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Delivery of AS-oligonucleotide microspheres to induce dendritic cell
tolerance for the treatment of autoimmune type 1 diabetes
United States Patent: 7,884,085
Issued: February 8, 2011
Inventors: Brown; Larry R.
(Newton, MA), Bisker-Leib; Vered (Woburn, MA), Scott; Terrence L.
(Winchester, MA), Lafreniere; Debra (Dighton, MA), Machen; Jennifer
(Export, PA), Giannoukakls; Nick (Coraopolis, PA)
Assignee: Baxter
International Inc. (Deerfield, IL),Baxter Healthcare S.A. (Glattpark (Opfikon),
CH), University of Pittsburgh-of the Commonwealth System of Higher
Education (Pittsburgh, PA)
Appl. No.: 11/127,360
Filed: May 12, 2005
George Washington University's Healthcare MBA
George Washington University's Healthcare MBA
AS-oligonucleotides are delivered in
microsphere form in order to induce dendritic cell tolerance, particularly
in the non-obese-diabetic (NOD) mouse model. The microspheres incorporate
antisense (AS) oligonucleotides. A process includes using an antisense
approach to prevent an autoimmune diabetes condition in NOD mice in vivo
and in situ. The oligonucleotides are targeted to bind to primary
transcripts CD40, CD80, CD86 and their combinations.
Description of the
1. Field of the Invention
The present invention generally relates to microsphere delivery of AS-oligonucleotides
in order to induce dendritic cell tolerance, particularly in the
non-obese-diabetic (NOD) mouse model. More particularly, the invention
relates to drug delivery technology by way of microspheres that are
fabricated using totally aqueous conditions, which microspheres
incorporate antisense (AS) oligonucleotides. These microspheres are used
for an antisense approach to prevent an autoimmune diabetes condition in
NOD mice in vivo and in situ.
2. Background of the Invention
Microparticles, microspheres, and microcapsules are solid or semi-solid
particles having a diameter of less than one millimeter, more preferably
less than 100 microns, which can be formed of a variety of materials,
including synthetic polymers, proteins, and polysaccharides. Microspheres
have been used in many different applications, primarily separations,
diagnostics, and drug delivery.
A number of different techniques can be used to make these microspheres
from synthetic polymers, natural polymers, proteins and polysaccharides,
including phase separation, solvent evaporation, emulsification, and spray
drying. Generally the polymers form the supporting structure of these
microspheres, and the drug of interest is incorporated into the polymer
structure. Exemplary polymers used for the formation of microspheres
include homopolymers and copolymers of lactic acid and glycolic acid (PLGA)
as described in U.S. Pat. No. 5,213,812 to Ruiz, U.S. Pat. No. 5,417,986
to Reid et al., U.S. Pat. No. 4,530,840 to Tice et al., U.S. Pat. No.
4,897,268 to Tice et al., U.S. Pat. No. 5,075,109 to Tice et al., U.S.
Pat. No. 5,102,872 to Singh et al., U.S. Pat. No. 5,384,133 to Boyes et
al., U.S. Pat. No. 5,360,610 to Tice et al., and European Patent
Application Publication Number 248,531 to Southern Research Institute;
block copolymers such as tetronic 908 and poloxamer 407 as described in
U.S. Pat. No. 4,904,479 to Illum; and polyphosphazenes as described in
U.S. Pat. No. 5,149,543 to Cohen et al. Microspheres produced using
polymers such as these exhibit a poor loading efficiency and are often
only able to incorporate a small percentage of the drug of interest into
the polymer structure. Therefore, substantial quantities of microspheres
often must be administered to achieve a therapeutic effect.
Spherical beads or particles have been commercially available as a tool
for biochemists for many years. For example, antibodies conjugated to
beads create relatively large particles specific for particular ligands.
The large antibody-coated particles are routinely used to crosslink
receptors on the surface of a cell for cellular activation, are bound to a
solid phase for immunoaffinity purification, and may be used to deliver a
therapeutic agent that is slowly released over time, using tissue or
tumor-specific antibodies conjugated to the particles to target the agent
to the desired site.
One disadvantage of the microparticles or beads currently available is
that they are difficult and expensive to produce. Microparticles produced
by these known methods have a wide particle size distribution, often lack
uniformity, and fail to exhibit long term release kinetics when the
concentration of active ingredients is high. Furthermore, the polymers
used in these known methods are dissolved in organic solvents in order to
form the microparticles. They must therefore be produced in special
facilities designed to handle organic solvents. These organic solvents
could denature proteins or peptides contained in the microparticles.
Residual organic solvents could be toxic when administered to humans or
In addition, the available microparticles are rarely of a size
sufficiently small to fit through the aperture of the size of needle
commonly used to administer therapeutics or to be useful for
administration by inhalation. For example, microparticles prepared using
polylactic glycolic acid (PLGA) are large and have a tendency to
aggregate. A size selection step, resulting in product loss, is necessary
to remove particles too large for injection. PLGA particles that are of a
suitable size for injection must be administered through a large gauge
needle to accommodate the large particle size, often causing discomfort
for the patient.
Generally, many currently available microparticles are activated to
release their contents in aqueous media and therefore must be lyophilized
to prevent premature release. In addition, particles such as those
prepared using the PLGA system exhibit release kinetics based on both
erosion and diffusion. In this type of system, an initial burst or rapid
release of drug is observed. This burst effect can result in unwanted side
effects in patients to whom the particles have been administered.
Microparticles prepared using lipids to encapsulate target drugs are
known. For example, lipids arranged in bilayer membranes surrounding
multiple aqueous compartments to form particles may be used to encapsulate
water soluble drugs for subsequent delivery as described in U.S. Pat. No.
5,422,120 to Sinil Kim. These particles are generally greater than 10
microns in size and are designed for intra articular, intrathecal,
subcutaneous and epidural administration. Alternatively, liposomes have
been used for intravenous delivery of small molecules. Liposomes are
spherical particles composed of a single or multiple phospholipid and
cholesterol bilayers. Liposomes are 30 microns or greater in size and may
carry a variety of water-soluble or lipid-soluble drugs. Liposome
technology has been hindered by problems including purity of lipid
components, possible toxicity, vesicle heterogeneity and stability,
excessive uptake and manufacturing or shelf-life difficulties.
