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Modulation of the activity of the insulin receptor, enhancement of glucose uptake by cells, and other effects significant in the control and management of diabetes are accomplished using compounds of the formula
Compounds in the genus of Formula (1) can also be used for structure activity studies to identify features responsible for the relevant activities.
1. A method to modulate the kinase activity of insulin receptor which method comprises contacting said insulin receptor or the kinase portion thereof with a compound of the formula
each A is independently a proton-accepting substituent;
each R is independently a noninterfering substituent;
each n is independently 0, 1, or 2; and
each linker is independently an isostere of —NHCOHN— or of —N═N— or of —NHCO—;
said compound provided in an amount effective to modulate said kinase activity.
2. The method of
4. The method of
6. A method to potentiate the insulin activation of insulin receptor which method comprises contacting said insulin receptor or the kinase portion thereof with insulin and with a compound of the formula
each A is independently a proton-accepting substituent;
each R is independently a noninterfering substituent;
n is 0, 1, or 2; and
each linker is independently an isostere of —NHCONH— or of —N═N— or of —NHCO—;
said compound provided in an amount effective to potentiate said insulin activation.
7. The method of
9. The method of
11. A method to potentiate the stimulation by insulin of cellular glucose uptake which method comprises contacting cells displaying the insulin receptor with insulin and with a compound of the formula
each A is independently a proton-accepting substituent;
each R is independently a noninterfering substituent;
n is 0, 1, or 2; and
each linker is independently an isostere of —NHCONH— or of —N═N— or of —NHCO—;
said compound provided in an amount effective to potentiate said glucose uptake.
12. The method of
14. The method of
16. A method to stimulate the uptake of glucose in cells displaying the insulin receptor which method comprises contacting said cells with a compound of the formula
each A is independently a proton-accepting substituent;
each R is independently a noninterfering substituent;
n is 0, 1, or 2; and
each linker is independently an isostere of —NHCONH— or of —N═N— or of —NHCO—;
said compound provided in an amount effective to stimulate glucose uptake.
17. The method of
19. The method of
21. A method to lower blood glucose in a diabetic subject which method comprises administering to said subject a compound of the formula
each A is independently a proton-accepting substituent;
each R is independently a noninterfering substituent;
n is 0, 1, or 2; and
each linker is independently an isostere of —NHCONH— or of —N═N— or of —NHCO—;
said compound provided in an amount effective to lower blood glucose.
22. The method of
24. The method of
27. A method to lower blood glucose in a diabetic subject comprising administering to the subject a blood glucose-lowering effective amount of the compound of
28. A pharmaceutical composition comprising the compound of
More than one reissue application has been filed for the reissue of application No. 08/784,854, filed Jan. 15, 1997, now U.S. Pat. No. 5,851,988. The reissue applications are application No. 09/748,665 filed Dec. 21, 2000, now reissue No. 38,915 and the present divisional reissue application.
The invention relates to the substitution of nonpeptide compounds for peptide ligands that activate hormone receptors. More specifically, it concerns simple nonpeptide compounds that behave as agonists for the insulin receptor and enhance the effect of insulin on this receptor.
Among the many functions performed by peptides and proteins in metabolism is the ability to stimulate receptors at cell surfaces to effect intracellular consequences important in maintenance and development of the organism. Peptide and protein hormones interact with receptors specific for them so that the activity of the hormone is felt on designated cells exhibiting these receptors. The insulin receptor is present on virtually all cells and at high concentrations on the cells of the liver, skeletal muscles, and adipose tissue. Stimulation of the insulin receptor with insulin is an essential element in carbohydrate metabolism and storage.
Diabetics either lack sufficient endogenous secretion of the insulin hormone (Type I) or have an insulin receptor-mediated signaling pathway that is to some degree resistant to endogenous or exogenous insulin, either through primary or post-translational structural changes, reduced numbers or poor coupling among signaling components (Type II). All Type I diabetics, and many Type II subjects as well, must utilize injection to obtain enhanced activity of the extant insulin receptors, since endogenous insulin can at present be replaced only with an alternative supply of insulin itself, previously isolated from native sources, and now recombinantly produced. While the recombinant production of insulin permits a less immunogenic form to be provided and assures a reliable supply of needed quantities, the necessity to administer the hormone by injection remains, due to the instability of peptides and proteins in the digestive tract. It has long been the goal to substitute for peptide ligands, including insulin, small molecules which are not digested and can be absorbed directly into the bloodstream. However, to date, nonpeptide substances which can exert the effect of insulin on its receptor have eluded discovery.
There have been many instances in which nonpeptide materials have been used to inhibit enzymes whose native substrates are peptides. For example, Brinkworth, R. I. et al. Biochem Biophys Res Comm (1992) 188:624-630 describe the inhibition of HIV-1 proteinase by various aryl disulfonates. The ability of triazine dyes to bind NADH oxidase from Thermus thermophilus was studied by Kirchberger, J. et al. J Chromatog A (1994) 668:153-164.
It has also been shown that certain nonpeptide components enhance the agonist properties of a peptide hormone. The ability of certain thiazolidinediones such as pioglitazone to enhance adipocyte differentiation by stimulating the effect of insulin has been described by, for example, Kletzien, R. F. et al. J Mol Pharmacol (1992) 41:393-398. These represent a class of potential antidiabetic compounds that act at an unknown site downstream from the insulin receptor itself and enhance the response of target tissues to insulin. Kobayashi, M. Diabetes (1992) 41:476-483. It is now know that most of the thiazolidinediones bind to PPARγ thus triggering certain nuclear events that may result in enhanced sensitivity of the target cells to insulin. However, the complete mechanism is still unresolved.
In any event, it has not yet been possible to utilize simple molecules to provide the effect of a peptide hormone by stimulating receptor activity independently of the peptide hormone binding site.
It has now been found that several aryl di- or polysulfonate compounds which share certain common structural features are able to effect stimulation of the insulin receptor to activate the autophosphorylation activity required for signal transduction. The availability of these compounds permits construction of assays and comparative procedures for evaluating additional candidate compounds as well as the design and synthesis of therapeutics for primary treatment of insulin resistance and diabetics with the appropriate structural features.
The invention takes advantage of the behavior of, and information provided by, certain compounds, whose synthesis is straightforward, in order to conduct assays for the ability of candidate small molecules to activate the insulin receptor and to design these candidates. The method of identifying a primary member of this group, TER12 and of obtaining the remaining members is described below. These small molecules represent the first instance of direct agonist activity on the insulin receptor by a nonpeptide. Compounds identified in this way are useful in the control and management of diabetes in suitable subjects.
Thus, the invention is directed to methods to modulate the kinase activity of the insulin receptor or the kinase portion thereof; to potentiate insulin activation of the insulin receptor; to potentiate glucose uptake stimulation by insulin; to lower blood glucose; and to stimulate glucose uptake per se in cells by use of compounds having the formula
These compounds are thus useful in regulating the glucose metabolism of mammalian subjects which are afflicted with diabetes.
In another aspect, the invention is directed to a method to screen candidate compounds for ability to activate the insulin receptor. The method comprises first obtaining a fingerprint of each candidate with respect to a reference panel and obtaining a fingerprint of TER12, TER3938, TER3935, TER16998 or other compound shown to activate the kinase activity of the insulin receptor with respect to the same reference panel. Then the fingerprint of each candidate is compared with that of any of these compounds. Successful candidates are compounds whose fingerprints resemble that of any of these compounds.
