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Hemoglobin for forming the basis of blood substitute is modified by crosslinking it by reaction with a polyaldehyde produced by ring opening oxidation of a di/tri-saccharide such as raffinose, wherein the o-saccharide solutions are maintained and the reaction is conducted at a pH from about 5.0-7.0, and at a stoichiometry from about 1:1-4:1 based upon the molar ratio of di/tri-saccharide to hemoglobin tetramers, followed by appropriate reduction of the Schiff base linkages so formed to stabilize them. Careful control of the pH of ring opening of the di/tri-saccharide ensures consistent production of the polyaldehyde without unwanted side products and reaction of this product with the hemoglobin at the specified stoichiometry leads to high yields of stabilized, tetrameric hemoglobin and oligomers thereof of predetermined composition and beneficial properties.
1. A process of chemically modifying hemoglobin to obtain an oxygen transporting modified hemoglobin which is free from hemoglobin aggregates of molecular weight higher than 600,000 daltons and which is suitable for use as the oxygen transporter in a blood substitute in aqueous solution, which comprises:
(a) subjecting a di/tri-saccharide to an oxidative ring opening process to produce a polyaldehyde therefrom;
(b) adjusting and maintaining the pH of the resulting product solutions to a value in the range from about 5.0-7.0, so as to prevent any substantial hydrolytic degradation of the polyaldehyde so formed;
(c) reacting the product of process step (b) with hemoglobin in solution, at a stoichiometric ratio based upon di/tri-saccharide and hemoglobin tetramers, of from about 1:1-4:1;
(d) reducing the Schiff base linkages so formed to secondary amine linkages; and
(e) recovering the modified hemoglobin so formed.
2. The process of claim 1 wherein the di/tri-saccharide is a trisaccharide.
3. The process of claim 2 wherein the trisaccharide is raffinose.
4. The process of claim 3 wherein the hemoglobin is deoxyhemoglobin.
5. The process of claim 4 including the initial step of deoxygenating the hemoglobin by subjection to inert gas under non-reducing conditions.
6. The process of claim 5 wherein the deoxyhemoglobin is free from sodium dithionite.
7. The process of claim 1 wherein the hemoglobin is human hemoglobin.
8. The process of claim 1 wherein the hemoglobin is initially in the T-configuration and is stabilized into said T-configuration by reaction with the polyaldehyde.
9. The process of claim 5 wherein oxidative ring opening of the raffinose is effected by reaction with sodium periodate or potassium periodate.
10. The process of claim 9 wherein the reaction product solution is subsequently buffered to a pH 5.0-7.0 by use of a phosphate free buffer, and maintained within said pH range for subsequent use.
11. The process of claim 10 wherein the buffer is a bis-tris buffer system.
12. The process of claim 1 wherein, in step (c) the stoichiometry of the di/tri-saccharide to the hemoglobin tetramers is from about 2.5:1 -3.5:1.
13. The process of claim 1 wherein the di/trisaccharide is a disaccharide.
14. The process of claim 13 wherein the disaccharide is sucrose.
This application is a continuation-in-part, of application Ser. No. 08/031,830, filed Mar. 16, 1993, now abandoned.
This invention relates to blood substitutes and processes for their preparation. More specifically, it relates to blood substitutes based on hemoglobin, and processes for the chemical modification of hemoglobin to improve its suitability for use as the basis of a blood substitute.
Hemoglobin, as the natural oxygen transporter component of blood, is an obvious candidate to form the basis of a blood substitute, e.g. as an aqueous solution. Extensive scientific work has been done and reported, on attempts to provide a satisfactory hemoglobin solution to act as a blood substitute. The chemical properties of hemoglobin outside the red blood cells are, however, markedly different from its properties inside the red blood cells, e.g. as regards its oxygen affinity. The need for some form of chemical modification of hemoglobin to render it suitable for use as a blood substitute has long been recognized and has been quite extensively investigated.
It is well known that hemoglobin comprises a tetramer of four sub-units, namely two α sub-units each having a globin peptide chain and two β sub-units each having a globin peptide chain. The tetramer has a molecular weight of approximately 64 kilodaltons, and each subunit has approximately the same molecular weight. The tetrameric hemoglobin in dilute aqueous solution readily dissociates into α--β dimers, and even further under some conditions to α-sub-unit monomers and β-sub-unit monomers. The dimers and monomers have too low a molecular weight for retention in the circulatory system of the body, and are filtered by the kidneys for excretion with the urine. This results in an unacceptably short half life of such a product in the body. Moreover, uncrosslinked hemoglobin induces significant nephrotoxicity, so that there is a need to minimize the concentration of uncrosslinked hemoglobin in the products. The need for chemical bonding between the sub-units to ensure the maintenance of the tetrameric form ("intramolecular crosslinking") has previously been recognized. Also, the linking together of two or more tetrameric units to form hemoglobin oligomers and polymers of molecular weight greater than 64 kilodaltons ("intermolecular crosslinking") has also been recognized as desirable in many instances.
When present in the red blood cells, hemoglobin is bound to a natural ligand, diphosphoglycerate (DPG) at a particular site in the hemoglobin molecule known as the DPG cleft or pocket. When the red blood cell membrane is removed, the DPG dissociates from the hemoglobin, with consequent steric rearrangement of the hemoglobin molecule and consequent undesirable increase in the affinity of the hemoglobin for oxygen. A satisfactory blood substitute based on hemoglobin should be capable of binding, transporting and releasing oxygen largely in the same manner and under the same conditions as hemoglobin present in natural whole blood. This problem has been addressed in the past by covalently attaching DPG-analogs such as pyridoxal-5'-phosphate PLP to hemoglobin to form the basis of a blood substitute.
U.S. Pat. No. 4,857,636 Hsia, issued Aug. 15, 1989, describes a blood substitute based on chemically modified hemoglobin, in which the hemoglobin is intramolecularly crosslinked by reaction with polyaldehydes. The particular polyaldehydes recommended for use in the Hsia patent are the products of ring opening oxidation of saccharides such as raffinose, a trisaccharide. The reactions are said to bind the hemoglobin sub-units into tetramers by non-site specific crosslinking of the globin chains of the sub-units to one another, to stabilize the tetrameric hemoglobin in the T-configuration or the R-configuration for control over the oxygen affinity of the resultant tetramer. The reactions are also said to be controllable to allow the formation of oligomers of hemoglobin by intermolecular crosslinking in predetermined amounts along with the stabilized tetramer. Non-site specific crosslinking of the globin chains according the Hsia patent is taught therein to be advantageous in allowing the use of large molar excesses of polyaldehyde for enhanced yields of crosslinked, stabilized hemoglobin, as opposed to site specific crosslinking where stoichiometric quantities of reagents are usually necessary.
Further studies and investigations of the processes and products disclosed in the Hsia patent have revealed, however, that by variation of some of the conditions of reaction and other factors, unexpected improvements in the control and reproducibility of the process, and in the nature and consistency of the end products, can be achieved. A product such as a blood substitute, intended for administration to live animals, should have a controllable and reproducible composition of components, so that its efficacy and side effects can be properly monitored.
It is an object of the present invention to provide novel processes for preparing blood substitutes based on hemoglobin.
It is a further object of the present invention to provide improved methods and conditions of reacting hemoglobin with polyaldehydes derived from the oxidative ring opening of saccharides.
The present invention is based to some extent upon the discovery that the polyaldehyde product of the oxidative ring opening of a di/tri-saccharide (this term being used herein to denote disaccharides and trisaccharides) is highly specific in reacting with specific sites in the 2,3-diphosphoglycerate binding (DPG) cleft of hemoglobin, to crosslink two β-globin chains thereof, provided that the polyaldehyde product itself is substantially homogeneous. Ring-opened, oxidized di/tri-saccharides undergo hydrolytic degradation under alkaline conditions. Solutions of ring-opened, oxidized raffinose (o-raffinose), for example, stored at pH >7 undergo significant alkaline hydrolysis to provide oxidized disaccharides (e.g. o-sucrose) and oxidized monosaccharides (e.g. o-galactose),in admixture with the oxidized trisaccharide. Stabilization of o-raffinose solutions is achieved by maintaining stock solutions at pH <7, and preferably pH <6.
The process of the present invention, however, prepares a substantially homogeneous polyaldehyde by maintaining the pH of ring-opened, oxidized di/tri-saccharide solutions such as raffinose at pH 5.0 -7.0. This product can be reacted with hemoglobin at a stoichiometry (based on moles of di/tri-saccharide to tetramers of hemoglobin) of about 1:1-4:1, to give high yields of crosslinked, stabilized hemoglobin product. The very large excesses of crosslinking reagent recommended in the aforementioned Hsia patent for obtaining high yields of products, of 20:1 and thereabouts, turn out to be unnecessary. Moreover, the side effects experienced in using such large excesses of crosslinking reagent, namely lack of control and reproducibility of the nature of the composition of the resulting crosslinked product, are largely avoided. Formation of high molecular weight aggregates are avoided by using limited stoichiometry of crosslinking reagent.
Thus, according to one aspect of the present invention, there is provided a process of chemically modifying hemoglobin to render it more suitable for use as a blood substitute in aqueous solution, which comprises:
(a) subjecting a di/tri-saccharide to an oxidative ring opening process to produce a polyaldehyde therefrom;
(b) adjusting and maintaining the pH of the resulting product solution to a value within the range from about pH 5.0 to pH 7.0, so as to prevent any substantial hydrolytic degradation of the polyaldehyde so formed;
(c) reacting the product of process step (b) with hemoglobin in solution, at a stoichiometric ratio, based upon ditrisaccharide and hemoglobin tetramers, of from about 1:1-4:1;
(d) reducing the Schiff base linkages so formed to secondary amine linkages; and
(e) recovering the modified hemoglobin so formed.
The nature and composition of the crosslinked product obtainable by use of the present invention is not only controllable and reproducible, but also advantageous. The product contains little unmodified hemoglobin, and what little there is can if necessary readily be removed by diafiltration. It is free from high molecular weight (greater than 600,000 daltons) hemoglobin aggregates. It consists essentially of about 40% tetrameric hemoglobin, less than 5% of dimeric hemoglobin, with the balance being oligomers with molecular weights between 64,000 and 500,000 daltons.
It has previously been thought necessary to avoid crosslinking of hemoglobin at pH below 7.4, for fear of excess formation of methemoglobin. A further unexpected and advantageous feature of the present invention is that, with the crosslinking reagents described herein, hemoglobin crosslinking reactions can be conducted within the pH range 5.0-7.0 without excessive formation of methemoglobin. This is of course the pH range within which the o-saccharide (polyaldehyde) is maintained for stability, so that an extra process step of pH adjustment or the like, prior to the crosslinking reaction, is advantageously avoid.
FIG. 1 is a diagrammatic representation of the chemical reaction of oxidative ring opening of raffinose to produce a hexa-aldehyde, and the subsequent chemical equilibrium formation with the acetal compound;
FIG. 2 is a diagrammatic representation of the chemical reaction of the polyaldehyde with hemoglobin and the subsequent chemical reduction step;
FIG. 3 is the HPLC analysis curve of the product of Example 1 described below;
FIG. 4 is a diagrammatic presentation of the kinetics of the reaction described in Example 3 below;
FIG. 5 is a chromatogram illustrating the C4 globin chain analysis of unmodified hemoglobin from Example 4 below, showing heme, beta chain and alpha chain;
FIG. 6 is a chromatogram similar to FIG. 5, illustrating the C4 globin chain analysis of crosslinked hemoglobin from Example 4 below.
The preferred di/tri-saccharide for use in the present invention is the trisaccharide raffinose, and so the invention will be further described, for reasons of clarity, with specific reference to the use of raffinose. It is to be understood, however, that this is a preferred choice of di/tri-saccharide, and the invention is not to be construed as limited thereto. Other suitable trisaccharides include planteose, manninotriose, galactotriose, gentianose, melezitose, o-alpha-D-galactopyranosyl-(1-6')-mannobiose, maltotriose and cellotriose. Suitable disaccharides include sucrose, lactose, maltose, isomaltose, cellabiose, melibiose, planteobiose, galactobiose, gentiabiose, turanose and mannobiose. The invention is not to be construed as limited to the use of the specifically mentioned di/tri-saccharides.
Preferably, the raffinose is oxidatively ring opened, by reaction in solution with a strong oxidizing agent such as a periodate, for example sodium periodate or potassium periodate. This oxidation takes place at very low pH. After the reaction has been conducted, the solution is adjusted to pH 5.0-7.0 by suitable buffering, preferably to 6.0-6.5. Any salts formed as a result of the pH adjustment, which might interfere with the subsequent reactions with hemoglobin, are preferably removed at this stage, e.g. by crystallization, mixed bed ion exchange, gel permeation chromatography, reverse osmosis, etc. Phosphate buffers are effective but are preferably avoided, because residual phosphate ions in the solution can interfere with the subsequent crosslinking reaction. The resulting product can be stored, in aqueous solution, preferably to about pH 6.0, ready for use. Suitable buffers are those which buffer to a pH range 6-7, and include MES (2-[N-morpholino]ethane sulphonic acid); BIS-TRIS (bis[2-hydroxyethyl]imino-tris[hydroxymethyl]methane; ADA (N-[2-acetamido]-2-iminodiacetic acid; ACES (2-[(2-amino-2-oxoethyl)-amino]ethanesulfonic acid); PIPES (piperazine-N,N'-bis[2-ethanesulfonic acid]); MOPSO (3-[N-morpholino]-2-hydroxypropanesulfonic acid); BIS-TRIS PROPANE (1,3-bis[tris(hydroxymethyl)-methylamino propane); BES (N,N-bis[2-hydroxyethyl]-2-aminoethane sulfonic acid); MOPS (3-[N-morpholino]propanesulfonic acid); TES(N-tris[hydroxymethyl]methyl-2-aminoethane sulfonic acid); HEPES (N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid]), with BIS-TRIS and BIS-TRIS PROPANE most preferred.
Phosphate buffering of the raffinose reaction solution is also best avoided on grounds of efficiency of reaction. On subsequent crosslinking of the hemoglobin with the ring opened raffinose polyaldehyde product, the crosslinking reagent reacts specifically at the DPG binding site, but the phosphate would also interact at such a site. Accordingly, avoidance of phosphate avoids the reaction competition between the species, resulting in greater yields, faster reaction and better control over the resulting chemical products.