An objective for the medical community is the delivery of nucleic acids to
the cells in an animal for diabetes treatment. For example, nucleic acids
can be delivered to cells in culture (in vitro) relatively efficiently,
but nucleases result in a high rate of nucleic acid degradation when
nucleic acid is delivered to animals (in vivo).
In addition to protecting nucleic acid from nuclease digestion, a nucleic
acid delivery vehicle must exhibit low toxicity, must be efficiently taken
up by cells and have a well-defined, readily manufactured formulation. As
shown in clinical trials, viral vectors for delivery can result in a
severely adverse, even fatal, immune response in vivo. In addition, this
method has the potential to have mutagenic effects in vivo. Delivery by
enclosing nucleic acid in lipid complexes of different formulations (such
as liposomes or cationic lipid complexes) has been generally ineffective
in vivo and can have toxic effects. Complexes of nucleic acids with
various polymers or with peptides have shown inconsistent results and the
toxicity of these formulations has not yet been resolved. Nucleic acids
also have been encapsulated in polymer matrices for delivery, but in these
cases the particles have a wide size range and the effectiveness for
therapeutic applications has not yet been demonstrated.
Therefore, there is a need for addressing nucleic acids delivery issues,
and there is an on-going need for development of microspheres and to new
methods for making microspheres. Details regarding microspheres are found
in U.S. Pat. No. 6,458,387 to Scott et al., U.S. Pat. Nos. 6,268,053,
6,090,925, 5,981,719 and 5,599,719 to Woiszwillo et al., and U.S. Pat. No.
5,578,709 to Woiszwillo. These and all references identified herein are
incorporated by reference hereinto.
In accordance with the present invention, DNA to be delivered to dendritic
cells is delivered as microspheres. It is believed that such a delivery
approach prevents access of the nucleases to the nucleic acids within the
microsphere. Microsphere delivery of AS-oligonucleotides is carried out in
order to induce dendritic cell tolerance, particularly in the NOD mouse
model. The microspheres are fabricated using aqueous conditions, which
microspheres incorporate antisense (AS) oligonucleotides. These
microspheres are used to inhibit gene expression and to prevent an
autoimmune diabetes condition in NOD mice in vivo and in situ.
In a preferred aspect of the invention, three AS-oligonucleotides targeted
to the CD40, CD80 and CD86 primary transcripts are synthesized, and an
aqueous solution of the oligonucleotide mixture is prepared and combined
with a polymer solution. After processing, microspheres containing the
oligonucleotides are provided, and these are delivered to the NOD mice.
As required, detailed embodiments of the present invention are disclosed
herein; however, it is to be understood that the disclosed embodiments are
merely exemplary of the invention, which may be embodied in various forms.
Therefore, specific details disclosed herein are not to be interpreted as
limiting, but merely as a basis for the claims and as a representative
basis for teaching one skilled in the art to variously employ the present
invention in virtually any appropriate manner.
The preferred embodiment prevents autoimmune insulin-dependent diabetes by
formulating and injecting antisense (AS)-oligonucleotide microspheres
described herein targeting the primary transcripts of CD40, CD80 and CD86.
These oligonucleotides are designed to induce immune tolerance in an
attempt to prevent destruction of the insulin producing beta cells in the
NOD mouse model. The events leading to the destruction of these beta cells
is illustrated in FIG. 1 (see Original Patent). This illustrates how Type
1 diabetes is manifested by the autoimmune destruction of the pancreatic
insulin-producing beta cells in the NOD mouse, as well as in humans. At
the time of clinical onset, humans have 10-20% residual beta cell mass.
Sparing of this residual mass can result in remaining insulin levels which
are adequate to regulate glucose levels. The microparticles of the
invention are provided to interfere with the autoimmune destruction of the
beta cells which is illustrated in FIG. 1.
It will be appreciated that dendritic cells (DC) can be activated to be
potent antigen presenting cells found in all tissues and which are highly
concentrated under the skin. These antigen presenting dendritic cells
function as triggers of the immune response through the activation of
T-cells, particularly in lymph nodes.
FIG. 2 (see Original Patent) is a drawing of a plasmid vector containing
the Beta-galactosidase gene that can be used to transfect NIH 3T3
fibroblast cells. In vitro evidence for the transfection of NIH 3T3
fibroblast cells with the plasmid DNA microspheres is shown in FIG. 3 by
the cells which stain blue in color in response to the addition of the
Beta-Galactosidase x-gal
(5-bromo-4-chloro-3-indolyl-beta-galactopyranoside) substrate.
FIG. 4 (see Original Patent) illustrates the ability of microspheres to
protect DNA in solution. This is an agarose electrophoresis gel showing
nuclease protection imparted by microspheres of plasmid DNA produced
generally as noted herein. In the Plasmid samples 1, 2 and 3, naked
plasmid DNA was exposed to DNAse, with the smears indicating plasmid DNA
degradation at each of the three levels of DNAase application. In the
Particle 1 and Particle 2 samples, plasmid DNA microsphere formulations
were exposed to DNAase. The lack of smearing indicates the microsphere
formulations show shielding of the plasmid DNA from degradation. Particle
1 plasmid DNA samples show enhanced protection over Particle 2 plasmid DNA
FIG. 5 (see Original Patent) reports on Beta-Galactosidase activity of
four different plasmid DNA applications when transfected into cells. The
naked plasmid DNA application showed very low levels. Somewhat greater
levels are indicated for plasmid DNA cationic lipid complex application
using lipofectamine, a commercial cationic lipid, as the delivery vehicle.
Substantially greater activity is shown for two pDNA microspheres, with
Microspheres 1 corresponding to Particle 1 of FIG. 4, and Microspheres 2
corresponding to Particle 2 of FIG. 4.
In making the microspheres that are used for autoimmune treatment of
diabetes in mice, three AS-oligonucleotides are dissolved in aqueous
solution and combined with water soluble polymer(s) and a polycation. The
solution typically is incubated at about 60-70.degree. C., cooled to about
23.degree. C., and the excess polymer is removed. Microspheres are formed
which are believed to contain the three AS-oligonucleotides having the
following sequences, wherein an asterisk indicates thioation
-- see Original Patent.
More particularly, the nucleic acids typically comprise between about 30
and about 100 weight percent of the microspheres and have an average
particle size of not greater than about 50 microns. Typically, they are
prepared as follows. An aqueous solution of the oligonucleotide mixture is
prepared by combining aliquots from three oligonucleotide solutions, each
solution containing one of these three types.
