with a compound such as thionyl chloride to form a reactive chemical group such as an isothiocyanate. An isothiocyanate is preferred because it links directly to amino residues of a haptan such as a monoclonal antibody. The amiline group can be linked to an oxidized carbohydrate on the protein and, subsequently, the linkaged fixed by reduction with cyanoborohydride. The amino group can then also be reacted with bromoacetyl chloride or iodoacetyl chloride
to orm -N 2Z w t Z e ng brom e or odide. T s g oup reacts with any available amine or sulfhydryl group on a hapten to form a stable covalent bond. If tyrosine is used in the formulation of the macromolecule a carboxcylic acid or methoxy carboxylate group can be in this position of the compound. The most desirable substituents for this position are members selected from the group consisting of - O2, -NH2, -NCS, -COOH, -OCH2COOH, -OCH2COOH and -NHCOCH2-Z with Z being a member selected from the group consisting of bromide and iodide. The preferred substituent for this position is -NCS.
The haptens suitable for linking with the substituent at the X position of general formula I can vary widely. The most desirable haptens are members selected from the group consisting of hormones, steriods, enzymes, and proteins. These haptens are desirable because of their site specificity to tumors and/or various organs of the body. The preferred hapten for use in treating cellular disorders or various disease conditions is a monoclonal antibody.
The compound of this invention can have n equal an integer from 1 to 5. In the preferred embodiment, M equals 2. It is desirable for n to equal 2 versus 1 because the chelating ligand is further separated from the antibody and has more rotation. The increased free rotation allows a metal to chelate with the macromolecule more easily. When n is 3 or greater, the synthesis of the compound becomes lengthy.
Figure 1 illustrates the preferred reaction pathway or process for forming the compound of this invention. This reaction results in a compound of general formula I
w ere n n s . n s o equa , an a ona methylene group would be present between the alpha amino carbon and the aromatic grou . This compound is 2-amino-4-nitrophenylbutyric acid.
The process for synthesizing a compound according to this invention first provides a triamine with a substituent is in the 2-position. The embodiment of Figure 1 has a methylene [n = 1] as the initial substituent for linkage. The preferred embodiment has a phenyleythylene group. The process then provides a tetraaza macromolecule having the substituent in the 2 position. Alkylation with bromoacetic acid to form the four carbon to nitrogen bonds of the carboxymethylene substituents at the Rl, R2, R3, and R4 in the general formula.
The process of Figure 1 reacts p-nitrophenyl alanine with methanol and hydrochloric acid to form the ester compound II. This ester is reacted with ethylenediamine in the presence of triethylamine to remove the hydrochloride salt of the ester formed in compound II. The condensate of the amide of the ethylenediamine adduct or compound III is subsequently reacted with a diactive ester or compound VI to form a cyclic product or compound VII.
The desired diactive ester VI is formed sequentially from amidodiacetic acid for IV of Figure 1. The amine is first blocked by using the reagent BOC-ON or any other suitable blocking agent, such as FMOC, in the presence of triethylamine which serves to deprotonate the starting material. The subsequent nitrogen blocked diacetic acid V or other such nitrogen blocked compound is then coupled to N-hydroxysuccinimide, or any other suitable compound such as phenols, or N-hydroxydicarboximides which forms a
reactive ester. The choice of compounds which form active esters or blocking groups is within the scope of the art. The coupling is done by dicyclohexyl- carbodiimide or "DCC". This step produces the nitrogen blocked active ester or compound VI.
Ring formation under high dilution conditions between amino acidamide or compound III with the nitrogen blocked active ester of compound VI then occurs. This condensing step forms the triamide macrocycle or compound VIT. Compound VII is produced in very high yield. The yield is typically at least about 80 percent. The yield more desirably is between about 80 percent to about 95 percent.
The synthesis of the macrocycle of compound VII may be accomplished by two pathways. Th amine nitrogen of compound VII is deblocked with trifluoroacetic acid or "TFA". This forms the TFA salt of the triamide macrocycle or compound VIII. This compound is reduced with borane/petrahydrofuran or THF. The resulting borane adduct is cleaved by hydrochloric acid to form the substituted tetraazamacrocycle of compound IX. This tetraazamacrocycle can then be alkylated with haloacetic acid in the presence of base to form a nitrobenzyl DOTA or compound X. Alternatively, compound VII can be reduced with borane/THF and reacted with hydrochloric acid to form compound IX directly. This alternative pathway produces slightly poorer yields.
The nitro group of compound X can be reduced with hydrogen over platinum on a carbon catalyst to produce the amino group or the aminobenzyl DOTA depicted as
compound XI. Compound XI can then be reacted with thiophosgene to produce the isothiocyanate or compound XII.
The methodology in column 3 of U.S. Patent Number 4,652,519 to Warshawsky et al. , hereby incorporated by reference, provides the methodology to produce the -COOH substituent. This procedure produces the ethylene diamine intermediate. The desired intermediate macrocycle is produced by forming the analogous diactive ester of compound VI by using N, N 1 -ethylenediaminediacetic acid. Condensation of the diamine with the dinitrogen, diBOC diactive ester produces diamide intermediary which is reduced by diborane to produce the appropriate tetraaza macrocycle. The DOTA ligand can be made from this macrocycle. The synthesis of the X and Z groups are also disclosed by the Warshawsky patent.
The reaction steps described above to produce compounds X, XI, and XII are known. The novel feature of the process of Figure 1 is the cyclization procedure. The conversion reaction of compound IV with compound VI to form the macrocycle and the full reduction of the macrocycle to produce compound X produces the unexpected results of very high yields compound X.
In its preferred embodiment the coupling of an isothiocyanate chelate of compound XII of Figure 1 is done by direct conjugation of the isothiocyanate with a free amino group found in many residues of proteins, enzymes or other compounds such as certain hormones . An example of this situation with a hormone is found with the free amino group provided by the epsilon amino group of the lysine or the terminal amino group as the hormone
. isothiocyanate to form a thiourea linkage which is covalently coupled and irreversible. The use of a steriod as a hapten requires that an amino function be present in the steroid.
An advantage of the amine derivative chelate of compound XI of Figure 1 is that, when coupling to proteins and, in particular, when coupling to antibodies, the carbohydrate of the antibody can be oxidized prior to the coupling reaction. The amine reacts with the aldehyde that is formed on the protein. This aldimine formed can be reduced by cyanoborohydride to form a covalent secondary amine linkage to the antibody in a position that is site specific. This position is away from the binding site of the FAB'2 part of the monoclonal antibody.
A desirable embodiment of the invention is one having copper metal ion and n is an integer from 2 to 5. This embodiment of the invention can be used to label a monoclonal antibody with Cu°7__ When n is an integer from 2 to 5, there is less hindrance of the chain of the ligand with the protein than occurs when n is 1. When n is an integer from 2 to 5, sufficient space is provided between the ligand and the protein to allow freer rotation of the ligand. This results in more efficient chelation of the copper ion by the resulting conjugate.
An embodiment of the invention involves a ligand-hapten conjugate of general formula II:
This conjugate chelates metal ions. It is desirable to expose many metals to the protein conjugate in a concentrated metal solution for as short a period of time as possible. Certain metals, such as divalent metal ions, react rapidly and directly with the conjugate. The kinetics of the formation reactions for these compounds are so rapid that it is desirable to have the ligand-hapten conjugate available in the pharmacy immediately prior to use. The conjugate can then be mixed in the radionuclide to form a complex and, subsequently, the metal chelate conjugate formed can be purified by, for example, size exclusion high pressure liquid chromatography. A desirable hapten for the ligand conjugate can be selected from the group consisting of hormones, steroids, enzymes, and proteins.
The most commercially useful embodiments of the invention are chelate conjugates having general formula I wherein (1) n is an integer from 1 to 5, (2) X' is a member selected from the group consisting of -NHQ, -NCS-Q, -NHC0CH 2 -Q, -OCH2COOQ, and -C00-Q with Q being a hapten selected from the group consisting of hormones, steroids, enzymes, and proteins, and (3) M is a metal ion being a member selected from the group of elements consisting of Bi, Pb, Y, Cd, Hg, Ac, Th, Sr, and Lanthanides. These chelates conjugates can deliver radioactive metal ions such as Pb 2 2 , Bi 212 , Y 90 , Th 224 , and Sr90 to specific cellular disorders.
The preferred embodiment of the invention uses a chelate conjugate binding Pb 2 ! . Pb 2 ^ 2 is a very desirable pharmaceutical compound for delivering both beta and alpha radiation to a selected site for treatment of the cellular disorders. The delivery is made through
the P on which converts with a 10 1/2 hour half-life into Bi 2 2 . Bi 2 ! 2 and daughters deliver one alpha particle per Pb 2 l 2 nucleus. The desirable result of this chelate conjugate is that the Pb 2 ! 2 half-life is sufficient to allow site selection from the body fluid by the hapten before the alpha particle is emitted.
The invention includes a process for treating cellular disorders. This process uses the chelate conjugate with a hapten having a selective binding site at the cellular disorder. For example, Q can be a monoclonal antibody wherein the antibody is directed and created against an epitope found specifically on the tumor cells. Thus, when Pb 2 ! 2 is transported to the antegen site and, subsequently, decays in secular equillibrium to Bi 2 ! 2 and its daughters, a beta irradiation is produced from the lead disintegration. A beta radiation is produced by the bismuth daughters. This beta radiation is similar to the beta radiation from γ 0 3 ϊ-) Ut j_ n addition, each disintegration of bismuth also produces an alpha particle. In this manner, a radiotherapy is provided with a radiation dose from both an alpha and a beta particle. If desired, only Bi 2 ! 2 can be introduced in those cases where the disorder to be treated, such as with leukemic cells, can be easily reached within the 1 hour half-life of Bi 2 ! 2 . it ± s also possible to use this method to treat cancers where the cells are widely differentiated. This might be preferred where only a long range beta emitter, such as Y90 ? j_~ desired. In differing environments, in vivo, the Bi 2 ! 2 is retained inside the chelate after the beta emission in differing amounts. Most desirably, at least 95 percent of Bi212 remains in the chelate. In an acidic medium, such as the stomach, at least about 70 percent of the
Bi ! 2 is retained. Retaining at least about 80 or 90 percent, Bi 2 ! 2 is also desirable depending on the medium.
The invention includes a process for diagnostic testing. This process uses a chelate conjugate having general formula I wherein M is a member selected from the group consisting of Pb203 } c9 m 5 ι n lll, Ga 6 ?, Ga 6 8 5 Sc43 3 Sc 44 , Fe52 } Fe 4, Fe 6 } Fe 7, Fe58 } and Co55. The usefulness of metal ions with both in vitro and in vivo diagnostic procedures is disclosed in U.S. Patent Number 4,454,106, hereby incorporated by reference.
The most desirable embodiment of this diagnostic process uses Pb 2 ^3. pt,203 h s a 52.1 hour half-life as a gamma emitter. Pb203 has a unique property in that it decays at a high percentage only by a single photon emission. This gamma emission is preferred and dominant over all other emissions. This single photon emission makes Pb 2 03 useful for single photon emission computed spectroscopy [SPECT] which is a diagnostic tool. Thus, when Pb 2 03 i s linked by use of the chelate to a hapten which specifically localizes in a tumor, then that particular localization can be three dimensionally mapped for diagnostic purposes in vivo by single photon emission tomography. Alternatively, the emission can be used in vitro in radioimmunoassays.
The procedures and reagents described above for the preferred embodiment of making the compounds are used for this example.
The antibody specific for the IL-2 antigen is the monoclonal antibody alpha-Tac. This antibody is labelled with the chelate of compound XII of Figure 1 as follows. The antibody is suspended in a buffered normal saline solution having a pH of about 8.5. Solid ligand or compound XII is added to the protein suspension. The protein conjugate forms during reaction overnight and is purified by dialysis against metal-free 0.05 molar citrate/0.15 molar sodium chloride buffer at pH 5.5. Before labelling with metal, the protein is dialyzed against a solution comprising 0.02 molar N-morpholinoethanesulfonic acid and 0.02 molar acetate at pH 5.9.
The protein in solution is labelled with Y90 by reacting with an acetate solution of the isotope followed by passage through a TSK 3000 size exclusion column. This is a high pressure liquid chromotography procedure. The compound is mixed with a pharmaceutical excipient and is used in mammals in a therapeutic amount to treat adult T-cell leukemia in mammals. T-cell leukemia displays the characteristics of having an extraordinarily large amounts of IL-2 receptors located on the tumor cells. The antibody localizes specifically to these tumor cells to deliver its radiation.
EXAMPLES 2 and 3
The procedures and reagents described above for the preferred embodiment of making the compounds are used for these examples. The only difference between Example 1 and Examples 2 and 3 are the use of the antibody B72.3 which binds specifically to a glycoprotein on LS-174T cells. This glycoprotein is also in humans which have colon cancer. The model system of this example is an
athymic mouse which has been implanted with LS-174T cells to develop a tumor on the flank of the animal in the location of where the cells were implanted. The diagnostic method used to visualize the growing tumor involves the following components. The chelate of compound 12 is first coupled to gadolinium or Pb203 by mixture of the chelate solution at pH 4 to 5 with gadolinium or Pb203 nitrate. This material can be then linked directly to the antibody by mixture to react with the protein and purified according to the method of the previous example.
In Example 2, the gadolinium chelate ligand-protein conjugate is injected or introduced into body fluids of a mammal. The gadolinium then localizes along with the antibody to the tumor and conventional resonance magnetic imaging techniques are used to visualize the tumor.
In Example 13, the Pb203 i s used, the metal labelled protein conjugate is similarly introduced into the mammal, but gamma camera or SPECT imaging is used to visualize the tumor.
Next Patent: SUBSTITUTED 2-AMINOTHIAZOLES AS DOPAMINERGIC AGENTS