The chemical progress of this reaction is diagrammatically illustrated in FIG. 1 of the accompanying drawings. If the pH is not properly controlled, the o-raffinose partially hydrolyses to form a mixture of o-sucrose and o-galactose, and under some conditions to smaller oxidized fragments. The resulting product mixture of dialdehydes and tetra-aldehydes is not only an undesirable mixture on grounds of its non-homogeneity and nonreproducibility, but also is less reactive towards the hemoglobin, thereby requiring the use of greater quantities for good yields of product. Cross-linking of hemoglobin with o-sucrose is effective and useful within the scope of the present invention, but takes place more slowly, and with different specificity than in the case of o-raffinose.
The hemoglobin for use in the process of the present invention is preferably human hemoglobin, derived from red blood cells. However, the invention is applicable also to other types of hemoglobin to form the basis of a blood substitute, such as animal hemoglobins especially bovine hemoglobin, ovine hemoglobin and the like. Human hemoglobin is currently the preferred choice, to form the basis of a blood substitute for administration to human patients.
The hemoglobin can be recovered and prepared for use in the present invention according to standard, known techniques. Thus, red blood cells are lysed, and cellular debris and stroma are removed therefrom by standard techniques of centrifugation, filtration and the like. Preferably, a solution of hemoglobin with a concentration of 2-14% by weight of hemoglobin is used, to yield a product having the most desirable composition and combination of properties. The purity of the hemoglobin should be as high as practically achievable, to avoid toxicity in the final product. Final purification suitably takes place chromatographically.
Hemoglobin can naturally exist in the tight (T) conformation as normally assumed by deoxyhemoglobin, or in the relaxed (R) conformation as normally assumed by oxyhemoglobin. The oxygen binding characteristics of deoxy- hemoglobin are the more desirable characteristics, since this is the conformation naturally assumed by the hemoglobin inside the natural red blood cells of the blood. It is accordingly preferred to effect the process of the present invention on deoxyhemoglobin, the crosslinking reaction with the polyaldehyde derived from ring opening of raffinose serving to stabilize the hemoglobin in the T-configuration. If, however, one chooses for any reason to start with R-configuration hemoglobin, the crosslinking reaction according to the invention stabilizes the hemoglobin into the R-configuration throughout.
Deoxygenation of hemoglobin to form deoxyhemoglobin is preferably conducted, prior to the reaction with the crosslinking agent, by subjecting the hemoglobin solution to treatment with a non-oxygenating gas such as nitrogen, according to known techniques. Some prior art processes, including that described in the aforementioned Hsia patent, teach the use of a reducing agent such as sodium dithionite for removing the final traces of oxyhemoglobin. Such a technique is not preferred according to the present invention, since it has been found that the presence of dithionite residues inhibits the o-raffinose-mediated oligomerization of the tetrameric hemoglobin units. It is thus preferred to continue the treatment with a stream of nitrogen, followed by appropriate degassing, for sufficiently long periods of time to effect complete conversion to deoxyhemoglobin in this manner.
Reaction of the deoxyhemoglobin aqueous solution with the polyaldehyde crosslinking reagent so formed suitably takes place in aqueous solution, at a temperature in the range of 4-40° C., and for a period of time of from 2-96 hours, preferably about 24 hours. The reaction solution is buffered, preferably with a bis-tris buffer system, to a pH not exceeding 7.5 and preferably in the range 5.0-7.0 to avoid risk of hydrolysis and decomposition of the hexa-aldehyde. The molar ratio of polyaldehyde to hemoglobin is, as previously stated, in the range 1:1-4:1 on the basis of o-raffinose to hemoglobin tetramers, and preferably at a stoichiometry of about 2.5:1-3.5:1. The concentration of deoxyhemoglobin is suitably 1-15% (w/v) and preferably in the range 5-10% (w/v).
As a result of the reaction of the hemoglobin with the hexa-aldehyde, in which amino groups on the hemoglobin chain react with the aldehyde groups of the crosslinking reagent, a Schiff base linkage is formed which is a reversible linkage. The coupled product effectively enters into an equilibrium balance with the non-crosslinked hemoglobin and crosslinker. This is diagrammatically illustrated in FIG. 2 of the accompanying drawings. This linkage now needs to be reduced to a primary amine linkage, which is stable and irreversible, to complete the crosslinking of the hemoglobin for blood substitute purposes. The reducing agent is preferably added to the reaction mixture after the substantial completion of the crosslinking reaction. Whilst the prior art, for example the aforementioned Hsia patent, recommends the use of sodium borohydride as the reducing agent, there is used according the preferred aspect of the present invention borane dimethylamine as the reducing agent. This has the significant advantage over the prior art of avoiding generation of gaseous hydrogen, which occurs when sodium borohydride is used, and leads to difficulties in control and general conduct of the process. The use of borane dimethylamine is a significant improvement in this regard. Other water soluble borane lower alkyl amine reducing agents including but not limited to borane-tert-butylamine, borane-ammonia; borane-dimethylamine; borane-trimethylamine; and borane triethylamine, can also be used. Another useful but less preferred reducing agent is sodium cyanoborohydride.
Reduction of the Schiff bases formed during the crosslinking and reduction of unreacted aldehyde groups must suitably takes place in aqueous solution at a temperature range of 2°-25° C., for a period of time from 2-36 hours, preferably 24 hours. The reaction mixture is suitably buffered to pH 5-8, preferably to 6.5-7.0. The molar ratio of reducing agent to the sum of imine and aldehyde groups is in the range 2:1 to 5:1, preferably 2.5:1 to 3.5:1 based on the stoichiometry of reducing agent to aldehyde groups added to initiate crosslinking.
After the stabilization of the crosslinked product by reduction with dimethylamine borane has been completed, the product is suitably treated with carbon monoxide to form a protected complex of hemoglobin, for storage purposes. After treatment with carbon monoxide, which conveniently takes place by passing carbon monoxide into the reaction solution so formed at the temperatures of reaction, the mixture is preferably diafiltered appropriately to remove residual reducing agent and any other reagent residues. Residual buffer can be removed by gel permeation chromatography. If necessary in order to remove uncrosslinked hemoglobin residues, magnesium chloride can be added to dissociate the uncrosslinked tetrameric hemoglobin, followed by diafiltration for removal of the residues The resulting material is then ready for storage under sterile conditions until use.
The invention will be further illustrated by reports of specific, non-limiting examples, as below:
To a solution of raffinose (76 gm, 0.128 mole) in sterile water (1 litre), cooled to 4°-10° C. on an ice bath, solid sodium-m-periodate (181 gm) was added in aliquots and the temperature maintained at <15° C. by adjusting the rate of addition and cooling in an ice bath. After the final addition of sodium-m-periodate, the solution was maintained at 10°-15° C. and stirred for 2-24 hours for completion of the oxidation reaction. The solution was then cooled to 4° C. and excess periodate was then neutralized by the controlled addition of sodium bisulphite. The pH of the solution was then adjusted with 10 N NaOH (100 ml), solid Bis-Tris (to a final concentration of 20 mM) was added and the pH carefully adjusted to 5.0. The solution was partially desalted by storing at 4° C. for 16-24 hours to induce crystallization and the clear supernatant, containing the oxidized raffinose, was decanted and filtered. The final pH of the solution was carefully adjusted to 5.9±0.1.
The HPLC analysis of the product of the above process, taken after storage of the reaction solution at pH 6.0 for 21 hours, is presented in FIG. 3. The presence of only a single peak relating to ring-opened saccharide products, namely the hexa-aldehyde o-raffinose, is noteworthy, and indicates homogeneity of the product and absence of alkaline hydrolysis products. The only other significant peaks on the chromatogram pertain to salts and formic acid, which are readily removable.
The o-raffinose may be purified further by desalting on using a) ion exchange mixed bed resins b) size exclusion chromatography or c) reverse osmosis.
A solution of o-raffinose (20 ml, pH 5.65) was adjusted to pH 1.6 by dropwise addition of 6 N HCl and then the solution was passed through 30 mL of Biorad AG 501-8 (D) analytical grade mixed bed resin. The eluent was collected and purified sample lyophilized to provide a solid, white crystalline product.
A 30 mL solution of purified human hemoglobin (8% w/v) in 50 mM Bis-Tris buffer at pH 6.5 was converted to deoxyhemoglobin under a stream of moisturized nitrogen gas for approximately 4-6 hours at room temperature with constant stirring. The ring-opened, oxidized raffinose (112.5 μ moles) was degassed and added to initiate the crosslinking and oligomerization reactions. After 24 hours, 3M sodium acetate was added to provide a final concentration of 30 mM and then followed by reduction with 2.25 mmole of dimethylamine borane dissolved in 1.3 ml of degassed water. The reduction was allowed to proceed overnight.
The progress of the reaction was monitored by FPLC, and the results are presented diagrammatically on FIG. 4. Peak no. 1 derives from hemoglobin dimeric sub-units (32 kdaltons) present in the mixture--clearly they are few in number. Peak no. 2 derives from the tetrameric (64 kdalton) crosslinked hemoglobin constituting about 40% proportion of the product mixture. Peak no. 3 derives from dimerized (128 kdalton) and peak no. 4 derives from oligomeric hemoglobin units of average molecular weight about 380 kdaltons. It is to be noted that the product mixture contains no fraction of higher molecular weight higher than 600 kdaltons.
To monitor the progress of the crosslinking reaction, o-raffinose: Hb solutions were reduced with dimethylamine borane, in the presence of sodium acetate, after crosslinking for 1 hr, 2.5 hr and 23 hrs. The stabilized crosslinked 64 kD fractions were isolated by preparative size exclusion chromatography on a Superdex (Pharmacia) gel permeation using a mobile phase of 0.5M magnesium chloride.
The effect of the magnesium chloride solution is to dissociate the uncrosslinked tetrameric hemoglobin into alpha-beta dimers (32 kdalton). Magnesium chloride does not dissociate crosslinked hemoglobin. In this way, crosslinked hemoglobin can be separated from uncrosslinked hemoglobin for analysis purposes.
The heme and globin chains of the crosslinked 64 kD species were separated by reverse phase HPLC using 330 angstrom pore size C4 Vydac columns (250×4.6 mm for analytical and 250×10 mm for preparative; The Separations Group, Hesperia, Calif.) and developers containing 0.1 % trifluoroacetic acid and various gradients of acetonitrile starting at 38% and ending at 60% were employed to effect separation. The effluent was monitored at 220 nm and the globin chains recovered from the effluent by lyophilization.
In a similar manner, the heme and the globin chains of the uncrosslinked, unmodified hemoglobin were separated.
FIG. 5 of the accompanying drawings shows the reverse phase globin chain chromatography for the unmodified hemoglobin, and FIG. 6 shows that for the modified, crosslinked hemoglobin. In each case, as will be readily recognizable to those familiar with hemoglobin analysis, and as readily deducible from reference publications thereon, peak 1 represents heme, peak 2 represents unmodified beta-globin chains, peak 3 represents unmodified alpha-chains, peak 4 represents predominantly modified beta-dimers and peak 5 represents predominantly modified alpha-dimers. By comparison of FIGS. 5 and 6, one can readily see that crosslinking according to the present invention takes place specifically on the beta-dimers, i.e. in the beta-chains of the hemoglobin tetrameric units.
To determine the specific position of the modification (crosslinking), the globin chains represented by peak(fraction) 2 on FIG. 5, peak (fraction) 3 and peak (fraction) 4 on FIG. 6 were submitted to enzymatic hydrolysis using trypsin, followed by peptide analysis, as follows.
Isolated, globin chains were first dissolved in 8M urea (to increase susceptibility to hydrolysis) and kept at room temperature for 2 -4 hours. The solution was diluted to 2M urea with 90 mM ammonium bicarbonate buffer at pH 8.5. Trypsin (2% of total protein) was added and the solution was digested for 18-20 hours at room temperature. The tryptic hydrolysate was then heated in boiling water for 2 minutes, diluted to 1M urea with 80 mM ammonium bicarbonate buffer and digested with endoproteinase Glu-C (1% of total protein) for another 18-72 hours at room temperature. The hydrolysates were centrifuged or filtered before injection onto the HPLC column.
Peptide fragments were separated by reverse phase HPLC on Vydac C18 columns (25×0.46 cm, The Separations Group, Hesperia, Calif.). Separations were made using developers of 0.1% TFA and gradients of acetonitrile starting at 0% and ending at 100% over a period of 100 minutes. Eluent was monitored at 220 nm for detection of peptidyl fragments.
Trypsin specifically cleaves a protein chain at a lysine residue having a free primary amine group. It is specific in its reaction to primary amine groups which in hemoglobin can only derive from a lysine residue or a terminal amino acid group. The amino acid sequence of globin chains of hemoglobin is known. Thus, by peptide analysis of the tryptic digest, using reverse phase HPLC, on fraction 2 from FIG. 5 and fraction 4 from FIG. 6, it was shown that the crosslinking was specific to lysine-82 on the beta-chains, all of which were missing from the fraction 4 sample, and the terminal valine group from the beta-chain, half of which were missing from the fraction 4.
Lysine-82 on the beta-chains of hemoglobin is known from prior work to be located in the 2,3-diphosphoglycerate binding site of hemoglobin. Thus the specificity of crosslinking in the DPG binding site, using beta-lysine-82, by the process of the present invention, is demonstrated and established.
The preparation was conducted according to the procedure described in Example 1 for periodate oxidized raffinose, using 3.8 gm (11.1 mmole) of sucrose dissolved in 50 ml of sterile water and 10.4 gm of solid sodium-m-periodate.
A 30 ml solution of purified human hemoglobin (8% w/v) in 50 mM Bis-Tris buffer at pH 6.5 was converted to deoxyhemoglobin under a stream of moisturized nitrogen gas for approximately 4-6 hours at room temperature with constant stirring. The ring-opened, oxidized sucrose (115 mMoles) was degassed and added to initiate the crosslinking. After 24 hours, 3M sodium acetate was added to provide a final concentration of 30 mM. This was followed by reduction of the crosslinked product with 1.44 mMole of 10 borane dimethylamine dissolved in 0.8 ml of degassed water. The reduction was allowed to proceed overnight.
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Orlando, FL.
A great addition to my "avengers" plated sixth scale Loki. Glad I bagged the limited edition before it sold out. I regret nothing!
— A Viewer
Santa Barbara, CA
Unbelievable likeness!
— A Viewer
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|Total Rewards at FirstEnergy
|FirstEnergy's total rewards package includes a comprehensive package of benefits and pay to keep you healthy and reward you for being part of a successful company. Here you will find information and reference materials to help you get the most value from the programs and benefits you receive.
Healthy Living Wellness Program
Learn more about the Healthy Living program