A solution containing the three types of oligonucleotides is prepared. The
solutions preferably contain about 10 mg/ml oligonucleotide. These are
combined with aliquots of a 10 mg/ml stock solution of polycation solution
at volumetric ratios of polycation:oligonucleotide of from about 1:1 to
about 4:1. Polymer solutions of polyvinyl pyrrolidone and/or of
polyethylene glycol are prepared and combined with the other solutions.
Heating, cooling, centrifuging and washing multiple times provide an
aqueous suspension which typically is frozen and lyophilized to form a dry
powder of microspheres comprising oligonucleotide and polycation.
Microspheres according to the invention are a viable non-viral delivery
tool for plasmid DNA and antisense oligonucleotides and other nucleic
acids. They allow for in vitro delivery of Beta-Galactosidase plasmid DNA
in 3T3 fibroblast cells. The microspheres protect plasmid DNA from
nuclease activity. High levels of Beta-Galactosidase activity are
expressed following transfection with the microsphere formulations.
Microspheres containing the antisense oligonucleotides of interest
down-regulate surface cell antigens CD40, CD80 and CD86, known to be
critical in the activation of the autoimmune reaction that results in
destruction of insulin-producing beta cells of the pancreas. This can be
accomplished by subcutaneous injection to dendritic cells located under
the skin. NOD mice studies demonstrate effective prevention of the
autoimmune destruction of beta cells. The DNA and oligonucleotide
microspheres are effective transfection vehicles in vitro and in vivo.
Dendritic cells appear to take up the oligonucleotide microspheres and
suppress the expression of surface cell antigens CD40, CD80 and CD86. The
anitsense oligonucleotide microspheres effectively prevent diabetes
development in the NOD mouse.
The following Examples illustrate certain features and advantages of the
invention in order to further illustrate the invention. The Examples are
not to be considered limiting or otherwise restrictive of the invention.
Three AS-oligonucleotides targeted to the CD40, CD80 and CD86 primary
transcripts were synthesized by the DNA synthesis facility at University
of Pittsburgh (Pittsburgh, Pa.). The AS-oligonucleotides sequences are
-- see Original Patent.
An aqueous solution of the oligonucleotide mixture was prepared by
combining aliquots of three oligonucleotide solutions, each of which
contained one type of oligonucleotide, to form a 10 [mg/ml] solution of
the three types of oligonucleotides. 10 [mg/ml] poly-L-lysine.HBr in diH2O
(poly-L-lysine.HBr up to 50,000 by Bachem, King of Prussia, Pa.) was
prepared. Poly-L-lysine.HBr was added to the oligonucleotides solution at
a volumetric ratio of 1:1. The mixture was vortexed gently. A 25% polymer
solution containing 12.5% PVP (polyvinyl pyrrolidone, 40,000 Daltons,
Spectrum Chemicals, Gardena, Calif.) and 12.5% PEG (polyethylene glycol,
3,350 Daltons, Spectrum Chemicals, Gardena, Calif.) in 1M Sodium Acetate
(Spectrum, Gardena, Calif.) at pH=5.5 was made. The polymer solution was
added in a 2:1 volumetric ratio as follows: 750 .mu.l of AS-oligonucleotides,
0.75 ml of poly-L-lysine.HBr, 3.0 ml of PEG/PVP, and a total volume of
4.50 ml.
The batch was incubated for 30 minutes at 70.degree. C. and then cooled to
23.degree. C. Upon cooling, the solution became turbid and precipitation
occurred. The suspension was then centrifuged, and the excess PEG/PVP was
removed. The resulting pellet was washed by resuspending the pellet in
deionized water, followed by centrifugation and removal of the
supernatant. The washing process was repeated three times. The aqueous
suspension was frozen and lyophilized to form a dry powder of microspheres
comprising oligonucleotide and poly-L-lysine.
FIG. 6 (see Original Patent) presents a scanning electron micrograph (SEM)
of the 1:1 poly-L-lysine:oligonucleotide ratio material. Microspheres,
0.5-4 .mu.m in size, with an average particle size of approximately 2.5 .mu.m
were fabricated. Precipitation of an unknown material was also observed.
Additional studies by HPLC determined that the precipitation was comprised
of residual PEG/PVP, mostly PVP.
AS-oligonucleotides targeted to the CD40, CD80 and CD86 primary
transcripts were the AS-oligonucleotides sequences of Example 1. An
aqueous solution of the oligonucleotide mixture was prepared by combining
aliquots of the three oligonucleotide solutions, each of which contained
one type of oligonucleotide, to form a 10 [mg/ml] solution of the three
types of oligonucleotides. A solution of oligonucleotide mixture was
prepared. 5 [mg/ml] poly-L-ornithine.HBr in diH.sub.2O (poly-L-ornithine.HBr
11,900 (vis) by Sigma) was prepared. Poly-L-ornithine.HBr was added to the
oligonucleotides solution. The mixtures were vortexed gently. A 25%
polymer solution containing 12.5% PVP (40,000 Daltons, Spectrum Chemicals,
Gardena, Calif.) and 12.5% PEG (3,350 Daltons, Spectrum Chemicals,
Gardena, Calif.) in 0.1.M Sodium Acetate (Spectrum Chemicals, Gardena,
Calif.) at pH=5.5 was made. The polymer solutions were added. Incubation
and rinses followed as described in Example 1. 1.5 ml of the AS-oligonucleotides,
1.5 ml of the poly-L-ornithine.HBr, 3 ml of the PEG/PVP, and a total
volume of 6.0 ml was prepared.
FIG. 7 (see Original Patent) presents an SEM of this 1:1 poly-L-ornithine:oligonucleotide
ratio material. Microspheres, 0.2-8 .mu.m in size, with an average
particle size of approximately 2 .mu.m were fabricated. Precipitation of
an unknown material was also observed. Additional HPLC studies were able
to prove that this precipitation was comprised of residual PEG/PVP, mostly
In vivo studies were conducted using the NOD mouse model of Type 1
diabetes mellitus. Type 1 diabetes is manifested by the autoimmune
destruction of the pancreatic insulin-producing beta cells as illustrated
in FIG. 1. AS-oligonucleotides were used in three applications in an
attempt to interfere with the autoimmune destruction of beta cells. The
goal was to interfere with the dendritic cell function by targeting the
primary transcripts of CD40, CD80 and CD86, which encode dendritric cell
surface proteins required for T-cell activation. Dendritic cells with low
levels of CD40, CD80 and CD86 are known to promote suppressive immune cell
networks in vivo. These cascades can result in T-cell hyporesponsiveness
to beta cells in vivo.