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subset: commoncrawl


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Now that we've shared the results of the Design Your Own Sex Toy competition, we've decided to let you know about some of the more memorable (if non-winning prize entries).
We'll be putting the most distinctive of the also-rans on this blog over the next few weeks, so watch this space for eye-boggling toy action.
A few themes were immediately apparent - a surprising number of you wanted to have sex with a USB port, making teledildonics the hot tip for future sex-toy developments; a high proportion of male toys were labour-saving wank devices for the terminally lazy - we never realised a simple knuckle shuffle was such a major undertaking for some people - and there were two entries each in the dildocam (for people who want to see what girls are made of) and root vegetable dildo categories, the latter moulded on non-GM organic carrots and parsnips, naturally!
Some entries set a high standard for sheer shock value, but the many rose to the challenge admirably, we think. In the interests of authenticity we've retained original spelling and grammar.
Design A Sex Toy Entry
This one had our jaws hitting the floor for two reasons. First up, we couldn't quite work out whether he was having a laugh or whether he thought that "getting in the back of the vagina" was what girls wanted.
And while we admired him for creating a prototype, we wondered why it looked less like a sex toy and more like a Lego Mindstorms kit…
Description: Get in the back of the girls vaginas.
Ok so this is the most awesomest Sex Toy ever you just stick it up there press the button and KABAM!!!!! It his the back caves of your Vaginal express!!!!!!!111