In another aspect, the invention relates to a method to design and synthesize a molecule that exhibits agonist activity or insulin agonist stimulating activity with respect to the insulin receptor. This method comprises assessing an activator identified as above for structural features which correlate with said activities. Structural features include those discernible from examination of the conventionally depicted structure as well as those derived by examination of the X-ray crystallographic structure and obtained from computer-generated docking experiments. Compounds containing these structural features are designed and synthesized.
In still another aspect, the invention is directed to a method to identify a candidate compound capable of activating a receptor which undergoes autophosphorylation by screening said receptor with a maximally diverse panel of candidates.
In still another aspect, the invention provides an alternative method to identify a candidate compound which will activate the insulin receptor. This method comprises contacting a sample containing at least the kinase portion of the insulin receptor with an activator identified by any of the foregoing methods in the presence and absence of said candidate.
The binding of said activator is then measured in the presence and absence of said candidate. For a successful candidate, the binding of activator is diminished in its presence as compared to its absence.
The structure of the insulin receptor and some aspects of its mode of action as currently understood, are illustrated in FIG. 1. The receptor consists of four separate subunits consisting of two identical α and two identical β chains. The two β chains contain a cross-membrane domain; the α portions are in the extracellular domain and accommodate the binding of insulin. The illustration in
The invention, in general, is directed to methods to regulate and manage subjects with diabetes by virtue of administering compounds which affect the activity of the insulin receptor. Without intending to be bound by any theory, it is believed that the compounds useful in the methods of the invention act directly on the kinase function of the receptor and do not necessarily compete with insulin for binding at the insulin-binding site, nor do they effect activation of the receptor by a mechanism similar to that exhibited by insulin. The compounds of the invention are able directly to activate the kinase of the receptor to autophosphorylate, to potentiate the effect of insulin on the receptor, to activate the kinase function of the receptor in phosphorylating exogenous substrates, to effect the increased uptake of glucose by adipocytes and insulin receptor-bearing cells in general, and to lower blood glucose levels in diabetic subjects.
The compounds of the invention are generally of the formula
In the compounds of Formula (1), the proton-accepting substituents represented by "A" may be anionic or may be sufficiently nucleophilic to accept a proton at physiological pH. Particularly preferred embodiments of A include —SO3X, OP(OX)3 and —COOX where X is a hydrogen atom or a cation depending on pH. Suitable cations include inorganic cations such as sodium, potassium, calcium and the like or may be organic cations such as those provided by organic bases, for example, caffeine. Also included in embodiments of A are amino substituents including primary, secondary, and tertiary amines, as well as typical bioisosteres of anionic ligands such as tetrazole rings, even when they are not charged.
The noninterfering substituents on the naphthyl moieties in Formula (1) may or may not be present—i.e., each n is independently 0, 1 or 2. The position of R is arbitrary in each case; preferred embodiments of R include substituted or unsubstituted hydrocarbyl moieties, whether straight-chain, branched, or cyclic and whether aromatic or nonaromatic. Among these are included but not limited to alkyl substituents of 1-6C, alkenyl substituents of 1-6C, and alkyl or alkenyl substituents wherein the carbon chain is interrupted by one or more heteroatoms such as O, N or S. Substituents may also be of the formula —OR′, —NR′2 and —SR′, wherein R′ is H or is R as defined above. Particularly preferred embodiments include —OH and additional aromatic moieties containing proton-accepting substituents.
In the compounds of Formula (1), each linker is independently an isostere of —NHCONH—, such as —NHCNHNH—, —NHCOO— or —OCOO— or may be an isostere of —N═N—, such as —CH═CH—, —CH═N— or —CH2CH2— or —NHCH2—. The linkers may also be isosteres of —NHCO—, such as —OCO— or —COO—. General methods for forming all of these linkages between aromatic systems are well known in the art.
Particularly preferred compound of Formula (1) are those wherein each R is independently OH or is
Also preferred are embodiments wherein the compound of Formula (1) is selected from the group consisting of
Particularly preferred are compounds shown in
In addition to protocols to control diabetes in relevant subjects, the invention is directed to methods to identify additional compounds which are useful in these protocols. In general, such methods include identifying an active compound by a screening process that utilizes a set of maximally diverse candidate compounds. This method comprises, in a preferred embodiment, contacting each member of a set of maximally diverse candidate compounds with said receptor or kinase portion thereof; detecting the presence or absence of tyrosine phosphate on the receptor or kinase portion contacted with each set member; and identifying as a successful candidate at least one member of the set wherein an increased amount of tyrosine phosphate is detected in the receptor or kinase with which it was contacted, relative to untreated receptor.
In addition, once a compound with at least moderate ability to activate the kinase activity of insulin receptor has been identified, additional compounds can be identified by comparing the properties of the candidates with those of compounds having known activity. One particularly useful property to compare is the affinity fingerprint of the compound against a reference panel of proteins which provide a first approximation of the binding modes of all proteins. This is described in U.S. Pat. No. 5,587,293, incorporated herein by reference. Further, analysis of compounds shown to activate the insulin receptor kinase using standard structure activity analysis will result in additional compounds which behave as activators. Compounds identified as activators of the receptor in any of the foregoing three ways can further be used in competitive analyses with respect to additional candidate compounds, particularly if radiolabeled. Receptor mutagenesis and photoaffinity analogs may also be used to identify the receptor site binding the compounds, for use in rational drug design.
The three primary methods of identification of compounds with the desired IR kinase modulating activity are illustrated below.
The activator compounds are able to stimulate the phosphorylation catalyzed by IR kinase alone, i.e., to behave as agonists with respect to the receptor and/or are able to enhance the ability of insulin to effect phosphorylation of the receptor. Either of these effects can be considered an activation of the insulin receptor. Thus, by "activating" the insulin receptor is meant either the ability to behave as an agonist or the ability to enhance the stimulation by insulin or other agonists of the receptor activity. Both of these effects can be evidenced by autophosphorylation of the receptor.
The compounds of the invention evidently do not interact with the receptor at the native insulin binding site, but rather at a site located on the kinase portion of the receptor. Thus, these compounds define a newly discovered activation site for this receptor. This permits not only the identification of compounds with similar activities through competitive binding assays with the identified compound (which directly identifies compounds which interact with the same site), but also permit these assays to be conducted with forms of the receptor containing only the kinase portions.
Identification of Desired Activator Compounds—Maximally Diverse Libraries
A traditional approach to the identification of a substance which binds to a desired target is through simple trial and error. Done in a random fashion with each compound available in a chemical library, this approach is labor- and time-intensive for a complex assay such as autophosphorylation of IRk. As previously described by two of the present inventors, the number of trials can be minimized by testing only representative substances across the totality of chemical space. Thus, only members of a maximally diverse set of candidate compounds is tested in the trial and error procedure. One way to construct a maximally diverse set of candidates is described in U.S. Pat. No. 5,340,474, incorporated herein by reference. In this approach, the members of the set are synthesized from subunits wherein the subunits are chosen to result in a systemic variation of parameters, such as hydrophobicity, hydrophobic moment and the like, which determine the position of the resulting compound in chemical space. Alternatively, the maximally diverse set of test compounds can be obtained by manipulating affinity fingerprints. The fingerprints of multiple members of a compound library can be searched and clustered to obtain groups with similar fingerprints. Each group represents a different general location in chemical space. Iterations of this process may be continued until a manageable number of compounds representing the totality of chemical space are identified. Thus, from a cluster of, for example, fingerprints for 100 compounds with similar properties, only one of these 100 compounds need be included in the group of compounds to be tested for binding to the target. This is described in U.S. Pat. No. 5,587,293, cited above.