In the first group of test animals, dendritic cells were propagated ex
vivo from bone marrow progenitors of NOD mice. Combinations of the three
AS-oligonucleotides targeting the primary transcripts of CD40, CD80 and
CD86 were added to the cells in tissue culture. After incubation, the AS-oligonucleotide
transfected dendritic cells were injected into syngenetic recipients of 5
to 8 weeks of age (not yet diabetic). This is a known ex-vivo delivery
In parallel, AS-oligonucleotide microspheres were injected directly into
other NOD mice of the same age. A single injection was carried out on each
thus-treated mouse. Another group of these NOD mice was not treated and
served as a control.
FIG. 8 (see Original Patent) shows that the control, untreated NOD mice
all developed diabetes by age 23 weeks. The ex vivo AS-oligonucleotide
transfected and re-infused dendritic cells group (AS-ODN DC) showed
delayed development of diabetes, with 20% remaining "Diabetes Free",
indicating glucose levels are maintained within a non-diabetic range. Of
the microspheres in vivo-injected NOD mice, 71% remained "Diabetes Free"
at 43 weeks.
Claim 1 of 23 Claims
1. A composition that comprises
microspheres comprising oligonucleotides for treatment of type 1 diabetes,
wherein said microspheres contain a first antisense sequence that targets
a primary transcript of CD40, a second antisense sequence that targets a
primary transcript of CD80, and a third antisense sequence that targets a
primary transcript of CD86, wherein each of said first, second and third
oligonucleotides reduces or suppresses in vivo expression of CD40, CD80
and CD86 respectively, and wherein said oligonucleotides comprise greater
than about 30 weight percent of the microspheres, based on the total
weight of the microspheres, said microspheres having an average particle
size of not greater than about 50 microns and at least 0.2 to 8 microns,
and said microspheres, when administered, treat type 1 diabetes.
If you want to learn more
about this patent, please go directly to the U.S.
Patent and Trademark Office Web site to access the full


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Definition of the noun condescendence
What does condescendence mean as a name of something?
noun - plural: condescendences
- The act of condescending; voluntary descent from one's rank or dignity in intercourse with an inferior; courtesy toward inferiors, condescension. [jump, the act of condescending, s]
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Encyclopædia of the laws of England with forms and precedents by the most eminent legal authorities (1908)
by Alexander Wood Renton, Maxwell Anderson Robertson, Frederick Pollock, William Bowstead
Condescendence is an articulate statement annexed to a summons, setting 164 ...
Reports of New Magistrates' Cases Argued and Determined in All the Courts of Common Law at Westminster ... 1844-[1851] (1846)
by Great Britain. Courts, Adam Henry Bittleston, Edward Wise, Paul Parnell, Jelinger Cookson Symons
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a dictionary of universal knowledge by David Patrick, William Geddie
CONDESCENDENCE. In the judicial procedure of Scotland, a C is ...
The Encyclopaedia Britannica (1902)
latest edition. A dictionary of arts, sciences and general literature by Day Otis Kellogg, William Robertson Smith
The summons goes more into detail than the English writ of summons, though it no longer states, as it once did, the grounds of action, now stated in the condescendence and pursuer's pleas in law annexed to the summons. The form of the ...
Chambers's New Handy Volume American Encyclopaedia (1883)
Being a Reprint Entire of the Last Edinburgh and London Edition of Chambers's Encyclopaedia. A Library of Universal Knowledge for the People. With Very Large Additions Upon Topics of Special Interest to American Readers; and Giving American Statistics of Population Down to the Census of 1880
condescendence), the defences or annwers, the revised condescendence, the revised answers, &c. The peculiar technic:il rules to which the pleadings of parties must conform, are capable of being understood only by lawyers. PLEBEI' ANS ...
Chambers's Encyclopaedia: Catarrh to Dion (1896)
CONDESCENDENCE CONDITION 403 coast, salt water may bo distilled and condensed. See Distillation, Gas. The Electric Condenser is an apparatus consisting essentially of two parallel conducting plates, separated by a layer of ...
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Scrabble value of C3O1N1D2E1S1C3E1N1D2E1N1C3E1
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|06 Oct 2009
Aero and ATI Catalyst?
Hi all,
I recently changed my gfx card from a 7900GS to a HD 4870. However, one annoying problem I have been experiencing is with regards to Aero on Windows 7.
I noticed that when running certain programs, such as Firefox in particular, sometimes when I try to click a dropdown box or just access a menu very quickly, before the menu appears, there is a black thing appearing behind it for a split second, before it finally appears (i.e. something similar when you try to resize the services.msc window). This is especially apparent when I am multitasking, perhaps due to lag.
However, I did not get this problem with my 7900 GS before. I tried a reformat already but no use.
Today, I decided to install Windows Vista on another separate hard disk. I noticed that this problem does not occur in Vista.
I am using Catalyst 9.9 on both Vista and Win7. However, the problems with Aero only occurs on Windows 7 but not on Vista.
Does anyone have the same problem with ATI cards as well? Is this a driver issue due to the WDDM 1.1 model used in Win7 for Aero?
|My System Specs
|06 Oct 2009
Windows 7 Ultimate x64, XP Mode, W8.1 Preview VM - 7 Pro x64 second remote tower
Hello trenzterra Welcome to the Se7en Forums!
This is not any driver or hardware problem but part of 7's new process of reverting to the Aero Basic theme in order to conserve video memory for the program being run at the time. When opening up the application for a tv tuner card here the Start taskbar will suddenly revert from the trasnparent Aero theme there to a light blue color.
The same is eeen here running the older HD 2600XT model with the Cat. 9.9 on presently as well. Once the tuner card's app is closed the transparency returns as if the tuner card was never used. This was also seen with the previous catalyst versions as well not just the 9.9 presently the latest.
|My System Specs
|06 Oct 2009
Hmm I'm sorry but I think you misread my question?
I do not have a TV tuner of any sort; the problem occurs in Firefox and Aero Glass is running the whole time; I do not see it reverting to Aero Basic at any point of time.