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At a Glance
NASA contract allows PNNL to improve space travel
Scientists at Pacific Northwest National Laboratory have been contracted by NASA to manipulate microtechnology—small-scale electronic and digital systems—to produce rocket propellant in space and breathing oxygen for interplanetary travel.
These microchemical and thermal systems, or MicroCATS, will be used to produce propellant from resources found on Mars and the moon. They also will be designed to regenerate breathable air for life support.
The NASA contract is valued at $13.7 million over four years. "The contract is four times larger than any PNNL has previously had with NASA," says Martin Kress, Battelle's NASA relationship manager. "We hope this technology system ushers in an entirely new approach for lunar and Martian exploration and habitation."
Gravity independence and reduced size and weight make microtechnology an ideal candidate for many NASA applications.
Agreement partners U.S. and Italian research efforts
Representatives of the Italian government and the U.S. Department of Energy have approved an amendment to a 1995 Agreement of Cooperation for research and development. "This agreement is a great step toward moving PNNL capabilities into new markets," said Tara Eschbach, the Lab's relationship manager for the National Agency for Environmental Protection and Technical Services (APAT).
The amendment allows scientific and technical transfers between APAT and DOE's Office of Science. The agreement will be mutually beneficial by improving the technical quality of Italian research and policy development and allowing DOE scientists access to research facilities and scientists in Italy who are conducting similar work.
Areas of exchange include renewable energy, carbon management and global climate change, waste management, decontamination and decommissioning, environmental remediation and restoration, environmental safety, and public outreach and risk communication.
Students donate research vessel to Marine Research Operations
While most high school students spend their weekends hanging out, five students from Port Townsend, Wash., chose to spend their Saturdays using math and engineering to create an underwater research vessel. Referred to as the ROV, the vessel was designed for diving to the depths of the Puget Sound to conduct marine research.
Local entrepreneur Gary McLuen challenged the students to develop the unmanned, remotely operated ROV. Upon completion, the students gifted it to PNNL's MSO facilities.
"This vehicle will become an important resource for PNNL scientists as we work to examine and sustain our precious northwest marine ecosystem," said Dick Ecker, director, PNNL Marine Research Operations (MSO), Sequim.
The vehicle collects and stores real-time data such as the levels of dissolved oxygen in water, vehicle depth, water temperature, turbidity and pH levels.
"So far we've used the ROV for demonstrations," said Parks Gribble, development engineer, MSO. "But we will use it for other measurements required for various programs."