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Consumers repudiate and recoil from a central organising principle of modern marketing: that brands can — and do — target advertising and other messages at them based on their web browsing behaviour and other personal data.
Participants in the global digital marketing ecosystem have convinced themselves that consumers are thoroughly on board with the industry's huge global, commercial data surveillance infrastructure. Yet the evidence suggests the contrary: that internet users are actually appalled once they understand how their data is used.
That is a key insight from a study conducted exclusively for Which-50 by Pureprofile. The results demonstrate how little consumers understand that their every move online is being logged, tracked, repackaged into data products, and quite literally sold to the highest bidder every moment they spend online.
The research was conducted last week and is based on a survey of 1000 consumers. It reveals an extraordinary level of antipathy towards the kind of data matching required to deliver personalised messaging and advertising that is common to almost all digital campaigns on a daily basis.
The results suggest that brands — and the marketing technology industry that supports them — have lost touch with the reality of consumer sentiment on the issue.
Don't drink the Kool-Aid
That is a dangerous place to be, and one that can provoke a fierce backlash and brand damage when things go awry — as they did for Facebook last year during the Cambridge Analytica scandal.
The only exception in our study to all this hostility came when there was a clear price benefit to the consumer. Seventy per cent said they wanted web sites they visit to show them discounts on products and services tailored to their interests.
The Which-50/Pureprofile Data Privacy study also echoes a study of US consumers by the New York Times which was published recently.
We asked Scott Brinker, Editor at chiefmartec.com, VP Platform Ecosystem at HubSpot, and the driving force behind the famous marketing technology Lumascape, what he took away from the two studies.
Brinker told Which-50, "My 'hot takes' reaction: I tend to agree with the consumers.
"Data is certainly helpful in modern marketing, particularly from the perspective of analytics to measure performance across a broader spectrum of customer experience touchpoints. But I think the use of data for personalisation is overrated in most scenarios.
"Most of the time, I don't think consumers are saying, 'wow, if only this experience was personalised, it would be awesome'. More often, they're saying things like, 'why is this web site so confusing to figure out? Why do I have to wait 45 minutes for a representative on a chatbot queue? Why can't I get what I need in an online self-service manner?'"
According to Brinker there are still plenty of opportunities to improve digital customer experience, and martech products and data can be a big part of that transformation process. "But respecting data privacy shouldn't be a barrier in that mission. In fact, hopefully more data privacy legislation will force marketers to pay more attention to the quality of the experience instead of superficial personalisation."
Two years ago MIT and Capgemini investigated the nature of the relationship between consumers and organisations in a study which lead to a report called "From UX to CX: Rethinking the Digital User Experience as a Collaborative Exchange".
We asked one of the authors of that study, Didier Bonnet, Capgemini's London-based Senior Vice President and Global Practice Lead for Digital Transformation, to describe the results of our study in the context of his own work.
He told Which-50, "The survey data clearly shows the current discomfort between consumers and brands when it comes to the use of personal and behavioural data. This is not surprising to me. The Cambridge Analytica episode and the recent personal data regulation introduced in Europe, for example, have increased the awareness of consumers that firms are doing things in the background with their personal data."
Bonnet says that martech analytics technologies are today very sophisticated and, to some extent, ahead of the ability of most consumers to grasp the way their data is used and manipulated.
This creates dissonance, he argues, and that dissonance increases when data is indirectly collected by brands and Martech firms.
"For example, I don't want to give you my age, but it can be scraped from another online profile without my consent. This is clear in your data."
To the numbers
A majority (52 per cent) of consumers we surveyed said it is unacceptable for companies to monitor their behaviour on the brand's own web site in order to tailor advertisements shown to the consumer on that same web site.
The figures get even worse when consumers were asked about the very common practice of tracking their browsing activity on other sites and then using the data to target them. 70 per cent said this was unacceptable.
Nearly three quarters (73 per cent) of those we asked also rejected the use of data from offline sources such as shopping or magazine data to target them with advertising.
When the advertising contained political content almost 80 per cent rejected targeting based on their interests.
To understand the extraordinary level of consumer sensitivity on this issue, consider the response when asked "What, if anything, should be a company's single punishment beyond fines if it uses a person's information illegally?"
Fully one quarter said executives at companies that did this should be imprisoned. And 15 per cent said the company should be put out of business.
According to Pureprofile Chief Scientist Uwana Evers, who designed the survey, "The majority of consumers do not think that it is acceptable for companies to collect information on their online browsing activity in order to deliver targeted advertisements. Companies and brands should take note! This sentiment will continue to get stronger if privacy concerns continue to increase and consumers perceive that they do not have a choice about how their personal data is being used online."
Evers said it was also clear that a large proportion of consumers would prefer no advertisements at all. That is, if they had the choice. "Consumers most preferred targeted advertisements for discounted products and services of interest (70 per cent). Otherwise, the rates drastically dropped for targeted ads on products and services (51 per cent), news (46 per cent), or political messaging (22 per cent)."
She told Which-50, "Only a quarter of Australians stated that it was acceptable for companies to collect information on their online browsing activity in order to deliver targeted advertisements. This reduced to only 17 per cent when asked about the acceptability of companies capturing data from consumer activity on other sites, or from consumer offline activities."
Furthermore, more than one in ten people were unsure about the acceptability of allowing companies to monitor their browsing behaviours for the purpose of targeted advertising. "This shows that some people know very little about the way that their data is captured and used; some consumers perhaps have not thought too much about it, and do not yet have an opinion about the collection and use of their browsing activity."
Asked about the finding that a quarter of consumers would want executives to be jailed if they misuse consumer data, she said, "[The] data does actually surprise me! I did not expect that a quarter of the sample would advocate for such a harsh penalty. This tells us that consumers take data misuse very seriously."
She suggested that the majority of consumers may not truly appreciate the extent to which their data is being collected and used for targeted advertising. "However, while they want to feel that their personal data is secure and that they are aware and informed when their behaviour is being monitored, they still want to access online content on demand, for free."
Love our ads or we kill the puppies
Gary Nissim, Managing Director of Indago Digital, a specialist search agency, said "The average consumer believes that we're trading their personal information like Panini soccer or top trump cards.
"This is far from the case. At Indago we invest a lot of our clients' marketing budget with Google, where we use their third-party data. That data is normalised we can't access it and we target a set of consumers (not an individual) based on Google's perceived interests and current needs."
He said without effective and targeted advertising much of the internet would cease to be commercially viable and consumers would have to pay to access certain web sites. "That is why an increasing number of sites don't allow access if you have an ad blocker on your browser."
Some marketing leaders, however, believe marketing technology vendors – and the brands themselves – could do a better job explaining to consumers how data is used.
Cat Prestipino is the CMO of Employment Hero, an Australian HR software business that offers a unified payroll and employee benefits platform to its clients. She is also a former APAC marketing leader for digital advertising retargeting business AdRoll.
She told Which-50, "The adtech/martech sector has done an incredibly poor job at educating people on what data they're actually collecting and what they are using it for. If consumers don't understand how their data is being used or can't control how their data is being used, then naturally they want to stop their data being used. The worst thing a brand can do is surprise consumers with how they're using data."
However, she also noted an important point in the debate. "We know that personalised ads work. We know that when brands use data to give you a seamless customer experience consumers rave about it."
According to Prestipino, "What is also interesting is that there was a study from the US that found people were OK with relevant advertising but not with targeted advertising despite these being the exact same thing."
Prestipino suggested that if the adtech and martech sector spoke in plain language about how it collected their data — and if people had the right, at any time, to quickly and easily control how that data was used — there would be less hostility towards targeted advertising.
The CEO of IAB Australia Gai Le Roy, whose organisation represents the country's leading digital publishers said, "Trust and transparency is increasingly important to consumers — not only in media but any sectors that may have access to their data whether that be behavioural or explicit."
She also questioned the methodology saying, "I would challenge some of the research from both Which-50 and the NYT as in my 20-years-plus career of running and reviewing surveys on consumer attitude to advertising there is always a large group of people who would prefer not to see any advertising. If the question was worded 'would you rather have relevant or non-relevant advertising' the responses would have been very different."
However, she also acknowledged "As an industry — whether that be industry bodies, media organisation, brands or trade press — the sector can do a better job of educating consumers on how the ad ecosystem works, levers they have to control their data, legal rights when it comes to their own data as well as education around the value exchange with online media and services."
Raz Chorev, the Chief Marketing Officer of Orange Sky CMOs, a professional services company, likewise suggested the question should have been framed differently to describe the benefits to the consumer.
"Currently, you're browsing the internet for free, and consume information compiled on various web sites for free. If you had the choice, would you be willing to pay to access those sites, or would you be open to provide some details regarding your browsing behaviour, to keep using these web sites for free, but that means you'll see some adverts which will be tailored to your preferences (as demonstrated in your browsing history), which option is more appealing to you?"
He said most people wouldn't want to give something of theirs without seeing a direct benefit.
However, he also spoke a truth that many in the industry do not want to acknowledge: "Seeing a tailored ad isn't a benefit to the viewer. It is only a way to maximise return for the advertiser. Therefore the consumer isn't interested in giving away information, to give benefit to the advertiser. I think this is pretty straightforward."
None of the industry respondents we contacted proffered an alternative view; that consumers might prefer not to be targeted at all if that meant they could be spared the always-on global data surveillance that underpins the martech ecosystem.
In many ways the arguments by brands and suppliers simply reinforced the distance that separates them from their consumers on the issue of data use, a point discussed by Aoife Marie O'Connell, the founder of AI agency Yarnly.AI.
O'Connell, who has previously had stints as a digital marketing for blue chip brands such as IAG, told Which-50, "The discrepancy between the adtech/martech/brands sector and the consumer is due to the current landscape of an industry fired up by the digital transformation revolution."
"Brands are playing catch up, and not addressing consumers' needs, in how they are operating.
"I feel customers are hostile due to the quality of the exchange and its model of interrupted marketing techniques."
She suggested the quality of personalised ads do not reflect consumers' best interests, creating a disconnected noisy experience. "I can understand why they're hostile. From the survey results, my understanding is consumers are mostly comfortable with their data being analysed. They are willing to trade their personal information, but only if they have a choice, and in exchange for that 'better deal' or 'discount code' for a particular product or service or information of value."
Transparency trumps creepy, every time
While the findings caused some controversy in the industry, there was consistency across vendors, publishers and marketers about how brands need to behave to maintain the trust of consumers.
For instance, Emil Mathias, the Commercial Director for MediaMath, a leading adtech platform in Australia, captured the mood of many, saying "Consumers want to be respected and understood. The risk of misunderstanding consumers will lead to brand distrust."
He cautioned brands against overlooking the value exchange and placing all focus on consumers 'seeing' their ads as many times as possible so as to be top of mind. Vendors have an important role to play in educating brands, he suggested. "Martech and adtech companies should have the vision to help brands instil the belief that it is now possible for consumers not only to 'see' but also engage with their messaging in a way that is appropriate and relevant for them."
According to Employment Hero's Prestipino, "Be upfront and honest about what you're doing with data. Make sure your opt-out is clear and in plain language. And, for god's sake, use the data to make a better experience for your customers — not just sell your product!"
Rajan Kumar, co-founder and Managing Director of martech consultancy The Lumery, also emphasised transparency, saying it is important to provide consumers with easy to understand information on how data is collected and used.
"The 30 page, font size 10 privacy policy and terms-of-use needs to get overhauled."
He also echoed the views of Brinker, Bonnet and others, that it is important to actually use the data they collect to create better consumer experiences.