The problem I'm having seems to be sort of related to the menu transitions. Before the said menu in Firefox appears I am seeing a black box where the menu is supposed to be, but only for a few milliseconds before the menu actually appears. In pre-7 what I would see in this case, I guess, would just be nothing, i.e. I'd be waiting for the menu to actually appear.
|My System Specs
|06 Oct 2009
Windows 7 Ultimate x64, XP Mode, W8.1 Preview VM - 7 Pro x64 second remote tower
I've never seen any of that when having FF on previously and am running a fresh install now. When first finishing up the installation you have to figure how you want things like second windows opening in tabs or a new window instead.
With your mention of Aero the only thing seen here is when using the tuner card I have here not when opening up any browser. You could have a gltch with FF itself where a fresh download/install would clean it up for you. Which release are you running? The 3.5.3 now seen?
|My System Specs
|06 Oct 2009
Yes, fresh install, latest Firefox versions.
I'm using a Core 2 Duo E7300 with 3GB RAM and Win7 RTM x32 if it matters. My Win7 version is from Microsoft Connect (I was a BETA tester).
Hmm, may I ask what graphics card you are using? 'Cos I'm experiencing it only with this ATI card.
|My System Specs
|06 Oct 2009
Windows 7 Ultimate x64, XP Mode, W8.1 Preview VM - 7 Pro x64 second remote tower
I have it listed right in my system specs but I presently have an MSI Radeon HD 2600XT 512mb card in on this build. The latest FF version out is the 3.5.3 beta there that went on the 64bit RC here without a hitch.
I'm one of those that will have to wait until 10/22 to get into the retail 7 Ultimate then while still keeping the RC on for some time in order to make a lengthy list of comparisons and take notes on the improvements and discovery of any problems that come up not seen in the RCs.
As far as the ATI catalysts and the Aero themes I've never run into any real issues since the 7.9 version included on the software disk for the card itself! The following updates have been going on ever since without problems. But your card is two model series newer and may simply need the 10.1 or going back to the 9.8 if you are seeing problems directly related to the 9.9 with the model you have there.
Another thing that may be a help for you is the form of update that works on both FireFox and Opera as far as a flash player. One thing that comes to mind about the popup that appears and vanishes is an update alert.
When you were mentioning problems with the Aero that's where I was referring to seeing it revert to basic here when going to use the tuner card as being normal. For any browser even FF the catalyst shouldn't have any effect while the flash players, for IE active x, plugins, and other things would be what to look at. Which version are you running?
The WDDM or HDMI driver for ATI cards usually is for the external output for audio/video when adding on a tv or other projection screen type display as well as a receiver for sound. That's a hardware configuration/driver issue unrelated to the browser as a separate item. You may have to go back and try out a Vista update for the 9.9 or 9.8 since that's part of the Catalyst update or separate drivers only option while at the support site.
|My System Specs
|07 Oct 2009
Windows 7 Ultimate x64 SP1
Did you rerun the WinSAT tool once you updated the drivers for the new card?
|My System Specs
|07 Oct 2009
Yeah I just did, but it didn't solve anything.
Processor 6.2
Graphics 7.5
Gaming Graphics 7.5
Primary HDD 5.2
|My System Specs
|07 Oct 2009
I am running 7 32-bit though, could that be an issue?
|My System Specs
|07 Oct 2009
Windows 7 Ultimate x64 SP1
maybe i missed this but did you remove all the old drivers for the 7900GS?? Also checking in device manager to make sure its correct in there?
|My System Specs
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Rugs USA Overdye RE21 Orange Rug
Item #: 200SPRE21A-P Add to Wishlist
Features: This product has the following features:
- Collection: Overdye
- Brand: Rugs USA
- Material: 100% Wool
- Weave: Hand Tufted
- Styles: Traditional Rugs
- Origin: India
- Available in the following sizes: 5' x 8'
- Clean & Care: Vacuum regularly as new wool rugs can shed yarn fibers for up to three months. Avoid direct and continuous exposure to sunlight. Do not pull loose ends, clip them with scissors to remove. Clean liquid spills immediately by blotting with cloth or sponge. For hard to remove stains, professional rug cleaning is recommended.
Price: $279 - $1,539
Best online purchase ever. Love this rug! It looks exactly as it did online... Will definitely purchase from Rugs Usa again!RECOMMENDED: Yes, I would recommend this to a friend.
Gorgeous rug, especially for the price! Vibrant colors, thick pile, fun pattern.RECOMMENDED: Yes, I would recommend this to a friend.
We really like this rug! We bought it a bug discount so we got it at a very reduced price which made it worth the money. If you're going to pay full price it's definitely worth spending that money on a true vintage rug instead of this. The yellow is a but more brownish/olive greenish, the red is more pink and the light blue isn't quite as vibrant. Overall though, we really like this rug and it was a great deal that brings a lot of color to our house!RECOMMENDED: Yes, I would recommend this to a friend.
This rug is beautiful!!!! It just sheds a little. I have been finding it on my pants and little clumps of fur around even after I vacuum. But the price couldn't be beat!RECOMMENDED: Yes, I would recommend this to a friend.
This rug looks beautiful in my living room and the quality is better than expected for the price. The colors in the rug are bright and beautiful. It does shed a little bit, but nothing really noticeable and I have wood floors. Don't hesitate to buy this rug!RECOMMENDED: Yes, I would recommend this to a friend.
I love this rug, the colors are great, the delivery was fast and the quality is better than I had imagined. Great product at a great price.RECOMMENDED: Yes, I would recommend this to a friend.
This is a beautiful rug at a great price. Vivid color, nice and thick.RECOMMENDED: Yes, I would recommend this to a friend.
Perfect color and really plush - love it! I have already ordered another rug that coordinates.RECOMMENDED: Yes, I would recommend this to a friend.
the rug can with 4-5 days and was just as pictured. the quality is terrific, much better then i thought. the rug is very thick and plush. GREAT DEALRECOMMENDED: Yes, I would recommend this to a friend.
This rug is gorgeous! The color is true to what I see on my screen and the quality is amazing for this price (very thick pile). It is shedding, but that is perfectly normal and is expected.RECOMMENDED: Yes, I would recommend this to a friend.
I know colors can appear different on different monitors, however the coloring on the rug pictured here is WILDLY lighter and has much more contrast than the rug delivered to me. In fact it appears the rug I was given is actually the Trans Ocean Petra Agra Rug in Mandarin, except they are slightly different sizes and the size I received is correct for this rug. The blue/teal color is VERY DARK and the orange and the red could almost be the same color. There is no relief for the eye and it is just very disappointing.RECOMMENDED: No, I would not recommend this to a friend.