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A Kardashian Family Photo Album: The Reality Stars Before They Were Famous
Credit: Facebook
Kardashians Get Candid
1 of 28
Kris Jenner's younger sister, Karen Houghton (far left), posted old school photos on Facebook of her reality star family. She even had a chat with In Touch magazine, opening up about everyone, including Khloe (clad in leopard print at a Christmas party) regarding her marriage woes with Lamar Odom: "Khloe's been going through hell. She's vulnerable and keeps everything inside. But she's one of the strongest girls I know. I see her coming out of this. I know she loves Lamar, but he has issues right now," she told the mag.


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Protect your breath in style with vogmask™, the world's first good looking filtering face mask. With the choice of high-tech microfiber or organic cotton, these comfortable, reusable masks combine pr
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After you purchase a vanity number, we will contact you within 1-2 business days with all the information you need to provide to your carrier to transfer your number. You should be able to use your new number within 1-3 days of contacting your carrier.
The number is yours to keep. If you decide to change carriers or phones at any point, you can continue to use your vanity number.
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Gear Guide
The Gear Guide is meant to help with purchasing decisions. If you are a member of the MIT community and you would like to rent gear, please go to the gear rental page.
Purchasing scuba gear can be a confusing and frustrating task, but it doesn't have to be. There are numerous options for getting outfitted, depending on your budget and preferences. However, the one thing that most divers agree on is the added level of comfort and safety that comes with diving in your own gear that you know well.
The most important factor when buying gear is fit. Scuba gear needs to fit you physically as well as fit the tasks you will Fit is critical to the gear working properly.
New and used gear
Generally, gear falls into two categories: new and used. There are pros and cons to buying both new and used gear. New gear comes with warranties, incorporates all of the newest advances, and is readily available at your local dive shop or through the internet. Used gear offers a significant price advantage for equipment which often functions perfectly. What to buy just depends on your budget and needs.
The catch-22 to buying gear is that the better you know gear, the better you are able to make purchasing decisions, but you only get to know gear by using it - either through buying or renting it!
A note for internet buyers. Some scuba equipment such as exposure suits and masks require a good fit. Unless you know exactly which size is right, you need to try on the gear before you buy it.


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Completing your associate's degree is the first step to completing the bachelor's and master's degrees necessary for entrance into the physical therapy field.Associate Degree Transfer ProgramLMC's Pre-Physical Therapy program gives you the core classes necessary to move on to a four-year college or university. This program is designed as a transfer program, working closely with Andrews University. The Andrews program is designed as a doctorate program.Transferring to Other Schools If you are interested in transferring to a four-year school other than Andrews University to complete your master's and then doctorate degree in physical therapy, you should work with your counselor or academic advisor to ensure that your courses will transfer to the school of your choice.
1 (800) 252-1562 or (269) 927-1000


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So, the StartUp Tour is over. Before you start singing John Lennon and wrapping yourself in tinsel and fairy lights, let's take some time out to recap how StartUp Britain's wonderful four week adventure went.
So, the StartUp Tour is over. Before you start singing John Lennon (Happy Xmas, War is Over… it rhymes) and wrapping yourself in tinsel and fairy lights, let's take some time out to recap how StartUp Britain's wonderful four week adventure went.
For those of you that haven't heard about the StartUp Tour, here's a video which sums it up:
It all began in Lewisham on the 15th October: the double-decker bus pulled up to Lewisham College and we rolled out the entrepreneurs, business advisers, and even the Enterprise Advisor to the Prime Minister, Lord Young, to inspire and accelerate enterprise amongst the college's students.
StartUp Britain then weaved its way through the southern regions of England – spreading entrepreneurial joy through Plymouth, Bristol and Kent. Our journey featured performances from Cynikal, the blossoming of mentor & mentee relationships, and the launch of an enterprise society.
The bus then made its way through south east England, visiting Reading, calling in at the University of East London, and then creeping up to Stevenage, and East Anglia; encountering many inspiring and inspired students. We also encountered a chorus of praise: the Deputy Principal of North Hertfordshire College said that the bus gave an "outstanding opportunity for our students to engage with the increasingly important entrepreneurial agenda. It has provided resources for employment opportunities and sound advice to students of ours who are looking to start a business."
Here's a video made by SeaMedia, students at the University of East Anglia:
The third week of the tour took StartUp Britain to the Midlands, and beyond; reaching out to students in Birmingham, Staffordshire, Bolton and Nottingham. StartUp Britain proved to students that there's nothing scary about starting up, even on Halloween. Our visits brought cupcakes aplenty, Apprentice stars, and some of the youngest entrepreneurs to have graced the bus.
In week four, the bus went up North, to Newcastle and Hull, and passed the Scottish border, visiting students in Edinburgh and Glasgow. The team stumbled upon a rapping entrepreneur in Sheffield, J C Clack, who performed a StartUp Britain freestyle, telling fellow students to "make something out of nothing", and to "keep on doing your thing", we met an egg-cellent entrepreneur, who sells specialist eggs on eBay, witnessed a beautiful balloon launch, and a pizza-off.
The team has met some brilliantly determined entrepreneurial students, some business ideas have been risqué – at the University of East Anglia, one student proposed a student sex line (I will say no names). Some have been strangely brilliant – I talked to a college student in Stevenage about a second hand Goth Shop, which would also provide a tattoo parlor for the alternative folk. Some are already underway – a surplus army backpack-selling entrepreneur in Bolton approached the bus to get funding in order to manufacture his own backpacks, as the demand for them in New York is so huge.
Most importantly, an entrepreneurial message has been spread. Nearly 600 business advisers showed a passion for their community, by offering help to local College and University students. CEO of StartUp Britain, Emma Jones, explains the reason why:
"Young people represent part of the future of business and our economic prosperity – that's why it's so important to offer them support by delivering the message that they can set up a business"
Not only has our message been spread by our physical presence in Colleges and Universities, alongside the inspiring business advisers, but our social media campaign has made over 7,000,000 impressions over the past month: sparking interest in the #StartUpTour and its delivery of assistance in enterprise.
Not only are students, and the general public, now more aware of the potential of going it alone in business, but those already starting up are being helped along the way. Entrepreneurial students have networked with local business advisers that are happy to help them (avoiding approaching the scary men in suits alone), are now in the process of getting funding for their dream from StartUp Loans, and have walked away with the StartUp Loans Kit, which provides a step-by-step guide on making an idea a reality – and then growing it some more.
Enterprise is bigger than ever – all thanks to the StartUp Britain Bus Tour – we celebrated this on November 14th – otherwise known as StartUp Day - at the British Library with the StartUp Britain Bus in tow.


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Results 11 to 20 of 1453
Keeping up the hypocrisy theme:
0:57 "because it's easy to go on facebook or something and pretend you're an Aarnold Schwartzeneggar or somebody when in actual fact you're a 10 stone weakling"
- or something like youtube Mr.Daw?
2:05 "and there's always going to be people who hate, because, they can't really do it themselves.
2:54 "the last thing I want to talk about is all this MMA, UFC crap. Aboslute fucking rubbish. I'm not going to hold by tongue here. MMA, UFC, Morons Martial Arts."
- well he should know.
3:58 "these MMA UFC crap, if you come up against someone like me who actually does fight, who actually can hold they're own and you try all this rubgy tackle crap you're going to get your fucking ass handed back to you. You're going to get your head kicked in."
- hahahaha, irony.
Dum spiro, spero.
Tada gan iarracht.
- Join Date
- May 2011
- Location
- israel
- Posts
- 1,332
Posted On:
11/20/2013 3:49am
I'm going to download his youtube vids for prosperity as suggested above.
Anyone know where he is based? It can all be said to his face easily.
EDIT: Having trouble believing this level of BS is happy putting videos up on youtube, comments disabled for obvious reasons. How can he talk about fraud ffs!
Last edited by Resonance10; 11/20/2013 11:23am at .
- Join Date
- Aug 2005
- Posts
- 1,818
Posted On:
11/20/2013 11:32am--
I created a thread years ago about Ian Prescott where he had rank signed from Ashida Kim giving him rank in multiple Kung Fu Systems. I have the documents so let me know if and when you need them.
Ashida sells rank in anything from his association.
This pudgy mouthboxer could not fight his way out of wet tissue paper.
He needs to get back on his Haldol.
Registered Member
- Join Date
- Nov 2007
- Location
- London
- Posts
- 645
Posted On:
11/20/2013 11:32am
- Join Date
- Aug 2013
- Location
- Alexandria, VA
- Posts
- 792
Posted On:
11/20/2013 11:58am
Style: TangSooDo/Yubiwaza3
Its one thing to claim great MA skill, if you don't display it nobody can call you on it. But the videos he's posted are so bad, so obviously bad, that you have to wonder whether the man is not a conscious money seeking fraud, but is seriously deluded and actually believes in his own fantasy.
Registered Member
- Join Date
- Feb 2011
- Location
- Seattle
- Posts
- 273
Posted On:
11/20/2013 12:55pm
So Grandmaster even gets some time to refine his badass snake karate and stick it to some fatties.
CapnMunchh: But the videos he's posted are so bad, so obviously bad, that you have to wonder whether the man is not a conscious money seeking fraud, but is seriously deluded and actually believes in his own fantasy.
Last edited by Resonance10; 11/20/2013 1:03pm at .