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You're probably wondering what happened to Edward Cringle in the volcano right? Don't worry he's made it through, he's a hero, he has made it through the tough Volcano! He went through so fast that he couldn't even take picture of all the enemies he defeated.. I know you're jealous right? Lol okay. I'll stop kidding around now! After the Volcano I went to Captain Avery only to get a ticket to Puerto Mico!
|Edward Cringle has arrived in Puerto Mico!
After arriving here in Puerto Mico, I was given a quest from a monkey to defeat ships. I was worried because these ships were a lot tougher than the ones close to Skull Island, here's what I went through!
|Sailing to get to my quest, oh yeah a new ship!
|Almost defeated! No, my crew wasn't defeated, almost though!
Okay, Now to go back to finish this outfit. I couldn't wait to see what it was to defeat these tough ships, I'm pretty sure its going to be epic right? Well maybe not. Here's a picture of it.... The things I do for monkeys!
What a great adventure eh? Well after finally dressing up.. in the weird costume? The monkeys told me more about the Gold Mine the next place that I have to go to.. I have no idea how bad this is going to be so you'll have to wait on an update in a few days. They told me its very bad. Wish me luck! Here's a picture..
|See ye around the Spiral!


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Those quotes around "GM Advice" exist because when you pick up this book (or PDF), you will not be getting a how-to laundry list. When you thumb through the text, you'll be Mr. Miyagied (yes a verb) into a particular play style. The undercurrent of the whole thing is that awesomeness can occur by the GM taking off the kiddy gloves and craft an experience which makes the players feel for the characters and their sacrifices. It does this through examples of past games run this way, the effects of this approach, and what you need to do to make it work.
The smooth bits:
- An easy, pointed, and conversational flow, a John Wick trademark I believe.
- A great example of a particular GM-style
- Good concrete examples of positive things a GM can do, whether you like the style or not
The sandpaper slide:
- Though this book is often touted around the 'net as an Advice Handbook and it does give advice, its really a collection of articles not a single cohesive narrative. This is obvious if you read the author's description, but less so if you impulse buy. Know what you're getting.
- There is a strong voice in this book which implies that this perspective as being a 'better' way to run games. If you can look past that, its a great resource.
- A little short (then again its just 5 bucks for the PDF).
I urge folks that rankle at the whole idea of making your players twist, to still think about reading this book. Without some negative or low points in your game, you run the danger of being bland and having players feel very little investment. Even if you don't go full bore, there are a few techniques which you can add to spice up your game. I read this book in part based on wanting to hear from a "firebrand" personality in the pen and paper industry, and while the author has a message it's much more measured and helpful than the buzz suggests. Also kudos for a sane $5 pricepoint for this PDF, a trend for nearly every product in the John Wick Presents library.


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The two main Rastafari rituals are reasonings (an informal gathering involving cannabis and discussion) and nyabingi (a festive dance). Most Rastafarians are vegatarians or vegans, and the most observant Rastas follow a dietary law called ital, which is based on natural vegetarian food. Many Rastafarians wear their hair in dreadlocks, a pratice with rich symbolism.
Cannabis (Marijuana) in RastafarianismRastafarians are well known for their religious use of marijuana, which grows plentifully in Jamaica. Rastas call the cannabis plant ganja, the holy herb, Iley or callie, and believe it was given by God... full article →
Dreadlocks in RastafarianismOne of the most visible practices of Rastafarians is the wearing of one's hair in dreadlocks. Dreadlocks have several purposes and layers of meaning for Rastafarians, including: - the biblical command not to cut one's hair (Leviticus 21:5) - the appearance of a lion's mane, representing strength, Africa, Ethiopia, and the Lion of Judah - naturalness and simplicity, which are associated with Africa - the Rasta's roots in Africa full article →
ItalThe most observant Rastas follow a dietary law called ital, the name of which is derived from the word "vital." Ital food is food which is completely natural (not canned and free of chemicals and preservatives) and eaten as raw as possible... full article →
NyabinghiThe nyabinghi, or binghi for short, is a nighttime drumming and dance ritual held on Rasta holidays and special occasions. Nyabinghis can last for several days and bring together hundreds of Rastafarians from all over Jamaica... full article →
ReasoningIn Rastafarianism, the reasoning is an informal gathering at which a small group of Rastas smoke ganja and engage in discussion. The reasoning ritual begins when one person lights the ganja pipe, or "chalice," and recites a short prayer while all other participants bow their heads... full article →
Further Reading
- McAlister, Elizabeth A.. "Rastafari." Encyclopaedia Britannica Online. 17 Dec. 2004. Web. Accessed 15 Feb. 2017.


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California-based JT Holmes spends his winters in the Lake Tahoe area, skiing his home turf at Squaw Valley Ski Resort. When he's not on skis, the multi-talented athlete can be found pushing the limits of human flight, whether in a wingsuit, on skis, or a combination of the two. Holmes' sport transcends the outdoor world as well—he has coordinated and performed flying and BASE jumping scenes for the films Transformers 2 and Hangover 3. You can track his adventures here.
Gear Institute: What are you up to these days?
Holmes: Well, I love skiing and I love flying. My favorite pastime at the moment is Speedriding and I want to enjoy this activity to its fullest! This means linking up with Chris Santacroce to learn some proper barrel rolls and also to just log as much time in the air as possible with my skis and wing.
Gear Institute: What items—other than sponsor's gear—do you ALWAYS bring when venturing?
Holmes: I rely on a G-Drive Hard drive for durable storage of footage from my adventures. I love flying my Gin Yak 18 meter speed wing. It is a great tool for mountain transportation. And I live in my Lululemon first layers. The apparel carries a hefty price tag but the silver linings have undeniable benefits.
Gear Institute: As a sponsored athlete, you have a lot of gear at your disposal. What items from your sponsors do you always carry?
Holmes: My number one piece of gear that is always with me is the GoPro Hero. I use it with the GoPro Gooseneck mount with Jaws Flex clamp, on every adventure. The clamp allows me to mount the camera about anywhere.
My go-to shoes for everything from travel to technical approaches are my Five Ten Guide Tennies.
Gear Institute: Are there any special packing or gear-protecting techniques/tricks you use?
Holmes: I use a scale so that I can be sure not to encounter troubles at the check in. Furthermore, I opt for low bulk zero frills duffel bags so that all the weight I carry with me is my toys and not the baggage itself! Wheeled duffles weigh a ton and I would rather pay an extra 5 bucks for a cart rental at the airport than 50 bucks for an extra 50-pound bag.
Gear Institute: What is one thing that you are especially excited about in your sport?
Holmes: I just need a sharp hat and a reasonable amount of sleep and I am ready to go!
Gear Institute: Anything else you want to share?
Holmes: Warren Miller's new ski film No Turning Back is touring and worth attending. If you choose a west coast viewing, I may see you there!


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There are simple steps to keep your computer optimized.
First off never install and run some registry optimization program.
A Big Problem we have found is people browsing the web go to a site an see a popup that tells them there computer is infected, not running smoothly or something similar.
Don't Fall For this these programs are very bad and usually result in crashing your system or giving you a unrecoverable virus.
to keep your pc running smoothly do these 5 simple task
- Keep Your System hardware Drivers Up to date
- Keep Your OS Updated with the latest updates (Windows Update)
- Run Checkdisk (Scandisk)
- Run Defragment tool
- keep you anti virus and anti malware software up to date.


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...well, before we get to that, let me say this: Ann Hathaway and James Franco did a well enough job as hosts of this year's telecast. The problem is that well enough was not good enough to prevent a 9 percent drop in viewership from last year. Producers were clearly looking to draw in a younger demographic. This is also why Jon Stewart and Chris Rock were picked to host in years past. Many felt Stewart's humor was too wry, and Rock's too edgy. Whether any of that is true is beside the point. The producers keep getting it wrong with their recent hosts.
Three burning questions relating to Hollywood: (1) Why haven't Julia Roberts and Sandra Bullock teamed up yet - the way Al Pacino and Robert Dinero did in Heat? (2) When are Denzel Washington and Tom Hanks going to work together again, because they were awesome in Philadelphia? And (3)...why not consistently have an Oscar host with international starpower and undeniable box office mojo, who is also...funny? Next time, I would pick Will Smith.
To me, it's a no-brainer. My favorite Oscar host of all-time is Bill Crystal. He's hilarious, has great comic timing, and is beloved in the film industry. So too, is Smith. He can hold the attention of young people for three to four hours, and even increase viewership. Hathaway and Franco will continue to have great careers in film, but they should never host the Oscars again. Time to think big. Give Will Smith a shot. If not him, then please make sure future hosts are funny.