This was rug was even better in person than on the computer. I had a few friends tell me from the online picture they did not like it and then they came and saw it in my dining room and told me Great Choice!!! I love every single color its an orange with bright pink and blues. It is perfect in my dining room!!!! I would highly recommend this rug to anyone considering it I was very pleased with the quality and colors!RECOMMENDED: Yes, I would recommend this to a friend.
This rug looks even better in person than it does on this site. Delivery was quick, customer service great! The rug goes beautifully in the spot we bought it for. Could not be happier! I would definitely buy a rug here again!RECOMMENDED: Yes, I would recommend this to a friend.
true to color, beautiful, some shedding, but really looks amazing.RECOMMENDED: Yes, I would recommend this to a friend.
Lovely thick rug in fun colors not often found in traditional oriental rugs. The price was fantastically low and delivery was quick. I would definitely buy other rugs from RUGSUSARECOMMENDED: Yes, I would recommend this to a friend.
Most Beautiful Rug I Have Ever Purchased!!!!!!!!! Well made wool rug has not shed so far! Have had it down over a week now...simply love it...price at 75% off was amazing for this high quality over-dye rug...thanks again Rugs USA!...will be back soon!!!!RECOMMENDED: Yes, I would recommend this to a friend.
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Wednesday, August 13, 2014
At the Studio
I'll definitely want to share all of the photos I've taken while in Russia,as well as my Febuary trip to Borneo to celebrate my friend and colleague's wedding by the beach in her hometown in Kudat. Also made a quick trip back to my own home town in Penang Island up north..so yea,tons and tons of photos to go through and share everywhere.
It's been a nonstop chugging of daily work and requirements each week since coming back home and my body's been trying to cope with the onslaught. Not to mention I've now started taking on a bit of private art tuition for a friend's twin girls at their home over the weekend. They're showing great promise at such a young age so I'm all for passionate students with bright futures in the art industry.
Will def try to update when I can. Meantime, here's a lil sketchie of what happened at the studio today. I was venting my disappointment and frust at my colleague,Joe,with a rambutan just after lunch. Fun was had by all. Life's good innit?
Posted by Sandra Khoo at 11:26 PM No comments:
Tuesday, June 17, 2014
Hi hi, here's what's been happening to me lately. Been crazy busy trying to wrap up production on a series at work whilst at the same time been assigned to churn out dev art for another title I've been pitching. So aside from being swamped with work,have also been trying to make good my promises to visit and spend time with friends and family. Which brings to the reason for 2 upcoming trips this month. One happening this Wednesday. Going up north to Penang Island for a couple of days to hand out with my relatives and friends before getting back to a bit of work,...trying to feverishly wrap up what I can before my big blow out holiday with my pals, Mickey and Ksoosh,to their hometown in Omsk,Russia. Have been promising Ksoosh's parents I'd visit one day. So yea,am making good my promises.
Good Night and Sleep Tight,folks! Cheers!
Good Night and Sleep Tight,folks! Cheers!
Posted by Sandra Khoo at 1:59 AM 2 comments:
Monday, May 26, 2014
Busy Busy bee
Well I'm still alive. Been really busy focusing on the job. Have now been helping to oversee production and script editing. As well as going for recordings,churning out art for both the studio and if there's any energy left,try to churn art out for friends/self,pick out on my puppeteering classes and trying to learn a new language on the side. Will need to see about taking up music lessons professionally if I want to be able to show any solid results of it. I told my friend recently I think it's a mid-life crisis I'm going through. Taking on too many things,wanting to take them on,more than I can handle. I do make time for a social life now,allocating time for shopping or outings with friends,eating,gaming etc....as well as hitting out my subjects of interests if they happen to be within reach. Like yesterday's stake out for Jeremy Wade at Sunway Pyramid as Discovery's River Monsters is doing a promo for his new season show,and the 3 day National Achievers 2014 Congress at the Mines Exhibition Centre. It's all been awesome. Great folks and speakers,and even managed to make time to rush back home to have a pre-celebration of one of many birthday celebration for mum's 70th. Needless to say,the past 2 weeks,my bdosy has been yelling for time out. I'll give it some real time out soon. Cos among the things I've been hustling,is to also get my Russian visa ready for next month's escapade with my Russian pals back to their home town. I can hardly wait! But enough rambling...here are some pics from my outings. Should bring my cam out more..dunno what I'll catch.
Posted by Sandra Khoo at 12:55 AM No comments:
Friday, April 25, 2014
League Mascot
Posted by Sandra Khoo at 8:39 AM No comments:
Thursday, April 03, 2014
Thundercats Time
Good times ...good times....
Posted by Sandra Khoo at 9:22 PM No comments:
Monday, February 10, 2014
Posted by Sandra Khoo at 11:52 PM No comments:
Sunday, February 02, 2014
Happy Birthday Mr Brent Spiner!!!
First and foremost! A grand Happy Brithday wish to Lt Comm Data!!! Was so awesome to be able to meet and greet with a whole bunch of awesome talents and folks that day at SDCC 2010 alongside my long time friend and bro,Eric Searles. I really should see about uploading my pic library regularly,especially in my Flickr site which has sorely been neglected. Anyhoo....here's what else I've been busy trying to get creative with again.
And finally,where I was yesterday evening thanks to my twinnie having a spare ticket to Japan's Beat Bumper troupe for a one night performance this CNY hols. Brill brill brill! Thank you sis! Had a grand time hanging out with your pals too,Gabriel & Shahnim.
Nice way to keep my mind off my flu recovery during this festive season.
Cheers and have a wonderful productive week ahead everyone!
Posted by Sandra Khoo at 10:52 PM No comments:
Tuesday, December 31, 2013
Holiday Comic
Panel 01/top left : Experiencing Air Asia Flight regularities at Tawau Airport in Sabah,heading home back to KL. Lewat (in Malays) means Delay. Panel 02 : Peter did not know how to shower Village/Kampung style. Panel 03 : I shared a bed with my pal,Viv, on the left side of the room while Pete,unfortunately,had to share a bed with our taxi driver on the right side. We were both snoring so hard ,it vibrated our friend's entire farm house in Cambodia. Poor Viv couldn't sleep a wink while Pete is cringing and shivering from the progressively chilly air at night. First time I got to sleep with mosquito netting too! It's been an awesome holiday overall.
Happy New Year,Folks!