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- BlackBerry® smartphones
The following error appears on the BlackBerry smartphone:
SIM card is full please delete SMS messages
Short Message Service (SMS) text messages have been saved to the Subscriber Identity Module (SIM) card in the BlackBerry smartphone. The SIM card has become full and cannot store any more information.
For a possible resolution of this issue, complete the following steps:
For BlackBerry Device software 5.0:
- On the Home screen of the BlackBerry smartphone, go to Options > SMS.
- Press the Menu key and click SMS options.
- Go to Leave Messages On SIM Card.
- Press the Menu key again and click Change Option.
- Select No.
- Press the Menu key and click Save.
- Open Messages on the Home screen of the BlackBerry smartphone and press the Menu key.
- Locate the View Folder menu option.
- Select SMS SIM Card Inbox.
- Delete any unnecessary SMS text messages in order to create space on the SIM card.
For BlackBerry® Device Software 6.0 and 7.0:
- On the Home screen of the BlackBerry smartphone, open the Messages application.
- Press the Menu key and click Options.
- Click Text Messaging.
- In the SMS Text area, clear the Leave Messages On SIM Card check box.
- Press the Menu key and click Save.
By downloading, accessing or otherwise using the Knowledge Base documents you agree:
(a) that the terms of use for the documents found at www.blackberry.com/legal/knowledgebase apply to your use or reference to these documents; and
(b) not to copy, distribute, disclose or reproduce, in full or in part any of the documents without the express written consent of RIM.
Visit the BlackBerry Technical Solution Center at www.blackberry.com/btsc.


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Learn how to combine the simplicity of iPhoto with the power of Aperture and get the best of both worlds.
Covers the entire photographic workflow in Aperture, from import to enhancement to output, plus special 3.3 features like Retina display support and iPhoto integration.
"Through your company I am experiencing the real joy of education. It is incredibly motivating to see the passion of the teachers in each course." —Saif R.
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Middle school is a bustling, vibrant community of teachers and sixth through eighth graders. These "middle" years are a time for students to take on increased responsibility in academics but also to enjoy increased involvement in community service, student government, sports and a dizzying number of extracurricular activities from which to choose.
Along with clubs, activities and sports, middle school also offers students leadership opportunities to give them a voice in the daily operation of the school. Some clubs and organizations become involved in community service projects, while others may focus on the environment or the arts. In essence, the middle school is committed to helping young people grow and mature in as many ways as possible.
Click on the links below for course details.
Advisory Program
All middle school students are assigned to an advisory group, which meets each morning during the homeroom time slot. The advisory program plays a critical role in monitoring and supporting academic and social progress so that each individual feels known, heard and understood. Advisory groups are small, grade-level packs where each student has automatic membership.
Advisory groups focus on issues that relate to students in their roles as people, as learners, and as members of the community. The ultimate goal is for students to understand themselves better and to explore topics as varied as developing personal goals, celebrating accomplishments and avoiding making bad decisions. Advisors are also available to meet with families as the need arises.
Ambassadors Club
The Ambassadors Club promotes friendship, service, and school spirit as the "face of Keith" in the school community. Members volunteer at various admission functions throughout the school year, conduct shadow visits, and act as hosts at events such as the BEK Scholarship Exam, Information Fair, and new student orientation. The Ambassadors Club is open to middle and upper school students.
Camp Timber-lee
Each fall Keith eighth graders and fifth graders head off with their faculty advisors for team building, leadership training and outdoor education at Camp Timber-lee. This experience offers a wide variety of activities for students to be exposed to hands-on learning in the outdoors. Zip lines, camping, climbing towers, archery, boating and much more are all part of the experience.
Ceramics Club
Ceramics Club gives current potters an opportunity to practice their art under the guidance of renown Raku artist, Robert Sunday. The club is also open to students interested in learning pottery. In addition to pottery, the club also works on sculptures and other ways to work with clay as an art form.
Certamen is an oral team competition with a format which is a cross between that of College Bowl and that of Jeopardy. It requires a broad-based knowledge of the classics. Questions cover the Latin language (vocabulary, grammar, derivatives), as well as classical mythology, history, and culture. Teams of four students compete in four levels: Junior High, Latin I, Latin II, and Advanced (Latin III-V). Keith has been a member of the Illinois Certamen League for several decades, competing annually in three meets with schools in the Northwestern Illinois Regionals.
Honor Council
The Honor Council is a group of students responsible for enforcing the ideals expressed in the school's honor code. Students are elected by faculty and class vote at the beginning of the school year. The representatives in this group are expected to set the example for upholding these ideals themselves. The structure of the honor council is as follows:
* three representatives from the senior class (one non-voting chair)
* two representatives from each of the other high school classes
* a vice chair (senior)
* two secretaries (one a senior or junior, the other a junior or sophomore)
Interact Club
Interact is an international organization of service and social clubs for young people of secondary school age that fosters leadership and responsible citizenship and promotes international understanding and peace. The name was created by combining the words "international" and "action." Interact Clubs are sponsored by Rotary Clubs as a program of Rotary International. Rotary Clubs provide guidance and inspiration, but the Interact Clubs are self-governing and self-supporting. Clubs take a variety of forms, both single-gender and mixed as well as large and small. The membership base of a club can be drawn from the student body of a single school or from two or more schools from the same community.
Math Competitions
Keith middle and upper school students have opportunity to compete in high level mathematics competitions. Seventh and eighth grade students participate in MathCounts, an event designed to inspire excellence, confidence and curiosity in middle school students through fun and challenging math programs. Students participate in regional MathCounts competitions once a year.
MS Quiz Bowl/Scholastic Bowl
Is your brain filled with tons of facts, information, and trivia? Then this is the club for you! Quiz Bowl is a middle school activity where four-person teams compete in an academic competition. Competition material comes from social studies, mathematics, language arts, health, current events, fine arts, sports and popular culture. The quiz bowl season runs from the winter to late spring. There are teams available for a variety of grades and skill levels so any middle schooler is welcome to participate.
The Middle School Scholastic Bowl is an academic competition with a quiz-bowl format designed to encourage and promote academic excellence. Teams consists of five players who are asked questions that demand quick recall of facts from all academic areas, as well as general knowledge, current events, sports and the arts. Based on student interest, up to four scholastic bowl teams will participate in any given season with the top team competing at the end of the season in both regional and statewide tournaments.
Both Quiz and Scholastic Bowl teams will usually practice weekly. Regular season matches usually take place after school but the teams do occasionally compete in tournaments too.
Middle School Student Government
Have you ever thought of running for office and making a difference in the middle school community? Then MSSG may be the place for you! MSSG is the middle school student council and is an elected group of class representatives that meets weekly to organize middle school social opportunities such as dances, rec nights, fundraisers, open gym nights, off campus social events, and team building projects. There are two "Middle School Class Representative" positions open for each of the 6th, 7th, and 8th classes. The offices of Treasurer and Secretary are open to 7th and 8th graders and the offices of President and Vice President are open to 8th graders. MSSG class representatives and officers are elected by their classmates in September for a one-year term of office. Consider running for office and serving the middle school in this fun leadership and character building organization.
Ping Pong Club
The Ping Pong Club is a fun Friday activity for students to hang out after school and play ping pong on the third floor of the middle and upper school building. This activity is open to all students.
Tri-M Music Society
Tri-M is an upper and middle school music honor society. It is designed to recognize students for their academic and musical achievements, reward them for their accomplishments and service activities and to inspire other students to excel at music and leadership. The Keith chapter, run by the students but supervised by an advisor, is one of 4,500 participating in several countries.
Washington D.C. Trip
Experience our Nation's capitol with your classmates! This trip is offered every other year to 7th and 8th grade students. Students will spend four days in the Washington D.C. area seeing exciting places like the Smithsonian, the White House, Gettysburg, Arlington National Cemetery, Fort McHenry, the Spy Museum, National Monuments, the National Archives, and dozens more sites during this action packed trip. Details and preliminary signups for the April, 2014 trip will be available in February, 2013.
Mock Elections
The middle school organizes and runs school-wide "mock" elections during election years. All middle schoolers are welcome to participate and help organize the election, create the voter awareness assembly, "register" student voters, work the election booths, and give speeches for political candidates. It is a fun after-school activity, and all middle schoolers are most welcome to join! We will meet throughout the month of October in preparation for the Keith 2012 Mock Election.
Community Service
Three times a year, middle school advisory groups perform community service projects. Student groups rotate to different venues each time, providing the students with a variety of experiences to appreciate the diverse needs of the community. These projects are designed to promote philanthropy and prepare middle school students for the 90-hour community service requirement needed to graduate. Additional goals for the program are to:
1) To develop character by providing services to those in need.
2) To appreciate the diversity of the global community and to accept responsibility for the development of that community.
3) To foster the spirit of volunteerism as an integral part of the American way of life.
4) To share the resources and talents of the Keith student body while acquiring new skill as volunteers.
Rock Camp
In a fun and relaxed environment, you will have the opportunity to utilize and further refine your musical skills by being grouped with other musicians to form a rock band. It doesn't matter if you are a novice or an advanced player; Summer Rocks is an exciting environment to sharpen your skills, whether you play guitar, bass, drums, or vocals. Each day is planned with time to learn, time to rehearse, and time for fun.
Summer Rocks is about helping you pursue your rock music dreams by offering both instrumental master sessions and group rehearsals to enhance your playing skills while giving you some inside tips on how to interact musically with other band members. Best of all, it gives you the opportunity to experience actually being in a rock band. You name the band, you pick the songs. This camp gives you a chance to express your individuality as an artist while exposing you to some performance fundamentals that will develop your confidence and stage presence. For more information on Rock Camp, click on link on www.summer-rocks.com.
Summer Rocks Goals
- Provide useful musical instruction to students of all skill levels
- Develop practice skills and discipline to set goals
- Build self-esteem and confidence
- Promote teamwork
- Create an opportunity for collaboration and networking with fellow musicians
- Encourage and nurture the love of music and performing
- Perform in a live concert setting
- Learn and Have FUN
Rocks the Park Concert
A Summer Rocks highlight! Each Friday night, the young musicians who have participated in camp that week will perform in the Sinnissippi Park Band Shell. Selected songs will be rehearsed during the week to showcase the students' progress. Friends and family are welcome to attend.
Students are introduced to the techniques needed to play the music they love – rock! Campers attend classes and rehearsals each day, focusing on their chosen instrument during their morning master class and switching to a group emphasis during the Band Basics afternoon classes. Instructor-coached rehearsals throughout each day will cover the material for the Friday night concerts. In addition, special guests from the music industry will present discussions on their area of expertise. Past guests have provided instrumental clinics, tips on how to promote your band and insight on being successful in a rock band.
Student-to-Staff Ratio
Our student to staff ratio is 6-to-1 and our student to teacher ratio is 8-to-1. (Staff includes teachers and counselors.)
Playing with Bands
Campers play in bands under the direction of a faculty coach. Summer Rocks will make every effort to group students into bands by age and musical preference. Teachers guide their groups through a team-oriented process of learning, rehearsing and performing their selected music. Campers may request in advance to be placed in bands with their friends, and we will do our best to make this happen.
Camp is intended for current middle and upper school school students (grades 6-12), and is limited to 38 students per week.