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Skybox Suites at the US Open
The Ultimate VIP Luxury Experience for the Most Exclusive Tennis Matches in North America
USOpenTennisSuites.com specializes in providing our VIP clients and customers with the absolute best selection of seats in the house, especially the VIP Private Luxury Suites famous at Arthur Ashe Stadium. There is no better way to see the players and experience the action of the US Open. We custom fit all our US Open Tennis packages to meet the exact needs of our clients for every match. Many custom configurations available.
Contact us to book a suite at the US Open Tennis Championship.
Luxury VIP suites are perfect for corporate hospitality as well as special occasions with friends and family. The VIP skybox suites provide a more intimate and private setting enhanced by upgraded amenities and plenty of space to better enjoy your event. These VIP luxury suites, often called a "skybox" or "skybox suite", are in high demand matched by a very limited supply at the US Open.
When it comes to the US Open at Arthur Ashe Stadium, VIP luxury suites are the most exclusive seats in the building. Along with enjoying the absolute perfect views of the famous blue courts, you'll be very comfortable in upgraded VIP seats, with plenty of room for your family, friends, and colleagues. Catering is spectacular at the US Open with food and drink options varying. Multiple US Open luxury suites of different sizes and configurations are available depending on the match. Our US Open ticket and suites inventory varies and sells quickly.
Please contact us for more information about Arthur Ashe Stadium Luxury VIP Suites at the US Open.


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Skip to 0 minutes and 4 seconds In terms of errors, maybe, the W - we all know that here. The W is very difficult to pronounce for Hungarian students, as opposed to the R for Japanese when they learn Spanish, for example. And it makes it very interesting to always prepare a lesson because you have to expect and prepare those mistakes. In China for Chinese, lots of time you don't need to use the tongue. Just keep the same position of the tongue. And the way you speak English, you have to find the position of the tongue, and then you have to use it more often than Chinese. So this is a difficult part.
Skip to 0 minutes and 53 seconds And another part is that when you speak the sentence, there are lots of contraction, lots of change of the syllable, lots of rhythm and intonation. So this is the more difficult part for me.
What problems do learners have with pronunciation?
In this video you'll see Jonathan (a teacher) and Bobby (a learner) talking about problems some learners have with pronunciation.
Watch the video and note the different problems Hungarian, Japanese and Chinese learners have with pronunciation. Do you think that some of the problems Bobby mentions are true for other nationalities?
How can teachers help learners with pronunciation problems? Write your suggestions in the comments section. We'll talk about this some more in the next step.


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Summer Style: Hot Seasonal Color Trends
Update your home with lively hues that evoke the radiant feel of summer, from aqueous shades of silver and blue to classic pink and green.
Keep in mind: Price and stock could change after publish date, and we may make money from these links.
July 22, 2015
Nothing brightens up an all-white room quite like a lively shade of spring green. A vibrant mix between turquoise and sea green, this hue works best in a mostly neutral setting. Give your mood and interior an instant boost by incorporating spring green into your home, whether in small doses or through a daring piece of furniture like this living room cabinet. Image courtesy of Jesse
This regal shade of purple is ideal for year-round decor, but looks especially stunning during the summer months. Designer Brian Patrick Flynn spices up a simple patio with a purple-and-white striped area rug uniquely coordinated with a palette of yellow, brown and gray. Add some fresh lilacs or liatris to a vase to really accentuate purple in your home.
A bold color known for its masculine appeal, blue has found a spot in feminine settings, too. If you don't feel comfortable dousing your room with paint, let your accessories and decor do all the work when it comes to color. Designer John Gidding dresses up this simple dining room with a bold blue area rug coordinated with matching pillows and accented table settings. Complemented with a fiery shade of red, the design showcases a classic color duo without looking patriotic.
Mirroring the sun's radiant hues, this brilliant shade of daffodil livens up an otherwise all-white room. "The sunny-yellow chinoiserie wallpaper was paired with gray and bright white, as well as graphic black and navy accents, to turn a long, dark and uninviting room into a bright and cheerful spot," designer Christian May says.
Vaulted ceilings and open windows are an inviting environment for walls of turquoise. Mid-century modern furnishings in vintage mustard hues serve as a unique complement, while exerting a retro, urban feel within the space. This dynamic shade of blue can easily stand alone or be toned down with muted hues.
Slate-blue walls look crisp and stunning when coordinated with neutral furniture and accessories. Although deep in tone, this blue hue still evokes feelings of summer through its representation of ocean waves and coastal inspiration. Design by Vanessa De Vargas
Designer Shelly Riehl David adds a touch of whimsy to this graceful home by coating the walls with yellow green. From the furniture upholstery to the chandeliers, darker shades of green are used as accents to prevent the wall color from appearing out of place. When using a color with this degree of brightness, pair with browns and creams for a soft balance.
Although summer is typically associated with vibrant, saturated colors, bold primaries have been toned down with white to create shades of aqua, misty blue and azure. HGTV fan WhimsicalWitch gives her kitchen a shabby-chic makeover by adding sporadic splashes of aqua to the crisp, white space. Freshly painted chairs, distressed shutters and aqua-trimmed stemware bring a cool, delicate feel to the room, ideal for a true summer look.
Silver looks stunning with just about any color, especially summer whites and misty blues. Designer Sarah Richardson creates a tranquil and inviting bedroom by combining shades of white and ivory with soft hints of silver and baby blue. The serene palette will surely evoke sweet dreams and comforting thoughts.
Warm golden colors are often coupled with fall foliage and fall holidays. This year, however, both sandy golden hues and yellow gold are stepping out for summer. Gold is frequently associated with rich, elegant decor but when used correctly it can have a hip, retro vibe. This chic home office pairs gold accents with blush-rose walls and a muted-teal ottoman for a stunning contrast. Design by Domicile Interior Design
Brick red is a traditional color that can be successfully incorporated into any space or wardrobe all year round; however, a bold shade of red can deliver a classic summertime feel when used in a lighter color palette. While rich-red walls may be too brazen for some, designer Sarah Richardson shows that by using red as an accent with a creamy, off-white backdrop, you can still achieve the same eye-catching effect.
The vigorous use of green in this living room pays homage to lush, green grass in the summer. Designer Candice Olson integrates various shades of green into the space, from mint cream to kelly green. Unique color pairings of gray, tan and ivory with pops of green allow the lively hue to truly stand out for a fresh look.
Designer Allison Cosmos brightened this outdoor retreat with a dramatic burst of honeysuckle. Named Pantone's color of the year, this pretty shade of pink is still popular for summer decor and looks especially stunning with the lime-green accents and charcoal-gray backdrop. Sister shades, known as sea pink or orchid, are making an appearance this summer, providing the same feminine and whimsical effect as our dear friend honeysuckle.
Perfect for cottage-style homes and those nestled near the sea, mint cream pairs nicely with ivory, baby blue and other hues inspired by a creamy color palette. Designer Sarah Richardson brightened this dining room with a distressed mint-cream bench that sits between two ivory wing chairs covered in pale-green patterns. The look is elegant and sophisticated with cottage-style appeal that represents the true feel of summer.
This polished shade of purple is an elegant, feminine and inviting color that helps to stimulate conversation and creativity. The invigorating hue is ideal for living rooms, dining rooms and sitting areas where friends and family often interact. Take lavender to a daring new level by adding it to the wall with an eye-catching wallpaper pattern. Image courtesy of Kips Bay Decorator Show House
Whether used in the summer or fall, faded browns and creams deliver a peaceful palette. This serene sunroom features a monochromatic color scheme, allowing the outside views to provide a textural and interesting backdrop to simple ivory furniture and accessories.
Soft, pastel hues can serve as neutrals when placed with more saturated colors. Designer Erinn Valencich brings a lively touch to this tufted-pink headboard by joining it with lime-green and copper accessories. This unlikely color combination works perfectly together, creating a tranquil space with an energetic and colorful vibe.