In the present application, a library containing the fingerprints of 10,000 compounds obtained against a panel of 18 reference proteins was sorted as described; i.e., clusters of fingerprints with similar characteristics were grouped to select 50 representative compounds as a "training set." Each of these 50 representative compounds was tested with respect to the insulin receptor. A sample believed to consist only of TER12 shown in
The foregoing method can be generalized, in combination with the assay method described in Example 1 hereinbelow to screen for compounds which activate any receptor which undergoes autophosphorylation. In general, the method comprises identifying a compound that activates a receptor containing a kinase portion by autophosphorylation. The method comprises contacting each member of a set of maximally diverse candidate compounds with the receptor or kinase portion of the receptor and detecting the presence or absence of tyrosine phosphate on the receptor or kinase portion. A successful candidate is identified as a member of the set wherein an increased level of tyrosine phosphate as compared to basal is detected in the receptor or kinase with which it was contacted.
In a preferred embodiment, the set of maximally diverse candidates is obtained by a process which comprises providing fingerprints for a library of chemical compounds, which fingerprints consist of the recorded degrees of reactivity of each compound with respect to a reference panel of substances representing a majority of chemical space and then arranging the fingerprints into clusters of similar fingerprints. A compound representative of each cluster is selected and these compounds are assembled into the set of maximally diverse candidates.
Fingerprint Comparison
Chemical catalogs were searched for compounds with structural features similar to those of TER12 or which when tested had fingerprints showing essential matching features. Of 42 compounds identified as having similar substructures, four showed activity with respect to the receptor; among these was a sample containing TER3938 shown in
The fingerprints of these compounds identified with respect to a standard reference panel (further described hereinbelow) can be used as standards for comparison to fingerprints of candidate compounds likely to have the same activities.
U.S. Pat. Nos. 5,217,869 and 5,300,425, the contents of which are incorporated herein by reference, describe techniques for identifying compounds with similar properties by comparing their fingerprints. Briefly, a fingerprint for a single compound (which characterizes it) is obtained by testing the binding or reactivity of the compound with respect to a reference panel of substances which may, for instance, be antibodies or other substances which exhibit varied degrees of reactivity with respect to most compounds. The reference panels are chosen so that they represent virtually the totality of chemical space—i.e., a set of substances so varied in its spatial and charge contours that the ability to react with any other substance is contained at least somewhere within the panel. Each compound reacted with the panel, then, yields a characteristic pattern of reactivities which could be considered a fingerprint. Compounds which exhibit similar fingerprints exhibit similar patterns of reactivity and properties. Thus, if a target receptor is known to bind to a specific ligand, one can identify a compound which also binds to the receptor by choosing a compound whose fingerprint is similar to that of the known ligand. Here, the fingerprints or candidates from, for example, libraries of compounds are compared to the corresponding fingerprints of TER12, TER3938 or other compounds identified as activators of the receptor. It will be noted that it is of no consequence that TER12 and TER3938 were themselves later shown to be less active in the IR kinase assays than other components contained in samples of these compounds with respect to the utility of their fingerprints for identification of compounds that have IR kinase activity since the active contaminants are chemically similar.
Structure Activity Relationships
Assessment of the structural features of an individual active compound, especially those that are shared by several active compounds, in contrast, for example, to the compounds which do not activate the insulin receptor, permits the design of suitable candidates for synthesis and testing. Methods for such analysis and identification of such structural features are known in the art. See, for example, Nesnow, S. et al. J Toxicol Environ Health (1988) 24:499-513, which describes the assignment of structural features among a group of 36 arylazo dyes as related to their ability to be reduced by rat liver microsomal azoreductase.
Competitive Binding
Once activators of the insulin receptor (or any receptor) have been identified either by screening a maximally diverse library or by using the results of such screening to compare fingerprints and selecting fingerprints similar to those of the successful compounds, or by structure activity analysis of one or more activator compounds in comparison to those which are inactive, these successful activator compounds can be used to screen for additional substances which behave using similar mechanisms by competitive binding assays wherein the activator compounds, for example labeled with radioisotopes, fluorescent labels, enzyme labels, and the like, are contacted with the insulin receptor or the insulin receptor kinase in the presence and absence of candidate insulin receptor activator compounds. The amount of label bound to the receptor or to its kinase portion is measured in the presence and absence of the candidate; an increased level of label binding in the absence, as opposed to the presence of the candidate indicates that the candidate successfully competes for the newly defined binding site and is a successful candidate as an activator of the receptor.
The following examples are intended to illustrate but not to limit the invention.
This assay is a modified form of that described in Hagino, H. et al. Diabetes (1994) 43:274-280. Briefly, human insulin receptors (hlR) were partially purified from placental extracts or from cell line IM-9. The partially purified hIRs were captured into microplate wells by incubating them for 90 minutes with wells coated with a monoclonal antibody to hIR. The wells were then treated with various dose levels of insulin and/or test compounds for 15 minutes at room temperature; ATP (10 μM) was then added to permit kinase activity to proceed. After 60 minutes, the wells were washed, and then treated for 60 minutes with biotinylated antibody directed against phosphotyrosine (PY-20) and unbound materials again washed away. The wells were then incubated with a conventional streptavidin peroxidase system for 30 minutes to assess the level of phosphorylated tyrosine.
When tested in this assay, insulin gave a dose response curve showing an EC50 of about 0.3 nM and a maximal activity at about 100 nM. The EC50 is similar to that obtained for binding of labeled insulin to various cells and tissues.
Two sets of compounds of 50 members each, selected to be maximally diverse, as defined in U.S. Pat. No. 5,300,425 and incorporated herein by reference, were screened in the foregoing assay. Of these 100 compounds, only a sample composed mainly of TER12 (see
In addition, the sample enhanced the ability of insulin to stimulate autophosphorylation. The addition of 60 μM sample to hIR contacted with 0.3 nM insulin resulted in an increase in phosphorylation of approximately three-fold and to the maximal level shown by insulin stimulation at higher concentrations. The EC50 for this effect (enhancing insulin stimulation) was shown in additional experiments to be approximately 20 μM of sample calculated as TER12. These results were also confirmed by Western blot assay.
In an additional demonstration of the activity of a component in the sample containing TER12, the artificial substrate, poly(Glu4Tyr) was used as the substrate for phosphorylation. Incorporation of labeled phosphate from γ-labeled ATP was measured following activation of receptor prepared as in paragraph A. About 20 μM of sample calculated as TER12 provided 75% of maximal insulin-stimulated activity; it also enhanced the ability of 0.5 nM and 5.0 nM insulin to effect phosphorylation; 0.5 nM insulin alone showed 60% maximal phosphorylation; addition of 20 μM of the TER12 sample increased this to 120%; in the presence of 5 nM insulin phosphorylation rose from 95% of maximum to 140%.