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Google attempts to stymie Android fragmentation by locking down the Android SDK
- By Sebastian Anthony on January 4, 2013 at 12:58 pm
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A new clause in the Android SDK's terms of service hints that Google's open-source operating system might not be as free as developers, OEMs, and users might hope. This has led some bearded developers to claim that the Android SDK is now "proprietary."
These concerns stem from a new clause that was recently inserted in the TOS, which prior to this hadn't been updated since 2009. The clause reads:
3.4 You agree that you will not take any actions that may cause or result in the fragmentation of Android, including but not limited to distributing, participating in the creation of, or promoting in any way a software development kit derived from the SDK.
In short, this clause means that you can no longer fork Android — which is iffy, as one of the basic axioms of free, open-source software is that you can fork it at any time to create your own version. It is because of Android's open-source nature that Amazon could take Android and create a modified version for its Kindle Fire devices. CyanogenMod, the Ouya game console — in a world where fragmenting Android is forbidden, neither should technically exist.
Now, in theory, the Android Open Source Project (AOSP) is still free and open source — but the Android SDK is the de facto tool for developing apps for every flavor of Android. By downloading the SDK, and then developing apps for an Android fork, are developers breaking the TOS?
In all likelihood this will come down to the interpretation of "fragmentation." In the case of Google's Android and Amazon's Android, where apps developed for either platform are generally cross-compatible, Google probably isn't all that concerned. Google is probably trying to stave off fragmentation that breaks compatibility, which would harm the whole ecosystem. For what it's worth, you should still be able to download and build most of the SDK from source, potentially avoiding the new TOS. There are also alternative SDKs, like Replicant — though if you've already agreed to the new Android TOS, using Replicant would be verboden.
It is still a very odd move to lumber the SDK with such blatantly non-free language, though. I can't really imagine Google prosecuting someone for breaking clause 3.4, or revoking a developer's access to the Play Store — but then again, why would Google add the clause if it didn't serve some purpose?


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Touring version of 'The Price is Right' coming to the Keith-Albee
HUNTINGTON — Come on down, you could be the next contestant on "The Price is Right."
The touring version of the hit interactive show, "The Price is Right," is coming to the Keith-Albee Performing Arts Center at 8 p.m. Friday, May 3.
Tickets will go on sale at 10 p.m. Wednesday, April 3 at the Big Sandy Superstore Arena Box Office, www.ticketmaster.com , all Ticketmaster outlets or by calling 800-745-3000. Tickets are $45 and limited VIP tickets are $75.
"The Price Is Right Live!" is the hit interactive stage show that gives contestants pulled right from the audience the chance to "Come On Down" to win appliances, vacations and even new cars by playing classic games from television's longest running and most popular game show. From Plinko to Cliffhangers to the Big Wheel, and even the fabulous Showcase, all the favorite games are played just like the TV show.
Playing to near sold out audiences for nearly nine years, The Price Is Right Live! has given away more than 10 million dollars in cash and prizes and sold more than 1.2 million tickets.
The Price Is Right is produced by FremantleMedia North America and licensed by FremantleMedia International.
Additional purchase not required for contestant registration. Open to US legal US residents, 18 years or older. Ticket purchase will not increase your chances of being selected to play.
For complete rules & regulations, including eligibility requirements, visit or call the venue box office. To enter theater to watch show, a ticket purchase is required.
To register for the chance to be a contestant, visithttp://apps.absolutist.com/partners/pricelive/14/. All registrations must be received by noon EST Thursday, May 2.
Registration also available at the Keith Albee Performing Arts Center three hours prior to show time.
For complete rules & regulations, including eligibility requirements, visit or call the venue box office. To enter theater to w0061tch show, a ticket purchase is required.
Other upcoming scheduled events for the SMG Managed Big Sandy Superstore Arena include Willie Nelson, Sesame Street LIVE, Brit Floyd and Larry the Cable Guy/Bill Engvall among others.
For a full list, please visit www.bigsandyarena.com or download the Iphone/Andriod App.


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My MTB will not shift from the middle to the big ring on the front. It just happily grinds away but does nothing. Shifting between the middle and small rings is fine. Any ideas will be helpful.
My MTB will not shift from the middle to the big ring on the front. It just happily grinds away but does nothing. Shifting between the middle and small rings is fine. Any ideas will be helpful.
First thing I would do is check the limit screws on the front der. Have you crashed and bent it lately or has it always done this?
You probably have too much slack in the shifter cable. That or your front derailleur isn't straight.
Can you take a pic of it (from above, looking down)
Do this. Shift into the granny gear. Turn your barrel adjuster all the way "IN", Clockwise, then "out" one full turn. Loosen the cable crimp bolt. Pull all the slack out the cable. Tighten the crimp bolt again.
Shift into the middle ring and big cog. Turn the barrel adjuster so the inside plate barely scrapes the chain then turn it back in until the scraping stops.
Keep it in the middle ring, but shift to the small cog. Turn the barrel adjuster out until it stops scraping.
This will center the front derailleur over the middle chainring and should provide proper shifting into the granny gear and the big ring.
If that doesn't work, chances are your outside limit screw has been screwed inward and is preventing the derailleur from moving far enough outbound.
"Life is not a journey to the grave with the intention of arriving safely in a pretty and well preserved body, but rather to skid in broadside, thoroughly used up, totally worn out, and loudly proclaiming, "WOW, What a Ride!" - unknown
"Your Bike Sucks" - Sky Yaeger
If it is reallly bad, you will have to adjust the shifting cable and tighten it, what I do is I get it on gear 1 and then see if there is any slack in the cable, if there is either use the barral adjuster or tighten the cable. if there is no barral adjuster then loosen the bolt, or the screw. If there is a screw you will use and allen key. if it is a bolt, you will use a small wrench. Then make sure it is on the largest gear on the casette then tighten the cable, shifting through gears back and fourth, also make sure the low end screw isn't too tight or the high end isn't too tight. If you can't get gears like 7 or 8 then loosen the barral adjuster providing more slack to the shifter so it can go to the smallest cog.