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Arctic Blanket Collection
You will experience perfection at its best when you cuddle up with your precious pet in our new Arctic Blanket Collection by Hello Doggie. Your pet will feel special with this superb quality of softness to spend a lazy afternoon wrapped up in.
- Measurements:
Small Blanket - 14" x 17"
Large Blanket - 30" x 30"
Throw Blanket - 58" x 58"


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Beware a Wolfowitz in
Sheep's Clothing
[Editor's Note: This article was written just
before President Bush tapped Paul Wolfowitz to be President of the World
Bank on March 16.]
When I saw Paul Wolfowitz's smug grin in the January 17 issue of The New York Times, trouble was clearly on the horizon. The photo showed him in tsunami-stricken Indonesia, accompanying the country's defense minister, Juwono Sudarsono. His visit was under the guise of humanitarianism. But as always with Wolfowitz and Indonesia, a more nefarious project is in the offing: strengthening Washington's ties with the Indonesian military (TNI).
The first and only time I ever saw Wolfowitz in person was on May 7, 1997. I was in Room 2172 of the Rayburn House Office Building on Capitol Hill in Washington. The occasion was a hearing of the House of Representative's Committee on International Relations' Subcommittee on Asia and the Pacific. The subject was "United States Policy Toward Indonesia."
Wolfowitz walked in confidently from the front of the room just as the hearings were getting underway. Well-groomed and, at the time, in his mid-50s, he vigorously shook the hands of many of those present while smiling broadly. They called him "ambassador" as they greeted him.
Paul Wolfowitz would, of course, emerge a few years later as the infamous under-secretary of defense for the administration of George W. Bush. As such, he was one of the principal fabricators of Saddam as Hitler redux and a head cheerleader for the U.S. invasion of Iraq. Prior to that, Wolfowitz served as assistant secretary of state for East Asian and Pacific affairs from 1982 to 1986, and as ambassador to Indonesia during the Reagan administration's final three years. He thus was the primary architect of U.S. policy toward the resource-rich country in the 1980s. During his tenure, U.S. support for the TNI peaked despite, among many crimes, the military's illegal occupation of East Timor, which resulted in the deaths of more than 200,000 people.
At the time of the May 1997 hearing on Capitol Hill, Wolfowitz was dean of the prestigious School of Advanced International Studies at John Hopkins University and was an active member of the corporate-funded U.S.-Indonesia Society; he was thus still in a position to continue to exert influence on Washington's relations with Jakarta.
Douglas Bereuter, then a Republican representative from Nebraska, presided over the proceedings as chair of the subcommittee. A long-time supporter of Suharto's "New Order" government, Bereuter had proven to be among the staunchest opponents of efforts to block military aid to Jakarta. He opened the hearing by extolling the New Order's virtues, saying that it had "done much to preserve peace in Southeast Asia" and that it had "welcomed the U.S. security presence in the region and . . . granted U.S. forces access to Indonesian facilities." While Bereuter acknowledged the Suharto regime's less-than-shining human rights record -- including that in East Timor -- he argued for "continued military interaction" with Jakarta through American training and for "the sale of appropriately limited military equipment." Such "interaction," he opined, would "advance U.S. security interests as well as the cause of democracy and human rights."
Wolfowitz's testimony struck a similar tone, while explicitly arguing against any talk in Washington of support for East Timorese independence -- talk that he characterized as "destructive" -- and calling for a renewal of U.S. military training of the TNI. His testimony stressed Jakarta's many "achievements." "[I]n the 7 years since I left Indonesia," he declaimed, "on the positive side, there has been significantly greater openness in a number of respects. There is more open questioning of public officials on government decisions that have gone against the government, although in most cases, the government eventually prevailed. There have been court-martials of military officers for the massacre in East Timor in 1991. And I might note that I think for any military to court martial its officers for that kind of action takes an effort." [1]
The former ambassador was referring to Jakarta's charade-like prosecution and sentencing to minimal prison terms of a handful of low-ranking TNI officers in response to international criticism over what Indonesia termed "the Santa Cruz incident." This was Jakarta's euphemism for a massacre by the TNI of hundreds of peaceful pro-independence demonstrators in East Timor's capital in November 1991. The prosecutions and convictions dovetailed neatly with the official Indonesian line that the bloodbath--what a United Nations Commission on Human Rights' investigation characterized as a "planned military operation" -- was not the result of a concerted policy, but of the actions of a few rogue soldiers. [2]
In his prepared written statement submitted to the subcommittee, Wolfowitz praised Suharto, a dictator who seized power through what the CIA described "as one of the worst mass murders of the 20th century." Over the course of several months in 1965-1966, the Suharto-led military and its minions slaughtered members of the Indonesian Communist Party along with members of loosely affiliated organizations such as women's groups and labor unions. Amnesty International estimated "many more than one million" were killed. The head of the Indonesian state security system approximated the toll at half a million, with another 750,000 jailed or sent to concentration camps.
But such unpleasantness was clearly not on Wolfowitz's mind in composing his statement. "Any balanced judgment" of the country's human rights situation, he opined, "needs to take account of the significant progress that Indonesia has already made." Much of the progress, he declared, was due to Suharto's "strong and remarkable leadership."
In 1998, massive protests led Asia's longest-reigning dictator to step down. Hence Wolfowitz quickly changed his tune, later characterizing Suharto in an interview on PBS Newshour with Jim Lehrer as someone who "without any question was fighting reform every step of the way." [3] Yet, he continued to defend the Indonesian military as a force for good.
On February 17, 1999, Wolfowitz was in the secretary of state's private dining room for a working dinner called by its hostess, Madeleine Albright. The invited guests were academics, all of them Indonesia specialists. After a dessert of apple crisp and rum-raisin ice cream, the secretary of state asked the guests specific questions about developments in Indonesia, a country she was preparing to visit in March. The last topic of discussion was East Timor.
Geoffrey Robinson, a historian at the University of California, Los Angeles, had been designated to speak on the matter. A State Department representative had told Robinson that he was to discuss alternatives to a referendum in East Timor, to explain what would be viable options other than a one-person-one-vote process as there were elements within the State Department who did not support that concept. Despite those instructions, Robinson made it clear in his remarks that only a legitimate act of self-determination -- in the form of some sort of universal ballot organized and run by the United Nations -- would satisfy the East Timorese population, and that there were no viable alternatives.
Sitting at the other end of the table, Wolfowitz quickly responded, informing Albright and the other guests that independence for East Timor was simply not a realistic option. Employing language long utilized by Jakarta, he argued that East Timor would descend into civil war if Indonesia were to withdraw, leading to the same sort of chaos that unfolded in 1975. The problem in East Timor, he contended, was one of tribal and clan-based differences. Only the Indonesian military had been able to put an end to the fighting, according to the esteemed former professor.
A State Department official politely called the evening to a close as soon as Robinson informed Wolfowitz of the wrong-headed nature of his analysis.
Several months later, East Timor overwhelmingly opted for independence in a U.N.-run ballot. In response, the TNI and its militia proxies killed many hundreds of civilians, while raping untold numbers of women and girls and laying waste to the vast majority of the territory's buildings and infrastructure, before finally withdrawing. As when Indonesia invaded the former Portuguese colony in 1975, it was not the atavistic propensity of the East Timorese to fight amongst themselves that was the problem, but an aggressive and brutal TNI and its patrons in Washington (among other Western capitals).
The TNI's myriad crimes in East Timor could not have happened without the significant economic, military, and diplomatic support of the TNI from the United States. Indeed, such support was decisive in allowing the 1975 invasion to take place and for the occupation to endure as long it did. But Washington -- and a compliant corporate media and Beltway pundit class -- have effectively buried this history.
The intentional nature of this "forgetting" -- in addition to the deep bipartisan nature of support for U.S. empire and an ugly global status quo -- was on shameless display on May 13, 2000, in Italy at the Bologna Center of the Johns Hopkins University. The guest speaker was Richard Holbrooke, a man who had also served as assistant secretary of state for East Asian and Pacific affairs -- during the Carter "human rights" administration -- and who thus also has a great deal of East Timorese blood on his hands. Introducing him was Dean Paul Wolfowitz.
After Wolfowitz's flowery welcome, Holbrooke returned the favor, cracking a joke about how the introduction showed that he gets "better treatment from Republicans than Democrats in some quarters." He then praised the former ambassador to Jakarta as "a continuing participant in the effort to find the right policy for one of the most important countries in the world, Indonesia." Holbrooke proceeded to explain how Wolfowitz's "activities illustrate something that's very important about American foreign policy in an election year and that is the degree to which there are still common themes between the parties. East Timor is a good example. Paul and I have been in frequent touch to make sure that we keep it out of the presidential campaign, where it would do no good to American or Indonesian interests." [4]
Yet, despite such efforts, Congress significantly weakened military ties with Jakarta in 1999 and has since prevented reinstatement as a result of public outrage over the TNI's atrocities in East Timor and elsewhere, and past U.S. support for such. It is this situation that Paul Wolfowitz and the Bush administration are eager to reverse. The tragedy in Indonesia has provided an opportunity to do just that.
Almost all of the tsunami deaths took place in the region where over 160,000 people of a population of 4.2 million have perished. Much of its capital city of Banda Aceh and most of the province's coastal towns and villages are in ruins, with about 500,000 people homeless. Oil-rich Aceh is also the site of a long-standing war for independence, one that has resulted in the deaths of somewhere between 10,000 and 20,000 civilians, almost all of them victims of a brutal TNI counterinsurgency campaign against a pro-independence movement that enjoys widespread support. As a result, Jakarta's brutal efforts to crush the insurgency are unpopular to say the least.
At one of his two press conferences in Jakarta on Sunday, February 16, 2005, Wolfowitz argued, "Everybody recognizes that the most important thing right now is to meet the needs of the people of Aceh," suggesting that the best way to do so was to increase the TNI's logistical capacity. Referring to the Bush administration's post-tsunami decision to grant to Jakarta replacement components for U.S.-produced military transport planes, Wolfowitz asserted that there is "no controversy whatsoever in my country about the fact that we are now providing spare parts to get Indonesian C-130s flying." [5]
The East Timor Action Network, some human rights groups, and organizations of Acehnese refugees in the United States, however, have communicated to Washington that they do not approve of any assistance from Washington to the TNI-- including that characterized as "non-lethal"--as it inevitably increases the TNI's repressive capacity. At the same time, they do want the TNI--an institution widely distrusted, if not hated, in Aceh--involved in the distribution of aid in the province. [6]
According to various reports in the weeks following the tsunami, the TNI exploited the crisis and undercut the delivery of humanitarian assistance by refusing to allow local non-governmental organizations to distribute aid channeled through the Indonesian government. In addition, the TNI continued to target the Free Aceh Movement (GAM) and its civilian supporters despite the GAM's post-tsunami declaration of a unilateral cease-fire.
Nevertheless, Wolfowitz argued at both press conferences that weak U.S ties with the TNI exacerbate the problems of Indonesia, from the country's ability to respond to humanitarian crises to ongoing efforts of military reform. "I think if we're interested in military reform here, and, certainly this Indonesian government is, and our government is, I think we need to reconsider a bit where we are at this point in history," stated Wolfowitz. Echoing the same baseless arguments he made in the 1990s, Donald Rumsfeld's deputy claimed that the way to promote the TNI's supposed efforts to make itself more professional and accountable is to lift Washington's current restrictions and increase U.S. military sales and training. In this way, so goes the logic, the TNI would be exposed to democratic values and practices.
But just as before, there is no evidence that exposure to the alleged democratic values of the Pentagon improve the conduct of allied militaries abroad; to the contrary, U.S. training often makes them more efficiently brutal. At the same time, there is nothing to indicate that the TNI has changed or is interested in doing so.
Human rights groups report continuing widespread atrocities by the TNI--especially in Aceh and West Papua. An October 2004 report by Amnesty International, for example, writes of "evidence of a disturbing pattern of grave abuses of civil, political, economic, social and cultural rights" in Aceh for which Indonesian security forces bear "primary responsibility." The human rights violations--including extrajudicial executions, torture and the rape of women and girls--have taken place at a scale "so pervasive that there is virtually no part of life in the province which remains untouched," the Amnesty report says. [7] Meanwhile, Jakarta--partially following Washington's lead on impunity for international crimes for everyone except official U.S. enemies--has not held any Indonesian political or military personnel responsible for the myriad crimes committed in East Timor or elsewhere.
But such facts have fallen on deaf ears in the Bush administration. On February 27, the U.S. State Department announced the full reinstatement of International Military Education and Training (IMET) funding to Indonesia, stating that the program "will strengthen [Indonesia's] ongoing democratic progress." The reinstatement followed on the heels of Secretary of State Condoleeza Rice's fraudulent certification that the TNI had complied with conditions legislated by Congress. [8]
Such news undoubtedly brought another smile to Paul Wolfowitz's face. But for those truly concerned with human rights, democracy, and international law, there is nothing to smile about: As it did in the 1980s and 1990s, Wolfowitz's current recipe for Indonesia will not bring about "reform," but will only make Washington complicit in the TNI's war crimes and crimes against humanity.
Joseph Nevins, an assistant professor of geography at Vassar College in Poughkeepsie, New York, is the author of Operation Gatekeeper: The Rise of the "Illegal Alien" and the Making of the U.S.-Mexico Boundary. Cornell University Press will publish his latest book, A Not-So-Distant Horror: Mass Violence in East Timor, in May. This article first appeared in Indonesia Alert!. Thanks to Ben Terrall.
Other Articles by Joseph Nevins
Mass Murderers and Double Standards of Justice
* Beyond the Myth: Remembering Jimmy Carter, the President
Border Death-Trap: Time to Tear Down America's
Berlin Wall
(1) United States Congress. "United States Policy Toward Indonesia," Hearing
before the Subcommittee on Asia and the Pacific of the Committee on
International Relations, House of Representatives, 105th Congress, May 7,
1997, Washington, D.C.: U.S. Government Printing Office, 1998.