When tested with respect to insulin receptor agonist activity on whole cells, i.e., on the human lymphocytic cell line IM-9, the sample containing TER12 retained its ability to stimulate the receptor. In this assay, 2×107 cells were treated with and without this sample and with and without insulin for 5 minutes, followed by three washes in isotonic medium to remove the sample containing TER12. The cells were then lysed in 0.5% Tween 20 and lysates analyzed in an ELISA assay as described in paragraph A, without the steps of incubation with ATP. After 5 minutes exposure to sample containing 20 μM TER12, basal insulin receptor kinase activity was increased two-fold and insulin stimulated insulin receptor kinase activity was increased five-fold.
The assay described in paragraph B was conducted by substituting, for the human insulin receptor, a recombinantly produced β chain lacking the insulin-binding domain (supplied by Stratagene, Inc.). The ability of this kinase to phosphorylate a substrate peptide (Raytide from Oncogene Sciences) is stimulated by TER12 at 25 μM. (In addition, a known inhibitor believed to act at the ATP site on the kinase also inhibits this modified form of the receptor.)
Insulin is able to induce the differentiation of 3T3-L1 fibroblast cells to an adipocyte-like morphology as measured by Oil Red O uptake. The sample containing TER12 alone does not appear to effect differentiation; however, at a concentration of 20 μM it enhances the differentiating effect of insulin. This activity is similar to that exhibited by pioglitazone described above. Insulin also enhances glucose transport in this cell line. Again, the sample alone failed to stimulate glucose transport significantly, but enhanced the ability of insulin to do so.
Using substructure searching based on the TER12 molecule, 42 candidate compounds were obtained and assayed according to the procedure of Example 1.
A sample containing TER3938, shown in
TER12 was synthesized by the reaction scheme shown in FIG. 3. TER12 synthesized using this scheme, and TER12 when extensively purified from commercial sources were active in the assays set forth in Example 1.
In addition, the sample containing TER3938, also obtained from commercial sources, when purified to 95% purity by reverse-phase HPLC, retained its activity; however, when this sample was washed with aqueous sodium carbonate, the insoluble compound shown in
Component A, purified from a commercially supplied sample, enhances glucose uptake in differentiated 3T3-L1 cells, and the activity is not dependent on the presence of insulin. It is, however, dependent on the activity of PI-3 kinase, confirming that the glucose uptake is mediated via the insulin signaling pathway. The ability of 16 μg/ml concentrations of Component A to enhance glucose uptake at various insulin concentrations is shown in FIG. 4.
In the assay, 3T3-L1 pre-adipocytes were induced to differentiate into adipocyte morphology using standard protocols. Five days after induction, the cells were treated with 16 μg/ml of Component A in the presence of various levels of insulin for 30 minutes. Glucose uptake was measured using 14C glucose as label. As shown, 16 μg/ml of Component A alone effects uptake at approximately the level shown by 20 μM concentrations of insulin in the absence of this concentration of Component A.
An additional compound with a structure regioisomeric to that of TER3935, TER16998, was isolated by preparative reverse-phase chromatography from the reaction mixture produced by the synthetic scheme shown in FIG. 5. Spectral data confirm that the isolated compound was of the formula shown in FIG. 2D.
TER16998 activates the insulin receptor kinase directly, enhances autophosphorylation and substrate phosphorylation mediated through the insulin receptor, potentiates glucose transport and lowers blood glucose in the db/db mouse model of diabetes. These results were obtained as follows:
The assay described in Example 1, paragraph A, was conducted with a control lacking any additions, in the presence of insulin alone at 1 nM, in the presence of TER16998 at 2 μM and in the presence of a combination of these components at the stated concentrations. As shown in
In addition, in an assay for glucose uptake by 3T3-L1 adipocytes, described in Example 3, TER16998 produced an acute effect sensitizing the cells to insulin. This was inhibited, as expected, by 5 μM wortmannin which inhibits PI-3 kinase, confiring that TER16998 exerts its effect through the insulin-signaling pathway. These results are shown in FIG. 7. As shown, 40 μM of TER16998 potentiates the effect of insulin at a range of concentration.
Significantly, TER16998 was not able to stimulate the phosphorylation activity of epidermal growth factor receptor in an EGF receptor kinase assay.
The effect of TER16998, of Component A, and of insulin on the distribution of the Glut4 transporter in 3T3-L1 adipocytes was determined by incubating the cells for 15 minutes with insulin or one of these compounds, after which the cells were fixed and stained with an anti-Glut4 antibody followed by FITC-conjugated secondary antibody. The results were visualized under a fluorescent microscope. The results showed that insulin and Component A produce a dramatic redistribution of Glut4 to the membrane surfaces whereas in untreated cells a diffuse pattern is obtained. TER16998 has a similar effect but less dramatic than that of insulin or Component A.
Mice which are standard models of Type II diabetes, db/db mice, were administered TER16998 at 10 mg/kg and 40 mg/kg, or a vehicle as a control.
Compounds TER17004 and TER17005, shown in
The resulting compounds, TER17004 and TER17005, were tested in the IR kdnase assay set forth in Example 1, paragraph A, and found to be active in this assay.
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I agree with this article, basketball is one of those sports that is a team sport through and through so one big player isn't going to change your TEAM. I think these owners should really relook at how they do business. I will say though that most teams sign players such as Anthony because they score a lot which is what fans like to see. There is a reason the most popular NBA players are high scorers. So a lot of owners do it to sell tickets rather than win games.
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Harvard Crimson vs. Boston University Terriers
Tuesday, December 11, 2012 07:00 pm
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65 N. Harvard St.
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Here on our site, you can get Harvard Crimson Sports tickets Cornell Big Red, Virginia Cavaliers and Penn Quakers December 11 plus cheap tickets for Lavietes Pavilion adult theaters plays; moreover, you can reserve seats for Madison Square Garden, Coors Event Center and Alex Box Stadium children's theater.Whether you live in Massachusetts or may be in Boston, Chestnut Hill and New York and looking for Harvard Crimson tickets Virginia Cavaliers, Boston University Terriers and Yale Bulldogs December 11, you'll be able to get all your ticket needs here.If you live in Massachusetts and want to see a great play or want to find Harvard Crimson tickets December 11? we can offer even better seats for Haas Pavilion, Agganis Arena and Stockwell Jadwin Gymnasium shows and more.
Upcomming Harvard Crimson events :
- Boston Coaches vs. Cancer: BU vs. Northeastern AND BC vs. UMass AND Harvard vs. Holy Cross tickets November
- Charlottesville Virginia Cavaliers vs. Harvard Crimson John Paul Jones Arena
- Boston College Eagles vs. Harvard Crimson tickets 14
- Penn Quakers vs. Harvard Crimson Philadelphia The Palestra tickets
- February 21 Harvard Crimson vs. Princeton Tigers tickets
- Harvard Crimson vs. Yale Bulldogs tickets March 06


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Janey Davies
The first arrest over 3D printed weapons has been made in Japan, a country with very strict firearm laws. Police officers raided the home of a 27 year-old college employe...
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When it comes to 3D printing there is a lot of discussion about which printer is the best. Anyone who has browsed the internet looking for a filament based printer (also ...