Posted by Sandra Khoo at 11:39 PM No comments:
Monday, December 30, 2013
Merry Christmas & a Happy New Year 2014
Have been MIA for a good deal of November and December basically because have been away for the annual Company Trip to Bali this time around where we dug deep at Kuta Beach going through the Company Dinner and Team Building event before we're let loose around Bali. Here's a tiny snippet of where I've been and what I've experienced. I should really see about uploading all of my stuff into Flickr to share with whoever is interested in checking out my whereabouts. But mostly,if we know each other and add links to FB,you can basically go through all of my folders and check out all of the pics I've been sharing through the years. I wish I can afford membership to Flickr which allows the subscriber to share all of their pics from beginning to current without any limitations to the amount that can be shared. But till I can earn a bit more, this is what I have to cope with.
It's been a momentous and learning curve year for me. Thing are finally looking a lot brighter to say the least,but that doesn't mean that the year hasn't had it's struggles and heart aches. I've been very blessed and fortunate enough to be working with an awesome creative team in a supportive studio environment and it's nice that the pace never stops and we just find the enthusiasm and strength to just carry on each day with whatever life throws at you.
My trip wouldn't be complete without the coaxing of my colleague and good friend,Meng Yee,to take up surf lessons...and enjoying a swim and relaxing evening at the beach to watch the sunset on a deck chair with a refreshing fresh coconut handy. I will see about sharing some of my other trips with my good friend ,Pete, to Cambodia and around Borneo when I can get to it. Am still busily getting all of the pics together to share online. It's a ton of work in itself.
In other news, we've just wrapped up Christmas celebration 2013 with an impromptu invasion of the MnU gang to the apartment along with friendly faces from Mother Russia, my good pals, Mickey & Ksoosh. My twin came through for us with 2 turkeys beautifully roasted thanks to the helping hands from her friend and colleague,Alex. While I round it up with a new pasta recipe,potatoes,broccoli & cauliflower,sausages,salad and what not. Mum (not surprising) had gone out and got us roast duck as a side dish. She could never resist a good duck. The guys handled the drinks while Mickey & Ksoosh surprised us all with a lovely green tea cake. Next party stop...Russian style New Year Celebration at Mickey & Ksoosh's place! Can't wait!
I finally got to complete a special art gift request for my friend,Bob,but have also dedicated this piece to William Blake for obvious reasons. Hope you like it!
And finally,here's something Bob shared to me recently. What an awesome way to get the public to be aware of fine art once again!
Merry Christmas and a Happy New Year 2014 to everyone! Here's to a solid and prolific year ahead in spite of terrible rumours of inflation and rising costs and absurd new govt rulings...here's to hoping for a better future with better days. *click*
Posted by Sandra Khoo at 11:27 PM No comments:
Saturday, December 07, 2013
Cheers all!
Posted by Sandra Khoo at 4:49 PM No comments:
Wednesday, October 30, 2013
Today at the studio....
Wanted to kick start today by introducing to my fellow team mates Orson Welle's War of the Worlds live radio broadcast back in 1938.
75 years ago,today, Orson Welles broadcast live on radio a series of Alien Invasion coverage that to many of his listeners,seemed so startlingly real, it brought about widespread panic and fear. Let's re-live that special moment in history today and was prob one of the vehicles that propelled the sci-fi movement & intrigue into a branch culture long after HG Wells did.
Wallie dropped me another nice surprise package today. Another issue of P@per # 23 vol 1 with my lil strip contributed innit. WOO! Today is a gonna be a long but good day!
Posted by Sandra Khoo at 12:29 PM No comments:
Friday, October 18, 2013
Animation Job Openings in Cyberjaya,M'sia
Yes,that's correct folks! Giggle Garage here has new job openings for 3D animators (senior & junior positions) and we're also welcoming applicants for modelling,texture artists and 2D artists as well! Please feel free to give us a holler or help to spread the word if you can!
Here's the job link here : https://my.zartis.com/gigglegarage/jobs/679/3d-animators-senior-and-junior-cyberjaya?source=Facebook
and our company website : http://gigglegarage.com/
Cheers folks!
Here's the job link here : https://my.zartis.com/gigglegarage/jobs/679/3d-animators-senior-and-junior-cyberjaya?source=Facebook
and our company website : http://gigglegarage.com/
Cheers folks!
Posted by Sandra Khoo at 11:33 AM No comments:
Thursday, October 10, 2013
A quick round up of whats been happening towards the end of last month of my schedule....
A sad farewell to our colleague,Bee Yen, fellow animator who sat beside my workstation. We all wanted to make sure she's loved and is always welcome back if she decides to.
In other news,have completed our Puppeteer Training classes last week with Brian Zimmerman and friends at his new studio, Lil Critter Worshop at Damansara Perdana. It's definitely been the funnest class I've ever participated in so far and the laughter hasn't stopped since. es,it's definitely serious business to pratice and get the artform right,but once you've nailed it, you can expect a non-stop humorous and fulfilling career into this venture. http://www.lilcritterworkshop.tv/ Here's a sneak peek at what we've been up to....
This has got to be the hardest test we had to to yet. 4 minutes non-stop lip sync and body gestures to the tune of Billy Joel's We Didn't Start the Fire.
Another fun exercise we did in pairs. One puppeteer in charge of the character's lip sync and handling the Alphabet while the assistant helps to wrangle the hands of the character.
Debs & Steven working out their skit with the puppets of their choice.
Adrian and his friend in shades.
Elsewhere...been inspired by all of these awesome artists listed online in this feed here :
Made me want to get back in the groove and up my game further and further.
My now fellow Summoner friend,Eric Tan, shared this awesome new music vid clip of the latest character created for our League of Legends Online game. She definitely reminds me of an edgier Harley Quinn and definitely an overall likable character. Check out the awesome clip,mixing 3D and 2D elements in a very catchy music beat and lyrics below. LoL has definitely come very far from their humble beginnings.
Have recently checked out the trailer for Disney's Frozen ...
And have to confess,it's not really grabbing me as much as I'd like. Most probably because have been pretty put off by the style of the fake/shallow Disney Child-star chatter that doesn't really suit the time period and area the theme is covering. I appreciated that Belle didn't talk like that for Beauty and the Beast. Ariel had a bit of that teenage whine,but it was forgivable because she was so well drawn and animated in 2D,it worked. But I'll hope for the best and give it a shot before passing on further comments. Maybe it'll blow me away like Tangle and How to Train Your Dragon did. Astrid was the only character that put me off in How to Train your Dragon,but thankfully I think the producers/directors noticed that and toned down her character a lot to make her more likable now.