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Home of the Yeomen
June 1, 2020
Cox Communications recently ran a social media campaign honoring K-12 educators that demonstrated excellence while conducting virtual instruction.
Parents and students and staff nominated their teachers across Ohio, Rhode Island, and Connecticut for this award and Dentzler's own Jennifer Schweitzer was one of six selected to be a "Hero of Distance Learning."
With this honor, came a $1,000 grant for a virtual classroom makeover.
Schweitzer was nominated by Parma Council of PTA president, Heather Ekechi. "Ann (Jennifer) Schweitzer from Dentzler Elementary has gone above in working on educating her first grade class. Her enthusiasm and effort to go above for the kids is simply amazing! She has daily meetings via Facebook and posts learning videos, multiple links, and has even taught subjects like how to write a letter and is mailing the kids activities, etc."
"Ann (Jennifer) Schweitzer, I second your nomination," added Adria Fisher, a PCSD school psychologist. "She has simulated her students' day as if they are in the classroom with her, while helping parents learn her classroom language!"
Schweitzer was honored with this award on Monday, May 18th during a surprise Zoom meeting and was beyond excited with the news. She was the only teacher to be nominated twice out of all the teachers that were recognized.
Schweitzer is looking forward to using the grant award to obtain additional equipment and resources that can be utilized with distance learning activities as well as activities within her physical classroom.
Congratulations, Jen! You are a valued member of our Dentzler team and an asset to the PCSD.
PHOTO CAPTION: Jennifer Schweitzer, a First Grade teacher at Dentzler Elementary, was recently awarded a $1,000 grant from Cox Communications as a "Hero of Distance Learning" for her excellence in conducting virtual instruction for her students.


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When JW Player Doesn't Play On IE
I've used the JW Player flash player for lots of projects now. It's free, customisable enough and has a lot of documentation, plus community support, to help when something isn't working right.
I ran into an issue during my latest project however where JW Player was working fine in Firefox but on Internet Explorer I was getting a blank area where the video should have been appearing.
The Solution
It turned out the path to my swfobject.js was not valid. I was previously using:
<script src='/js/swfobject.js' type='text/javascript'></script>
In order to get the player to work in all browers I needed to change my code to either:
<script src='js/swfobject.js' type='text/javascript'></script>
<script src='http://www.mydomain.com/js/swfobject.js' type='text/javascript'></script>
See how the path to 'swfobject.js' is either relative or absolute, rather than referring to the root? After making the above amendments it worked perfectly across all browsers.