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Joris Laarman Lab has developed the world's first crowd fabricated open source 3D printable chair. Joris Laarman Lab, an experimental playground, set up to study an...
Oct 20,2014
Janey Davies | Oct 20,2014
We've written about how 3D printing has not made a significant impact on construction. It ...
Joris Peels | Oct 20,2014
The coolest thing at the recent Hong Kong Mini Maker Faire was a MakerJam featuring an e-N...
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3D printing has come to the rescue of the ancient burial chamber of the Pharaoh Tutankhamu...
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An update on NightScout. When we last left, I was so frustrated with it that I was about ready to march right up to that cloud (if I could find the right one) and give someone or something a piece of my mind. Now … I wanna marry it! And all it took was a $3.50 cable. The streaming connection to Charlie's Dexcom has been nearly flawless since receiving our new cable in the mail and I...


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Sir Elton John's partner David Furnish has confirmed that the couple will be getting married again very soon.
The 65-year-old British singer and his 50-year-old beau welcomed their second son Elijah on January 11 and the pair also share two-year-old Zachary. John and Furnish have been in a civil partnership since 2005.
Their native country Britain passed a law earlier this month that legalised gay marriage.
In celebration of the new legislation, the couple will get wed officially.
"We are going to get married again formally," David told British newspaper The Mirror.
"We'll renew our vows under the gay marriage act now that it's legal which is great. It's something we both want to do.
"We'd love for it to be able to happen in LA as well because it's like a second home to us."
John and Furnish are public supporters of gay and civil rights.
They believe that it is important to wed to set an example.
"It is one of the pivotal defining issues of our time," Furnish explained.
"Even though we have our relationship legally recognised, people are fighting hard for this issue every day.
"It's important Elton and I do this and make a statement."
John threw his famous annual Elton John's AIDS Foundation's Academy Awards viewing party in West Hollywood on Sunday.
The affair earned $6 million for the cause.
"We try to do our bit and apparently tonight we raised a record amount of money for the Elton John Aids Foundation which is amazing," David gushed.
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Responsible for providing systems analytical support to Public Sector customers and internal resources utilizing a defined implementation process and working...Senior QA Engineer
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Bachelor's Degree or foreign equivalent in computer science or a related technological discipline (to include computer applications, information technology,...Lead JavaScript Engineer - JavaScript, AJAX, XHTML, XML
You will also take part in the leadership function throughout the organization, and help to build out the existing team!...Senior Front End Web Developer - JavaScript, JQuery, Kendo
Very high match on 401K + a flexible spending account. Strong quality of life benefits so that you may enjoy your life outside of work!...Software Support Engineer
Customer technical support by email and. TNX offers excellent compensation, commensurate with experience,. Experience in using structural analysis and design...Software Developer
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Vanderbilt Museum and Planetarium reopens
The planetarium has been undergoing renovations with funds from Suffolk County. As it nears completion, it is preparing to reopen. Videojournalist: Jessica Rotkiewicz (March 4, 2013)
Adam Saalfield charged with stabbing death More Sandy funding from American Red Cross Cops: Driver killed when car is rammed from behind Excellent architecture on Long Island Whiskey Road Homicide, LIRR death subjects of police probe Hauppauge vs. Half Hollow Hills West Ward Melville vs. Half Hollow Hills East Bayport holiday light show preparations begin Stony Brook University partners with credit union NY Rising official talks delays in post-Sandy rebuilding Algieri talks Pacquiao relationship


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Find commute times to your work, school, gym and more.
- This property is no longer listed on Rent.com. For this reason please note that any pricing or description information may not be up-to-date.
Search Available Apartments
Property Features
- Parking
- Covered Parking
- Convenience
- Business Center
- Extra Storage
- High Speed Internet Access
- Leisure
- Fitness Center
- Playground
- Swimming Pool
- Laundry
- Laundry Facility
- Washer & Dryer Connections
- Utilities Included
- Some Paid Utilities
- Other
- 1 and 2 Bedroom Floorplans
- BBQ/Picnic Area
- Broadband Internet Access
- Contemporary Colors
- Emergency Maintenance
- Great convenient location
- Heated Outdoor Pool with expansive sundeck
- On Busline
- On-site Fitness Center
- On-site Mini Storage
- Patio
- Pets Allowed
- Private Patios or Balconies
- Se Habla Espanol
- Washer and Dryer Hookups
- Whirlpool Appliances
Units may feature
- Amenities
- Cable Ready
- Disability Access
- Garbage Disposal
- Oversized Closets
- Kitchen
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Property Details
Delightful Parkgrove, a modern Cape Cod style apartment community, is in every way, a place you'll look forward to coming home to each day. Surrounded by trees, close to Alton Baker Park and the beautiful Willamette River-you'll find Parkgrove the epitome of Pacific Northwest living. Featuring spacious floorplans in both our one and two bedroom apartment homes, including large kitchens with quality Whirlpool appliances and washer/dryer hookups. We even have mini storage available if you need it. With accents like oak trim, contemporary color schemes, and vertical blinds in the windows, the only thing missing here is you. Our on-site fitness center is a great place to get a work out or step outside and enjoy our heated pool and large sundeck. And keep in mind that Parkgrove is built with "Super Good Cents" energy efficient standards, ensuring that you are choosing quality construction.
Leasing Information
Pet Policy
Pets Accepted. Call for service animal policy.
Our lease terms are: 12 Months,6 Months,9 Months. (Please note that lease terms may vary, are subject to change without notice, and are based on availability. Inquire with property staff for complete details).
Cat Policy: 25 Pound Weight Limit.Call for pet policy!.
Dog Policy: 25 Pound Weight Limit.Call for pet policy!.
Office Hours
Monday-Friday: 9:00am-5:00pm
Saturday: 10:30am-4:00pm
Sunday: 11:30am-4:00pm
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Leonard Samuel "SAM" Hammond, Jr. passed away Sunday, October 09, 2011. The beloved husband of Sandra Ives Hammond. He was born in Camden. Sam was a retired real estate appraiser for Kershaw County. He was an honorable US Navy veteran having served in the Korean War.
Keziah Schofield, 17, of Camden, died Saturday.
Funeral service for Daniel Lee Wood, Jr., 37, of 1006 Kelly Street in Elgin will be held Friday, October 14, 2011, 2:00 P.M. at Sutton Branch Baptist Church with burial in the church cemetery.
Organizers for the inaugural Camden Antiques Fair announce that 33 antique dealers are booked for the event and many hail from out of state. They will bring items new to the South Carolina market and shoppers will find an array of offerings which feature furniture, toys, ceramics, sporting artifacts, rugs, silver, crystal, jewelry, books, maps, rustic furnishings and pottery. A list of dealers and ticket information can be found on line at www.steeplechasemuseum.org.
Throughout the month of October, the Camden High School volleyball team is participating in the "Dig Pink" National Breast Cancer Awareness Rally. They are promoting breast health education in the community as well as raising funds to help eradicate Breast Cancer.
The Camden High girls' tennis team picked up their second out-of-region victory last Thursday at Manning in convincing fashion, 5-1.
The Lugoff-Camden Elks Lodge is once again sponsoring its annual Soccer Shoot.