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We are excited to announce the dates for our Fall 2011 Ocean Friendly Garden Series, which will be taking place in Oceanside!
OFG Basics Class: Thursday, September 15th, 2011. Location and Time TBA, but it will be in north county sometime in the evening. Come learn how planting an Ocean Friendly Garden can benefit you and the environment. Learn how to promote healthy soil, select the right plants, and install the most efficient irrigation system for your space. Class is taught by a certified G3 Sustainable Landscape Professional.
Hands on Workshop (HOW): Sunday October 2nd, 2011. 10:30am-noon. 1807 Alvarado Street, Oceanside CA. Come join us at the site of our future Garden Assistance Program as we assess the site's current landscaping and discuss different ways we can turn the space into a beautiful OFG!
Garden Assistance Program (GAP) Workday: Sunday November 6th, 2011. 1807 Alvarado Street, Oceanside CA. Come and get your hands dirty as we put the concepts discussed at our HOW into practice! No gardening experience necessary, just bring your love of native plants and desire for a healthy ocean!
Additional details will follow as the events get closer. If you have any questions, please contact email@example.com
You can also stay on top of future events by "liking" Ocean Friendly Gardens - San Diego on Facebook!
Monday, August 8, 2011
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Author Archive: Vygantas
Vygantas is a former web designer whose projects are used by companies such as AMD, NVIDIA and departed Westood Studios. Being passionate about software, Vygantas began his journalism career back in 2007 when he founded FavBrowser.com. Having said that, he is also an adrenaline junkie who enjoys good books, fitness activities and Forex trading.
December, 2012 Desktop Market Share: Internet Explorer, Google Chrome, Opera – Up; Firefox, Safari – Down
When you look back, in 2011 a lot of people thought that Internet Explorer was pretty much doomed and that Google Chrome and Firefox will dominate the desktop space for an indefinite amount of time. Well, look how things have change… or did they?
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December, 2012 Mobile Market Share: Opera Mini, Chrome – Up; Safari, Android – Down
Ever wanted to know what happened to web browsers before (and after) the world has come to an end? Well, now you can, we have the technology.
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Play Dune 2 In Your Browser
Free of charge.
If you had a PC in the 90s, there is a high probability that hearing someone say "Westwood Studios" will send shivers down your spine. Unfortunately, all good things come to an end. The studios were later bought out by the EA Games, a lot of people left to join Petroglyph Games, Command & Conquer franchise was turned into a joke and your childhood memories were pushed down the drain.
Thanks, EA.
Download Google Chrome 25
With disabled silent extensions.
After abusing the silent extensions feature for some time now, the 3rd parties are about to get smacked.
According to Peter Ludwig, the Product Manager of Google Chrome, the recently released version of Google Chrome (25) will disable the silent extension installation feature. Not only that but the add-ons that were previously installed using this method will be automatically disabled as well. However, it will be done in a respectful manner thanks to a one time prompt, which will offer an option to re-enable some or all of the installed extensions.
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Microsoft Creates A Christmas Themed Benchmark For Your Web Browser
This is Penguin Mark.
As if we haven't seen enough holiday themed web sites and haven't heard enough Christmas songs, Microsoft has decided to combine all of these into a web browser benchmark.
According to the IE Team, this test utilizes "hardware-accelerated HTML5 capabilities like canvas, CSS3 animations and transitions, audio, WOFF, power and performance APIs, and more."
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UC Browser 2.7 For Windows Phone Released
For both WP7 and WP8.
Now here is something to fill the gap in case you are not satisfied with the IE9 or IE10 Mobile: a new version of UC Browser
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12 Best Firefox Add-ons Of 2012
Recently, Mozilla has published a list of the top 12 Firefox extensions of 2012. Unlike the majority of such recommendations, the following post actually includes a couple of new and less known extensions. Mostly because it's one add-on per month rather than the top 12 extensions by downloads. So, grab that mouse of yours and start clicking.
Here is a list of the more useful ones:
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Tip: Instagram For Opera's Speed Dial Tile
If you are addicted to both Opera and Instagram then here is something to distract you even more: a Speed Dial extension, which displays photos from your album.
Sounds interesting? Then head over to the following page and download the "Speedie-gram" add-on.
[Via: my.opera.com]
Happy Holidays!
This is it! As we are nearing the end of this year, we'd like to wish you a very happy Holidays and amazing upcoming year. Thank you for your support, tips, suggestions, comments, everything. Sometimes I wonder if anyone is actually reading these kinds of posts. Oh well, Happy Holidays!
P.S. We are just 9 likes away from hitting 1,000 fans on Facebook. That's awesome.
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Firefox: The 64 Bit Version Development Continues
Due to the ignorance, stupidity or both, Mozilla has decided to abandon the 64 bit version of Firefox for Windows and focus on 32 it builds. Now, it looks like they have changed their tune as Win64 nightly channel will not be completely abandoned.
On a downside, since win64 and win32 builds are not separated, Mozilla has decided to sit back and do nothing (as in "disable crash reports for the x86-64 builds") instead of solving the underlying issue, at least for now.
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Oxford, Warwick Castle and Stratford-upon-Avon Day Trip from London
We've selected the best candid trip photos submitted by our users to help you decide if the Oxford, Warwick Castle and Stratford-upon-Avon Day Trip from London is right for you. Make the most of your next trip to London with Viator's exclusive Photo Galleries.
Click here for tour details, schedule and pricing
January 2012
Poor Yorick....
January 2012
Shakespeare's house
Warwick castle
January 2012
Henry VIII with his girls )))
Warwick castle
Warwick castle
Inside Warwick
March 2010
View of the Castle
Warwick Castle
October 2009
Our first view of Warick Castle from the bus.
Inside Warwick Castle
October 2009
Wondering through Warwick Castle is like stepping back in time!
Shakespeare lived here
October 2009
View from the garden of Shakespeare's house. Very pretty!
October 2009
Complete with moving statue!
The White Hart Pub - Stratford
October 2009
We had a fantastic meal in this picturesque pub.
The bar of the White Hart
October 2009
The bar of the White Hart - complete with locals. It really felt like we had taken a step back in time when we entered this lovely old English Pub.
The Dining Hall, Christchurch College, Oxford
October 2009
Only Christchurch College members may sit here... Unless you are also enrolled in Hogwarts
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$141.11 Save $14.11


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It's been a very full week gone by - between Thanksgiving with friends and spending last weekend in Medfield for my 25th HS reunion. Great to see so many people, and especially the chance to spend some time together with certain longest-time friends (Big Dave, MCB, etc.) and dearest ones (Rick & Lauren). Added bonus to see my own brothers after too long.
And now, we welcome Hanukkah. The Festival of Lights begins tonight, and as if on cue, the snow started falling here in Michiana over the last several hours. It's gone from a mild fall to a surly winter in just more than 24 hours.
Anyway - Hanukkah, the minor holiday that we've jazzed up with lights, decorations and gift-giving, is really yet another chance to consider all of those things in life for which we're grateful - the warmth of family and friends, good stuff to eat and enjoy, and the meaningful (and fun) things that occupy our time. As you watch the glow of the Hanukkah candles this season, I hope you have the chance to reflect on all life's goodness.
CHAG URIM SAMEYACH - wishing you a very happy Hanukkah!
And all that jazz...


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By John D. BanusiewiczAmerican Forces Press Service
NORTH LITTLE ROCK, Ark., Feb. 4, 2005 It's never been more important for the United States to be strong, because the enemy in the global war on terror seeks to destroy U.S. society, the nation's top military officer said here Feb. 3.
Air Force Gen. Richard B. Myers, chairman of the Joint Chiefs of Staff, spoke at the annual Chamber of Commerce awards banquet here.
"They view the values that we represent and hold dear as a threat," the general said. "Their weapon of choice is fear. They know no limits, be they territorial or moral."
Torture chambers, weapons caches, fighting positions in mosques and videotaped beheadings are among the reminders of the type of enemy coalition forces face in Iraq, Myers said. Before the country's Jan. 30 election, he noted, terrorists warned Iraqis to save their lives by staying away from the polls, promising the voting sites would be attacked.
"The stakes in this war," he said, "simply couldn't be higher."
Eliminating extremism as a threat is a demanding and complex struggle, Myers said, and he acknowledged it's going to be a long one.
"There will be more attacks," he said, "but if we take a step back, we'll see that the U.S. and coalition forces are helping the Iraqi people build institutions of a strong and free society."
Myers noted that all the latest technology is being used to defeat the enemy. "But our most potent weapon, without a doubt, is the brave men and women in uniform," he said.
Whether they came from big cities or small towns across America, the chairman added, they have one thing in common: "They volunteered, and they answered their nation's call to serve," he said. "I believe that when the history books are written, this truly will be the new 'Greatest Generation.' They are absolutely awesome."
The chairman said U.S. troops in Iraq and Afghanistan have worked "with tremendous courage, with patriotism and with compassion to bring security and stability but most of all, great hope to these countries."
With tough challenges ahead, Myers said, the nation can't afford to lose its focus or its resolve. But the military can't fight the war on terror on its own, he emphasized.
"Our armed forces are very good at what we do," he said, "but it's going to take virtually every agency and department of our government working together with the international community and international governments to work more closely than we ever have before to defeat this threat of extremism."
Myers told the audience of business leaders and merchants that he understands the sacrifices that businesses especially small businesses have made in recent years, with so many of their Reserve and National Guard employees called to active service. "But I also know that a number of Little Rock companies have provided real support, outstanding support," he said. "So I want to especially thank you and all the employers of National Guard and Reserve for what you do for our troops."
He noted that more than 3,300 Arkansans have been mobilized to fight in the war on terror, "serving with distinction all over the globe."
"Your support of their service could not be more critical," he said. Anyone who needs ideas on how to do that, the general added, should visit the "America Supports You" Web site. "It's run by the Department of Defense," he said, "and it's a place where people trade ideas on how to support the troops."
Unlike in World War II, when rationing and shortages and efforts such as scrap- metal drives affected most Americans directly, life goes on fairly normally for most Americans during the global war on terror, Myers said. This, he warned, presents the potential danger of the nation losing its focus. But he assured the audience no such danger exists in America's armed forces.
"I can guarantee you that the active duty, Guard and Reserve are all 100 percent committed to winning this conflict that we are now engaged in," he said. "And they also couldn't be better role models for our nation, and I couldn't be prouder of them, as I know you are of all of them."
People serving in the military know the war on terror will be a long and tough fight, the chairman said. "And they really, really understand what's at stake," he added.
"They also know that they're making a huge difference," Myers said. "They realize the rewards are great freedom for ourselves and our friends, and most importantly, freedom from tyranny."
The chairman pledged victory in the war on terror. "No matter how long it takes," he said, "failure is not an option, and we will not fail."
Related Sites:America Supports You
Related Articles:Election 'Finger in the Eye' of Extremists, Myers Says