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Export 1 results:Author Keyword [ Title] Type Year
Filters: Author is Roy, B. [Clear All Filters]
"Effects of transionospheric signal decorrelation on Global Navigation Satellite Systems (GNSS) performance studied from irregularity dynamics around the northern crest of the EIA", Radio Science, vol. 49, no. 10, pp. 851 - 860, 2014.,


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By: Seth Resler, Jacobs Media
Sadly, we've seen way too many rock stars pass away in the past few weeks: Scott Weiland, David Bowie, Glenn Frey. So what should your station's digital response be when these tragedies occur? Here are some things you can do:
1. Do No Harm on Social Media.
First and foremost, make sure that every public-facing member of your staff knows better than to make light of the situation on social media. A poorly worded tweet can do a lot of damage, and a person's death is not a good time to go for laughs. If you have doubt about whether or not something might be misinterpreted, skip it.
2. Create Online Content.
Even if you're not going to drastically change your on-air programming in response to a death, you can use your website to pay homage to the departed. Create a blog post or page on your website celebrating the life of the deceased artist. Here are some ideas:
- Have each DJ write a short paragraph about their favorite song by the artist and embed YouTube videos to accompany each paragraph.
- Create a short listicle celebrating the artist. For example, "The Top 5 David Bowie Personas."
- If you have recordings of old interviews or performances, post them along with a remembrance.
Remember, if you include images in your content, make sure that you have paid for the rights to use them. Violating copyright can result in hefty fines.
3. Invite Listeners to Comment, but Police the Comments Carefully.
At the end of your content, invite listeners to participate by sharing their memories in the comments section of the page. Just make sure that somebody is keeping a watchful eye on what's posted. Immediately delete any distasteful comments.
4. Create a Vanity URL that Redirects to Your Content.
A vanity URL is an easy-to-remember URL, such as "yourstationname.com/glennfrey." Encourage your air talent to give out the URL when they talk about the artist. Create imaging production directing people to the URL. Create additional vanity URLs for common misspellings, such as "yourstationname.com/glennfry."
5. Send an Email Campaign.
Send an email campaign to your listeners inviting them to click through to your content and share their memories in the comments section.
6. Invite Your Listeners to Contribute Audio.
Your station can invite listeners to share their memories in audio form so that you can use them on the air. Use Speakpipe to allow listeners to leave voicemail messages on your website. If your station's mobile app was built by jacapps, this is a good time to take advantage of the Open Mic feature, which allows people to contribute audio from their smartphones.
While you may be limited in your on-air response when a major artist dies, you are not limited on the web. Your listeners have strong emotional connections to these musicians. Use your website to help them celebrate the lives of the artists who have left us.
As always, if you need help, please feel free to reach out to me.
Please contact me with questions, comments, and thoughts.


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Streamlining your business processes with an innovative ERP solution is no simple task. Many factors are involved in making the implementation a success, each an essential cog in the machine. If one is not completed correctly, the mechanism will undoubtedly be less efficient – or fail altogether.
At CloudGenX, we are Microsoft Dynamics experts. We specialise in helping businesses to enhance their profits and activities through the power of ERP. So, we have an in-depth understanding of what it takes to make your ERP endeavor a success.
To help you on your path, we have developed a list of the most important factors related to an ERP implementation.


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When choosing the best robotic welding system for your operation, make sure to pay special attention to the gun and consumables. One size does not fit all.
While the robot itself, proper programming, and oversight by a trained supervisor are all important components in the overall robotic welding operation, the robotic GMAW gun also has a direct impact on quality and productivity, as well as costs.
When it comes to robotic welding, precision, repeatability, and speed are essential to ensuring a successful outcome. Companies rely on the robot's ability to execute the same weld, exactly the same way, and as fast as possible.
While having the robot properly programmed and monitored by a trained welding supervisor is important, the gun used also has a direct impact on quality, productivity, and costs.
Consider some of the top things to know about robotic gas metal arc welding (GMAW) guns as a way to get the most out of this equipment.
1. One size does not fit all when it comes to robotic GMAW guns.
As with any piece of welding equipment, the right robotic GMAW gun for the job depends on the application— specifically, on the material being welded, the thickness, amperage, and required arc-on time.
Air-cooled guns provide the best results for low-amperage applications on thin materials (up to 0.16 inch thick) and for applications with short welds in high volume, such as those in the automotive industry.
These guns rely on the ambient air, as well as the copper in the unicable, to cool them during the welding process and typically are quite durable. In the event of a collision, the stronger neck construction helps reduce the opportunity for bends compared to a water-cooled model. Air-cooled guns generally are available in a range of 300 to 500 amps.
Water-cooled robotic GMAW guns are better suited to applications that require high- amperage welding for longer periods of time, particularly on materials over ¼ inch thick and on longer weldments.
Models often range from 300 to 600 amps at up to 100 percent duty cycle. These guns require an external cooler and, therefore, cost more upfront and require more maintenance. To prevent overheating on high-amperage applications, however, the additional cost and upkeep may be worthwhile.
For companies welding materials of varying thicknesses requiring both high and low amperages, a hybrid air-cooled/water-cooled gun is a viable option. These guns have a durable neck like an air-cooled gun with exterior water lines to cool the front-end consumables, making them easier to maintain. Should the gun have a water-line leak, it can still operate for a time (via the cooling capacity of the air-cooled unicable), so operators can address the problem before a complete failure occurs.
2. Added features benefit performance.
Manufacturers build robotic GMAW guns with precision in mind. The goal is to complement the robot with features in the gun that help the entire system maintain its repeatability, quality, and speed. Adding options like an air blast or wire brake to the gun can help.
An air blast feature blows high-pressure air through the front of the gun (air-cooled only), helping to remove debris. The goal is to remove any contaminants that could enter the weld pool and potentially cause poor weld quality. By reducing that risk, the air blast feature also helps reduce the need for rework. It supports more arc-on time, as it can be programmed to operate between weld cycles.
Another optional feature that can add to the consistency of a robotic GMAW gun is a wire brake. This feature stops the wire from feeding through the gun when the welding stops, allowing for uniform stick-out (or extension) at the start of the next weld.
For robots that use touch-sensing software, a wire brake is invaluable; it holds the welding wire in a set position while the robot moves and searches for the weld joint, helping to ensure that the robot can accurately determine the location of the weld joint and create a consistent, high-quality weld. A wire brake also helps prevent unspooling inside the gun during each stop and start.
3. The right neck and cables can help streamline the process.
Gaining access to the weld joint is critical for a robot to execute an accurate weld time and time again. In many cases, companies are moving to smaller robots and smaller weld cells to maximize floor space so they can produce more parts and become more competitive. These changes make it increasingly necessary for the gun to have a neck design that allows it to maneuver into the weld joint unhindered. Many gun suppliers offer various neck lengths and angles (with or without requiring special orders), and some offer online configurators that customize a gun for the exact application.
Sturdy cables that are easy to change out help to create a more efficient operation. Look for cables constructed of durable materials to protect against UV damage from the arc or general wear from air movements. Features like rotating power connections also can help by minimizing stress from routine torsion.
4. Guns operate more efficiently with the right consumables.
The right consumables—nozzles, contact tips, gas diffusers (or retaining heads), and liners—are essential for achieving maximum performance and reducing downtime. Gun manufacturers offer consumables for a range of applications, including heavy-duty products, such as chrome zirconium contact tips for high-amperage robotic welding. These tips are harder and more durable than copper tips, so they tend to last longer.
Contact tips that help improve arc starting also are available.
The liner used with the robotic GMAW gun can have an impact on the overall efficiency of the operation and gun performance. It is important to cut the liner to the correct length. A liner that is too short can lead to poor wire feeding and birdnesting (a tangle of wire in the wire feeder drive rolls). A liner that is too long can cause kinking, wire feeding issues, and shortened contact tip life, all factors that can interrupt production. Always follow the manufacturer's recommendation for trimming the liner. Use a liner gauge as a guide when possible.
The type of liner used also plays a part in keeping the system up and running more effectively. Front-loading liners help reduce downtime by allowing the gun to stay connected to the wire feeder while the operator completes the changeover from a safe zone in the robotic weld cell.
Spring-loaded modules work in conjunction with a front-loading liner to help minimize problems if a welding operator cuts the liner to an incorrect length. These modules are housed in the power pin and put forward pressure on the liner after the welding operator installs it from the front of the gun. They allow up to 1 in. of forgiveness if the liner is too short. Again, these types of liners can help reduce time for addressing wire feeding issues that could affect productivity.
5. Preventive maintenance is not optional.
Companies invest in robotic welding systems in part to seek out productivity gains in their operation. With that in mind, the goal is to keep the system running as much as possible, but scheduling downtime for gun maintenance is essential.
The scope of a preventive maintenance (PM) schedule for a gun varies according to the application, but all companies should have a general maintenance sheet that indicates how often components on the gun should be and are changed. Tracking the maintenance activities makes it easier to troubleshoot a problem should it occur; maintenance personnel can look at the last thing changed during gun PM to see if that variable is a factor in the issue.
Routinely look for secure, clean connections between the neck, the diffuser, and the contact tip. It's important to check that the nozzle is secure and that any seals around it are in good condition. Such activities can take place during routine pauses in welding, while other, more intensive maintenance can occur offline.
An effective PM program should include an appropriate parts inventory for the gun, including consumables. If something fails or needs to be replaced during PM but is not available, it can cause significant downtime in the production.
Other items to consider.
Be sure to select a gun with the right amperage to accommodate the application at hand. If you are using a conventional robot (as opposed to a through-arm style), selecting the right cable length for the gun also is important to prevent unnecessary wear.
Training employees on the proper operation and maintenance of the gun is critical. While GMAW guns are a seemingly small part of the overall robotic welding system, when they are selected, installed, and managed properly, they can contribute positively to the overall efficiency of a robotic welding system.