Ms. Miriam Denton Anderson will celebrate her 98th birthday Thursday. She was born Oct. 13, 1913. She plans to mark the milestone with friends and family. Ms. Anderson is the mother of three sons, five grandchildren and 14 great-grandchildren.
Local resident Neal Clark joins forces with fellow musicians and vocalists for a night of Broadway and classic songs to benefit the Fine Arts Center of Kershaw County (FAC.) "A Gala Evening of Song" will take place Saturday at 8 p.m. in the Wood Auditorium. There will be a reception catered by Carolina Café, with a cash bar prior to the performance starting at 7 p.m. Tickets are $15 for adults and $12 for students, seniors and military. The evening is sponsored by Miller Lumber, Sentinel Health Partners Carolina Cafe' and Colony Inn.
WASHINGTON -- Undoubtedly many Americans, not least among them television producers, are disappointed by Sarah Palin's decision not to run for president.
Alto saxophone players Ike Nooe, Judie Shiver, Mike Sox and Bob Loryea practice with the Camden Community Concert Band (CCCB) in preparation for its first concert of the season. The CCCB begins its 33rd season this Sunday with a concert in Rectory Square Park. The concert begins at 3 p.m. and is free and open to the public.
The Camden Music Association will host its fall general meeting at 4 p.m. Oct. 23 at the Douglas Reed House, on the grounds of the Fine Arts Center of Kershaw County. The objective of the Camden Music Association is to give the young musicians of the whole county a venue to showcase their talents and provide scholarships to help in their music study.
SAFE Federal Credit Union and the City of Camden present "Sunsets on the Green," kicking off tomorrow from 5 to 9 p.m. "Sunsets on the Green" is a free Fall Concert series and will be held at the Camden Town Green on Thursday evenings. The artist lineup is as follows: Thursday, Sun-Dried Vibes formerly Zac Fowler and the Essentials (above); Oct. 20, Joal Rush; and Oct. 27, Josh McCaa.
Here in Kershaw County there are hundreds -- perhaps thousands -- of people suffering from Alzheimer's Disease, the cruel malady that attacks the brain. There are millions of Americans across the country who have fallen prey to Alzheimer's, yet research efforts to find a cure have been consistently disappointing over the last few decades. But two researchers at Massachusetts General Hospital in Boston have been successful in essentially growing Alzheimer's in a petri dish, and scientists hope that's going to be a breakthrough in studying possible new treatments for the disease.
The board of directors of First Palmetto Financial Corporation, parent company of First Palmetto Bank, has declared a quarterly dividend of $350 per share of common stock. The dividend to stockholders of record as of Oct 24, 2014 will be payable October 31, 2014.
WASHINGTON -- Now, now, let's not panic.
Hollywood's most recent spate of pirate movies, the Pirates of the Caribbean series starring Johnny Depp, illustrates the age-old stereotype of "the pirate." Depp is the perfect swaggering pirate, his full head of dreadlocks wrapped in a cloth, waistcoat belted with heavy leather, on occasion an 18th century skirted frock coat and a tricorn hat. Pistols and swords in his belt within easy reach for a fight. Soft leather boots folded down at the top. Swashbuckling at its best. Depp embodies the definitive pirate style.
One of the best things about being an educator is the opportunity to share in the success of students' educational careers. Watching students learn to read, speak a foreign language or pass an AP exam are highlights that I've shared with numerous young people over the years, but none of them comes close to what I consider one the best highpoints I ever experienced: the excitement that I saw on the faces of the students from North Central High School years ago when I informed them about the improvements being made to their school as part of Phase 1 ...
The city of Camden needs experienced professionals, invested citizens working for everyone; the city of Camden needs Jeffrey Graham elected on Nov. 4. Join me in voting for a man with a proven record:
The probate court handles estates, conservatorships and guardianships among other things, all of which are important because they affect the lives of people. When choosing the right candidate for the position of probate judge, we first should take into consideration the candidate's experience and knowledge of the job they are seeking. Debbie Branham is a paralegal with 20 years of experience, handling more than 1,000 probate and estate matters. She has been in the courtroom assisting an attorney in trial. She understands the law, the procedures of the court and the probate process. She has the experience and ...
The 20th annual Marion duPont Scott Colonial Cup 10K road race and the Vonnie Holliday Foundation 5K run/walk will take to the streets of Camden on Saturday, Oct. 25.
With the 45th annual Marion duPont Scott International Colonial Cup Steeplechase Races a little more than a month away, patrons who had reserved parking spaces for last year's Camden fall classic have until Friday, Oct. 10 to assure they retain those spaces. All unsold spaces will be placed for sale to the general public.
A sure sign that fall and cooler weather is around the corner occurred last Friday with the mailing out of invitations to those on the mailing list for the 45th annual Marion duPont Scott International Colonial Cup Steeplechase Races.
The ABLE Club of S.C., the official athletic booster club of Lugoff-Elgin High School, is kicking off its membership campaign for the 2014-15 athletic seasons at the school.
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LEDscape® Bar is A-Glow-Glow at Hong Kong Museum of Arts
Hong Kong, 6 May 2008 – Hong Kong-based LED artist Teddy Lo has a reputation for his groundbreaking pieces of visual art. Committed to demonstrating both the illuminative and environmental benefits of LED lighting, he has used the latest Lighthouse LED technology for the maiden display of his newest – and biggest â creation, Phaeodaria.
An integral part of the A-Glow-Glow Macro Interactive Media Arts Exhibition, which took place at the peripheral area of the Hong Kong Museum of Art from 11-20 April 2008, Loâs âPhaeodariaâ comprised around 80 pieces of Lighthouseâs brand new creative video solution, LEDscape® Bar, arranged to form an eight metre diameter geodesic dome.
Inspired by Ernst Haeckel's illustrations of marine life forms, the project utilised wireless mobile telecommunications technologies to change the colours of the Lighthouse LEDscape® Bar – thereby illustrating in lit form the wireless information culture that Lo feels is highly representative of contemporary Hong Kong life.
To achieve this, he recorded the signals outside a large department store at Causeway Bay in Hong Kong which he then decoded to form a playback signal for controlling the LEDscape® Bar.
Lighthouse LEDscape® Bar comprises a matrix of 32 RGB LED pixels in a weatherproof enclosure measuring two metres long by 35mm wide. With a pixel brightness of 15,625 mcd, wide viewing angles and Lighthouseâs proprietary technology ensuring remarkable colour uniformity – 28.15 trillion colours can be accurately reproduced – LEDscape® Bar is the ideal solution for large scale installations – both indoor and outdoor – where the inventive and eye-catching use of light are essential.
"LED is a revolutionary technology," says Teddy Lo. "It's very environmentally friendly and has a huge impact on the world. The new LEDscape bars provide me with the scale and mechanical flexibility that I was looking for.â?
âWith incandescent light bulbs turning more than 80 per cent of the supplied energy into heat, using LEDs instead can make a very positive impact on the problems of energy shortage and global warming. My job is to promote this tech artistically.â?
With Lo and Lighthouse both absolutely committed to the very latest LED technology, the creation of âPhaeodariaâ is a perfect illustration of the natural synergy between them.
âAs a company, Lighthouse is absolutely thrilled that Teddy Lo chose LEDscape® Bar from which to construct this remarkable piece of art,â? says Peter Chan, general manager of Lighthouse.