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Cinderella App
You know the fairytale. Now experience the magic. Beautiful illustrations, exciting animation, and original music make this a picture book app at its best.
Read the story and get involved in the action!
★ Help Cinderella clean the kitchen.
★ Stack the King's invitations to the ball.
★ Dress up the Stepsisters for the party.
★ Build the magical carriage with the Fairy Godmother.
★ Select music for the Prince and Cinderella and watch them hit the dance floor! Do you want a waltz, disco or Bollywood?
★ You can even choose Cinderella's dress!
Special note:
The story is narrated by child actress Freya Wilson, seen recently in the movie The King's Speech.
Target Audience
Created for children ages 3 and up, but adults will love it, too.
Key features
Especially for young readers:
✓ Choose a mode: Read to Me, Read by Myself or Read and Play.
✓ Help is embedded in the story – characters offer hints about what to do on each page so even very young readers can participate fully.
✓ Choose how long text stays on the screen so beginning readers have enough time to read by themselves.
✓ Select either American or British spelling styles.
✓ Tap the characters to trigger additional dialogue.
Special technical features:
✓ Uses front-facing camera on iPad2 (and some iPhones and iPod touches) to capture the reader's image and display it in the story.
✓ Readers can move the main characters around in each scene like dolls in a virtual dollhouse. Characters can jump, giggle and spin.
✓ Uses accelerometers to let readers tilt the scene and zoom in to explore details in the illustration beyond the edges of the page.
✓ Interactive musical score – each character has a unique sound identity which reinforces his or her personality.
★ Winner, Best Children's App of the Year, UK FutureBook Digital Innovation Awards, 2011
★ Winner of iLounge.com's Best Children's App of the Year, 2011
★ Winner of Editor's Choice Award 2011, Children's Technology Review magazine
★ Winner, Children's Book App or eBook, 2012 KAPi Awards
★ Winner, Juvenile App, Publishing Innovation Awards, 2012
★ Winner, Best Story App, Junior Design Awards, 2012
Download from app store
Press Release
September 13: Nosy Crow Releases Cinderella Book App for iPad, iPhone and iPod touch
Download the US Press Release as a PDF
Download the UK Press Release as a PDF
November 1: Cinderella Wins iLounge.com's iPad Kids App of the Year Award.
Download the Press Release here.
Web sites
- More app information
- About the illustrator: Ed Bryan
Media Mentions
"App developer Nosy Crow has made its mark in the iTunes store by creating magical fairy tale apps for kids. They are the Steven Spielberg of apps, because they have a gift for telling stories that make brilliant use of the iPad or iPhone … Don't miss this magical and modern Cinderella."
"Nosy Crow is a London-based independent that publishes some of the best-quality digital children's books available. Take its retelling of Cinderella: the original illustrations and animation are first rate, and kids can read it or listen as it's spoken by other children."
"This modern rendition of the classic fairytale demonstrates just how far children's book apps have evolved. While this app can read the story out loud or kids can choose to read it themselves, it is the playfulness within the story that makes it delightful … Reading this fairytale is a charming experience filled with wonder."
"Demonstrates the exciting potential of this format for young readers … with many delightful interactive features to draw the reader in on each page."
"Swing an ugly stepsister on the App Store and you'll hit 17 Cinderella apps, but this is the best by far. Beautiful illustrations, voice narration from children, lots of interactivity and a dash of cheeky humour."
"An enchanting and highly entertaining take on the classic fairy tale … There are simply too many delightful elements and surprises to enumerate, but suffice it to say that a touch-tilt treasure trove awaits curious and persistent little fingers … A magical masterpiece that hits the technological and artistic bull's-eye."
"Gorgeous graphics and interactive elements give the familiar story a fresh new feel … looks spectacular, regardless of the device you use to view it."
"Nosy Crow's reinvention of Cinderella breaks free from Disney's rigid appropriation of the fairy tale chargirl. This stellar app features colorful illustrations and clever activities on every page."
Ranked #1 iPad Book for Kids
"Quite simply, the most charming and entertaining interactive book currently available on the iPad … it offers a level of interactivity and depth unlike any other."
Tap! app of the week
"This modern rendition of the classic fairytale demonstrates just how far children's book apps have evolved … Reading this fairytale is a charming experience filled with wonder."
"Nosy Crow pulls off yet another excellent storybook with Cinderella. Great production values combined with funny writing and well-designed interactive elements make Cinderella another worthy addition to Nosy Crow's storybook stable."
"It's interactive features and emphasis on the best parts of the story of Cinderella make this app a hit with us."
"The FutureBook Innovation Award-winning Cinderella app is delightful. It's a straight retelling, beautifully animated, with loads of hand-eye co-ordination enhancing interactivity (tidying up crockery, invitations and mice), plus added table tennis."
"If you want to see the potential the iPad holds for beautiful, interactive storytelling, you need to meet Nosy Crow's "Cinderella."
"A timeless rags-to-ballgown tale gets a delightful digital makeover"
"Never before have we seen such an enchanting and entertaining Cinderella story […] a beautifully illustrated picture-book app that is sure to enthrall your children."
"If you liked Nosy Crow's iPad treatment of "The Three Little Pigs," you'll love their rendition of Cinderella. The interactive design is springy, responsive and multi-dimentional." Recipient of our Editor's Choice Award.
"Cinderella raises the bar in children's ebooks with such touches as an orchestrated sound track and a magic mirror that puts your child's face into the story"
"Nosy Crow has totally reinvented the classic Cinderella story into an all new, engaging experience for your child, with its interactive storybook app, Cinderella. This is definitely a worthwhile app for the price."
"Our 3 and 5-year-olds, and me, have been mesmerized with this electronic book. We have been in fits of giggles and consistently surprised throughout this classic tale… this is sure the pinnacle of the mogul baby must haves, when considering the quality, value and instant accessibility to everyone. It is impossible to be disappointed with this masterpiece."
"What a great way to add more excitement to this classic story! Growing up, I had a book that was personalized with my name and loved it, but that's nowhere near as cool as having your face included the story!"
"Nosy Crow's imaginative retelling of the Cinderella… is a journey that lets your child become fully immersed in the adventure. Your young reader will want to come back to this story over and over."
"This innovative app for young readers significantly freshens a familiar tale with captivating illustrations, plenty to see and do on each page, and varied read-aloud options."
"Nosy Crow's rendition of Cinderella feels like a collection of playgrounds that let kids enjoy each of the story's pivotal moments… The "wow" moment came when we discovered that mirrors in the rooms were leveraging FaceTime cameras to reflect our faces back at the screen, a great little trick that will draw kids into the story even further." iLounge Rating: A
"With it's whimsy illustrations, engaging animation, wonderful children narrators and original music, this picture book app is top notch."
"This is exactly what a picture book app for children should be."
"The look of this app is quite beautiful, with the use of vivid, bright colors and fun, over-the-top, stylized stepmother and stepsisters wearing garish makeup and clothes, but I am happy that they are never referred to as "ugly," which would place an undue focus on one's looks, as the concept of "pretty is good, ugly is bad" can have unintended consequences later for girls as they grow up. It is also worth noting that this prince is thought of as being kind, a reason besides wealth that Cinderella would want to marry him, and I especially appreciate how Cinderella mutters to herself how the prince probably does not care about clothing as she dresses her demanding stepsisters."
"Cinderella is one of the best if not the best book app there is in the iTunes store at the moment."
"Cinderella has it all: thoughtful interactivity, engaging characters, and witty text that remains decidedly upbeat."
"it blends animation, interactivity and plenty of humour into something that's genuinely beautiful … One of the most sophisticated book-apps yet for children – and a real sign of how picture books are evolving digitally."
"The music, the animation and visuals, the dialogue… Cinderella is a marvellous piece of work."
"Cinderella is a top-notch production, with intricate but easy-to-interact-with animation, and funky, fun design."
"an entertaining and visually lavish retelling of this classic fairy tale … quirky, contemporary and wonderfully detailed."
"Like their previous app, Nosy Crow has not forgotten a single detail in this delightful title … My child has been completely enthralled with this book from the moment I downloaded it."
"Beautiful animation, sound and interactivity make it a treat for kids"
- The iMum
- Media Macaroni
- Appa Snap
- Mom Colored Glasses
- Apps4Kids
- bambino goodies
- Geek Mom
- Persian Cat Press
- Babyccino Kids
- bebè blog.it
- Barth Educational Consultants
- The iPhone Mom
Official App Trailer
Innovation in Storytelling: Deb Gaffin talks about Nosy Crow's approach
Behind the scenes: Ed Bryan shows how Cinderella's magical garden comes to life
Msnbc GadgetBox: Visually stunning kids apps for iPad
Click on an image to see a larger size or click on an image name to download a high-res copy.
- Cinderella menu
- Kitchen scene
- Palace scene
- Mirror scene
- Coach scene
- Dance scene
- Wedding scene
- Slipper scene
- Ballroom scene
- Nosy Crow Logo
For More Information
For a review copy or more information, please contact us.
Tom Bonnick
[email protected]


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Our Stories
Gary 'Turbo' Webb
In 2007, I decided to go back to school and change careers. I had been a retail manager for nine years and I found it unfulfilling. I wasn't happy and I was working an extreme number of hours.
Since I was 15 years old, people have told me that I have a good voice. I never really understood how to take that. Finally, after years of hearing that I would sound good on the radio, I decided that's what I was going to do.
On somewhat of a whim, I quit my job and decided to go to school to become an on-air personality. I wasn't very familiar with RSU but I decided to check it out. When I looked into the university, I was excited to find it had a communications degree, as well as a radio and television station.
When I started taking classes, I got as involved as I possibly could. I volunteered at the television station, joined the Student Broadcast Association and familiarized myself with the radio station. I pestered the radio station's general manager until a job opened up and was ecstatic when they hired me as the traffic director.
I had not completed enough prerequisites during my first couple semesters to take advanced classes like voice and articulation or audio practicum. To learn more about being on air, I met with Hugh Foley, fine arts professor and on-air personality. He had a weekly three-hour session where he took time to teach people how to operate the board and be on the radio. This helped me build a good foundation.
RSU has given me valuable hands on experience. That's why I think this university has a big advantage over other schools. The opportunities students have here are one of a kind. We have our own college radio station, we broadcast into Tulsa and you can stream the station live at http://www.rsuradio.com/. As far as programing goes, we run a college indie rock format with more than 20 different specialty shows, which is really rare these days.
If you have a dream that you are passionate about, go for it! My dream was to be on the radio and that's exactly what I'm doing.