âAs well as Teddyâs artistic vision, âPhaeodariaâ demonstrates the remarkable flexibility with which LEDscape® Bar can be both installed and controlled. It is the perfect demonstration of how inventive thinking and the latest LED technology can produce truly outstanding results.â?
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Argentinian boxer gives Pope Francis his world champion belt
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http://en.romereports.com The middleweight world champion Sergio MartÃnez, also known as Maravilla MartÃnez gave up the boxing ring for a day and traded it for St. Peter Square.
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It looks like Nintendo Everything has run across the real box art for Super Mario 3D World, which until now has only seen fan renditions. It's interesting to note that the box art shows the Nintendo Network logo at the top right, despite the game not including online multiplayer. The game will be released on November 22nd for $59.99.
What do you think of the box art? The image is a bit hazy because it had to be blown up to see better, but expect a larger image soon.
Continue reading:
- Nintendo Amiibo stations in retail stores
- Shadow of the Eternals still in development?
- Bayonetta 2 Contest Winners
- Super Smash Bros. releasing earlier in Europe
TAGS: Nintendo, super mario 3d world


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Dalton neighbour stole to feed his drink habit
Last updated at 16:37, Wednesday, 07 November 2012
AN ELDERLY woman was left worried about falling into debt after her neighbour repeatedly stole from her.
Peter Colin Martin admitted a charge of theft to the value of £1,180 at Furness Magistrates' Court yesterday.
The 51-year-old, of Lord Street in Dalton, admitted he had repeatedly stolen the cash between January and May from his neighbour Evelyn Cruse, who had entrusted him with her bank card.
Prosecuting, Miss Judith Knott said the 77-year-old woman, who died in July, had relied upon her neighbour for help.
She said: "Mrs Cruse came to really rely upon him.
"She did have a support worker who visited several times a week but she suffered from agoraphobia and would no longer leave the house, except for going into the garden."
Miss Knott said Martin used to go to the shops for her neighbour, and was given her bank card and PIN number.
On 26 occasions, the defendant took money out for Mrs Cruse but then withdrew similar amounts for himself.
The victim became distressed when a direct debit for her rent failed and confided in her support worker that she was worried about getting into debt.
A couple of days before his mother died, Mrs Cruse's son found out that Martin had been stealing from her and reported him to the police.
Defending, Miss Jane Tunn said that the defendant had stolen from Mrs Cruse because he was dependant on alcohol. She said that Martin admitted all the offences, but said he had not been bragging about stealing from her and was unaware that she was upset about her financial situation.
Chairwoman of the bench Mrs Sue Needham said that the circumstances around the case meant that an adequate punishment could not be handed out by the magistrates.
She committed Martin to crown court on December 11 for sentencing.
She said: "The victim was an elderly lady who had health problems and she was agoraphobic.
"She placed a lot of trust in you when you did her shopping.
"You took money from her over a considerable period of time and to her it was a lot of money, even if it was not to you."
First published at 12:29, Wednesday, 07 November 2012
Published by http://www.nwemail.co.uk
More Dalton news
- 'Family spat' probably led to Dalton monkey escape
- Dalton is named one of the best places for families
- Smurfs spotted out and about on Dalton school's sponsored stroll
- Kind £1,000 donation will help Dalton girl to watch the world go by
- Shoplifter caught in Dalton with £500 admitted money laundering
- Legal error results in Dalton zoo chief facing wrong charges (1 comment)
- Man shattered window in Dalton after row with his ex
- Dalton family's distress after raiders stole 'irreplaceable' jewellery
- Tributes to 'witty and lovely' Dalton man who died a month after transplant (1 comment)
- Cumbria Police investigate burglary in Dalton
- Dalton schoolgirl suffers broken foot following collision with vehicle
- Dalton hotel set to reopen after gas canister explosion in kitchen (2 comments)
- Naked men seen walking through Dalton (15 comments)
- Dalton zoo is handed series of new conditions after inspection
- Council hits back in Dalton zoo tiger feeding row (45 comments)
- Dalton fire station sold to highest bidder for £130,000 (1 comment)
- Dalton Leisure centre full steam ahead after grant for boilers
- Dalton man pleads not guilty to dangerous driving
- Dalton woman who has 30 identities slams NHS healthcare failings (9 comments)
- Cumbria music festival hailed by organisers as the biggest yet
- Closed Dalton fire station will be sold to highest bidder
- Barrow council bosses in Dalton pub car park showdown
- Dalton zoo owner denies allowing animals to escape
- Dalton great-gran praises heroes who saved her from blazing kitchen (3 comments)
- Dalton makes an impression on visiting Britain in Bloom judges
Evening Mail homepage
Quick links
- Council hits back in Dalton zoo tiger feeding row (45 comments)
- Chris aims to bring cool city-style bar to Furness (6 comments)
- Being a 'proper banana' gets the message across (1 comment)
- Legal error results in Dalton zoo chief facing wrong charges (1 comment)
- South Lakes Wild Animal Park boss tells his own story (27 comments)
- Mormon pioneers left for new life in America
- US Republican politician Mitt Romney's Dalton heritage goes back to 1642
- South Lakes Wild Animal Park boss tells his own story (27 comments)
- Bank clerk jailed over £100k theft (39 comments)
- Council hits back in Dalton zoo tiger feeding row (45 comments)
- Man in Barrow court on heroin supply charge
- Railway, Dalton
- Chris aims to bring cool city-style bar to Furness (6 comments)
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- First class cricket coverage with Dalton local
- Dalton Christmas tree festival
- Being a 'proper banana' gets the message across (1 comment)
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Leave the pavement-pounding to the work week. We found stunning trails from coast to coast located just a short trip from urban jungles.
FlashWhat's New Now
- Calculate Your "Fitness Age"—It May Predict How Long You'll Live 14 hours ago
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Birds & Blooms Photo of the Day for September 27, 2011: Daylily & Million Bell Petunia by Sandee Cosby.
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Welcome to your weekend picture post. I hope everyone has a great day. This is our Indian summer days here.. We had two killing frosts and freezes and…
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The Mickey Rooney's Taxi Toon Hula attraction during repairs
The Mickey Rooney's Taxi Toon Hula entrance is like a tour across the world of Toontown. The attraction taxis are supposed to look like Benny the Cob, and when you drive you can hula them by encircling the dashboard.
Beware Pirate Mode
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A Pants Aflame production


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Walther PPK/S for CC?
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Forgiveness- Holy Cross - Music Videos
7-Year-Old Fiddler Joins Band For 1 Beautiful Version Of 'Amazing Grace' - @untilweflyaway
00:05:33 11547 views
9-Year-Old Hallie Performs IMPRESSIVE Southern-Style 'Amazing Grace (My Chains Are Gone)' - @inspiredfaith
00:05:37 85945 views
Simon Stopped This 16-Year-Old Half Way Through. But You'll LOVE What She Did Next! - @alegator21
00:07:45 117410 views
Embed daveyd39 404 views 2013-07-04T11:02:03 Here's a video we did with our high school group at church about Forgiveness. We used Matthew West's song "forgiveness" along with some audio Bible stuff. Check it out and remember, to be a Christian is to forgive others as we have been forgiven by God through the blood of Jesus.
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Abby Belmont
I Warned You for A Reason
A fair warning is what I gave
And now you get what you paid
You became fate's puppet
Believing all of her dumb shit
Your puppet master calls,
Knocks down all your walls
You don't fight you don't try
And now you lay alone and cry
I warned you so many times,
She had the writing between the lines
Caught you in a lie
And now she could care less if you die
I said stay away don't play her game
But did you forget the name?
She took you on a short ride
Then said GOOD BYE! !
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United States News
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United States News
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Twitter on Wednesday set out to weave itself into mobile applications with a free "Fabric" platform to help developers build better programs and make more money. Twitter chief executive Dick Costolo touted Fabric as "the future of mobile software development" while unveiling the
AFP4hrs +
Twitter on Wednesday set out to weave itself into mobile applications with a free "Fabric" platform to help developers build better programs and...
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Happy Halloween Y'all! Here's a compilation of SoNailicious Halloween nails designs created during the almost 2 years of our online presence. Writing about gold nails felt somehow inappropriate on October, 31 when everyone is getting busy trick-or-treating and cutting pumpkins. So let's leave our gold nails compilation for next week and today, simply sit back READ MORE
nail art tutorial
6 SoNailicious Halloween Nail Designs with Tutorialson October 31, 2014
Mystical Flame Halloween Nails – Tutorialon October 23, 2014
These Mystical Flame Halloween nails were partially inspired by the film, Maleficent and partially the stunning acid green LimeCrime polish. This sleek design looks so simple but getting those flame silhouettes absolutely perfect requires some concentration. In today's tutorial we show how to re-create this look yourself and, should you wish to take it to READ MORE
Easy Spider Web Halloween Nail Art How Toon October 16, 2014
Are you going to dress up like Hiedi Klum this Halloween? Or will you celebrate in a more subtle way by just doing your nails? Either way, this easy spider web Halloween nail art how to will come in handy this October. The main advantage of this design is that it can be done in READ MORE
The Game of Foils – 1: Foil Nails How Toon October 8, 2014
Foil nails look so effortlessly chic in their shining glory. Who knew foil was so tricky to use?! One tiny mistake and your manicure is ruined. The foil can refuse to stick and lift the polish up, and even if you've somehow managed to stick it on your nail, a top coat can shrink those READ MORE
Black and White Negative Space Nails – Tutorialon September 17, 2014
Negative space manicures aren't new to nail art enthusiasts but it seems like they've finally made their big entrance into the fashion world. At the recent New York Fashion Week approximately 1/3 of all the nail designs were negative space manicures. The 2 other main looks were gradients and various types of French manicure. That READ MORE
SoNailicious X Mint Polish – 3 Nail Art Tutorialson September 10, 2014
Recently we collaborated with one of our favourite nail polish brands - Mint Polish to create 3 nail art tutorials. We were particularly excited about this collaboration because these polishes are set to become the next big thing in the polish world! The colours are fantastic (remember Czarina?), the packaging is stylish, and the 5-free READ MORE
The Sideways Ruffian Nails – How Toon September 4, 2014
Sideways Ruffian nails are a great alternative to the classic Ruffian manicure. It's chic and so much easier to do! No special nail art skills required, just make sure you have stencils and a detailing brush. For this design, I used the new Picture Polish colours - Douceur amd Bonkers purchased during our recent trip READ MORE


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U.S. Marshals arrest agitator in RoboVault bankruptcy
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It's not clear how McBride became involved in the RoboVault case. Early in January, McBride sent a letter to the trustee, Barry Mukamal, ordering him to turn over the facility. The letter claimed that McBride derives his authority from the Holy See, which is the governing body of the Catholic Church.
McBride spoke in the courtroom Thursday morning after Olson asked if anyone present was representing the pope. The hearing was called on a motion for sanctions against Chaney and Wrenn, neither of whom showed up.
Olson ordered McBride to stop talking after he hurled insults at Fierberg and the others in the room. U.S. marshals forcefully clapped him in handcuffs.
Chaney built RoboVault and another storage center, Off Broward, with a loan from BankAtlantic. The companies still owe the bank's successor, Florida Asset Resolution Group, about $35 million.
McBride is no stranger to federal custody. The Associated Press profiled McBride and other separatists in a 2010 story, when McBride was headed to jail on a previous contempt charge in a bankruptcy court.
Fierberg, of Rice Pugatch Robinson & Schiller, has previously said that Chaney was running a boiler room operation selling interest in the bonds, and that some of the operation seemed like a Ponzi scheme.
Paul Brinkmann covers venture capital, technology, energy and environment.
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Thursday, June 29, 2000 - Page updated at 12:00 AM
Miles to go: Prep star hopes to be next Garnett
Chicago Tribune
NBA scouts figure Darius Miles is more likely to develop into another Kevin Garnett than another Leon Smith.
The 6-foot-9 phenom from East St. Louis, Ill., is making the quantum leap from the high-school ranks to professional basketball, as Garnett has done so seamlessly.
Smith, the talented but troubled King High (Chicago) forward, encountered criminal, psychological and social problems last season in his quest to bypass the college experience after signing with the Dallas Mavericks.
"Leon is a great person - I know him," Miles said. "Leon is one of the greatest persons I know. My mom even loves Leon. My mom sat down and talked to him for a long, long time."
Smith, who was shuttled from various foster homes as a child, did not have the stable upbringing that Miles has learned to appreciate.
"Leon just didn't have anybody like my mom," Miles said. "My mom is real strict and she makes sure I do the right thing. If my mom had been with Leon instead of with me, I think Leon would still be in the NBA. Leon would be doing good."
To counter any off-court problems he might run into as an NBA teenager, Miles already has a plan.
"Wherever I go, I'm going to move my mom and my little cousin. It really is going to feel like I'm at home," Miles said. "I'm not too much of a fancy-type person. Really, I just stay in the house most of the time."
Miles has impressed scouts with his multifaceted game.
Michael Jordan, the Washington Wizards' director of basketball operations, said he would select Miles No. 1. Unfortunately for the Wizards, they didn't have a first-round pick, and the Los Angeles Clippers selected Miles yesterday with the No. 3 overall pick. Jordan compares Miles' game to Garnett's, and Miles says the comparison is not unfounded.
"To me, my game is exactly like Kevin's," he said. "I pattern my game off of Kevin. I've been watching him since he was in high school."
Because he's so young, Miles expects the Clippers to be patient with him, as Minnesota was with Garnett.
"I don't think the team that gets me is going to expect me to make the next `50 Greatest Players' list," he said before the draft. "I think they will like to see if my game can be like Kevin Garnett's. And if I can go higher and higher every year. I think that's what they are looking at me for."
Smith's unfortunate and aborted transition to the NBA does not appear to be a deterrent in the league's assessment of Miles.
Miles' leaping ability, adeptness at handling the basketball and shifty inside moves make him a high-potential player. He signed a letter-of-intent with St. John's, but the scouts' assessments of him changed his plans.
"A lot of NBA teams liked my style of play and my versatility," Miles said. "I probably wouldn't have come out if teams hadn't told me that I would probably be a lottery pick.
"I didn't think about turning pro until after all the all-star games. All the NBA scouts were at the games and they were saying: `Yeah, he's a lottery pick.' "
Copyright (c) 2000 Seattle Times Company, All Rights Reserved.
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