Here's something else that's been making waves online. A behind the scenes look at the making of Kon-Tiki last year. Am very happy to see grand works flourishing elsewhere around the world when other notable biggies have been struggling hard or is shut down due to bad management, budget cuts and so forth.
Another innovative take at the Horror movie fest I'm keen to participate in. Now there's one exception to acceptance of handphone usages in a movie screening. Brilliant!
I'll round up today's post with a link to an inspiring look into a troubled individual's artwork portfolio. No training. He just did it for his personal pleasure. And man is it looking spiffy!
Have a wonderful creative week ahead,folks. And enjoy the upcoming horror fests this month! Woo!
Posted by Sandra Khoo at 11:54 AM No comments:
Saturday, September 21, 2013
Zombie clips and inspirations :)
Enjoying some zombie clips from Key & Peele. Thank you Chi Ren for sharing this gem. :D
A touching take on the Zombie Apocalypse.
And am inspired by these cool kids. Wish I had the know-how and insight that they have when I was their age to take my dreams and aspirations to where I want to go and be.
A touching take on the Zombie Apocalypse.
And am inspired by these cool kids. Wish I had the know-how and insight that they have when I was their age to take my dreams and aspirations to where I want to go and be.
Posted by Sandra Khoo at 3:35 PM No comments:
Wednesday, September 18, 2013
Take On Me....
...Take Me On....
Thanks to my colleague,Joe, for sharing with me this nice commercial clip by Volkswagen. Nice little tribute back to the 80s with the exact idea laid out in the short clip. But dangit, it reminded me of how old I am as well. Oh well, the 80s was still the coolest year to grow up in. Cheers to A-HA and the 80s!
Thanks to my colleague,Joe, for sharing with me this nice commercial clip by Volkswagen. Nice little tribute back to the 80s with the exact idea laid out in the short clip. But dangit, it reminded me of how old I am as well. Oh well, the 80s was still the coolest year to grow up in. Cheers to A-HA and the 80s!
Posted by Sandra Khoo at 6:19 PM No comments:
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Uphill task for Nato and Nglande, but not for Nengomasha
Three Bidvest Wits players will be in action over the international break, but two of them face uphill battles as they go against the odds in search of qualification for the 2013 African Cup of Nations in South Africa.
Ofentse Nato's Botswana faces an almost impossible task if they are to continue in their qualification for the continental showpiece.
Botswana find themselves three goals down after suffering a heart-breaking 3-0 loss to Mali in their first leg qualifier in Bamako on Saturday 8 September 2012.
It was a horrible performance from Botswana away from home as goals from Cheick Diabate, Tenima Enday and Modibo Maiga handed them one of their worst defeats in recent time.
They will now need a miracle if they are to turn the tie around and many will be looking to Nato to provide that inspiration from the midfield in Gaborone on Saturday. One thing is for certain – Botswana will not be defending and will more than likely opt for all-out-attack which suits Nato's style of play.
Robin Nglande's Malawi also faces an uphill task as they will have to fight back from a two goal deficit against Ghana on Saturday if they are to continue on their Afcon journey.
In their first leg match on 8 September 2012, the Flames were solid defensively, but two minor lapses in concentration saw them conceded two silly goals scored by Christian Atsu and Anthony Annan.
Nonetheless, Malawi will take heart from them performance and will be looking to bounce back at home in front of what will surely be Malawian dominant crowd.
A lot, though, will be expected of Nglande if he plays as the striker and will be expected to take his chances in front of goal.
Finally, one Wits player will expect his national team to qualify for the 2013 Afcon as Tinashe Nengomasha's Zimbabwe go into their second leg tie against Angola 3-1 up.
The tough as nails midfielder was not present for the first leg match but has been recalled to the squad in order to sure up the midfield when the team takes to the field in Angola.
With Nengomasha in the heart of the midfield, Zimbabwe are sure to be difficult to beat and are more than likely going to qualify for the tournament next year.


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Archives for: December 2011, 29
Top 9: Thursday, December 29Posted Thursday December 29 2011 at 11:32pm
9.)Flo Rida- "Good Feeling" 8.)Karmin- "Crash Your Party" 7.)Avril Lavigne- "Wish You Were Here" 6.)Rihanna- "You Da One" 5.)Outasight- "Tonight Is The Night" 4.)Katy Perry- "The One That Got Away" 3.)Breathe Carolina- "Blackout" 2.)… more »


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Today marks the tenth anniversary of Xbox Live and Microsoft is celebrating the occasion by offering players a free XBLA game, as well as discounts on a range of titles.
Members can download Kinect XBLA game Wreckateer free of charge for the next 48 hours.
Meanwhile Battlefield 1943, Castle Crashers, Fruit Ninja Kinect, Geometry Wars Retro Evolved 2, Bastion, Peggle and Full House Poker are for a limited time available to download for half their regular price.
Marc Whitten, corporate VP of Xbox Live, wrote on Xbox.com: "I want to thank you for helping us make Live what it is today, and what it will be tomorrow.
"Over the past year an average of 9.4 million people a week using multi-player gaming on Xbox Live and in the 10 years of Live, nearly 14.5 billion Achievements have been unlocked worldwide, accumulating a total combined Gamerscore of more than 270 billion.
"So to all our 40+ million Live members in 41 countries around the globe, a very happy anniversary - we wouldn't be celebrating this milestone without you!"
In the US Microsoft has been marking Xbox Live's anniversary by sending out custom Xbox 360 consoles to a number of long-serving members.


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Ribble Soup Anyone?
Discussion in 'Recipes and Cooking' started by SweetSurrender, Jan 6, 2009.


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Manning, Obama and U.S. Moral Leadership
By Glenn Greenwald
On December 15, when I first reported the inhumane conditions of Bradley Manning's detention, I did not assign any blame to — or even mention — Barack Obama. Although, as Commander-in-Chief, Obama was technically responsible for Manning's treatment, there was no evidence that he even knew about it, let alone planned it. But since then, the Manning controversy exploded into national prominence and Obama has explicitly defended the treatment, leaving no doubt that it directly reflects on who he is as a leader and a person.
For that reason, as The Guardian reports this morning, a letter signed by "more than 250 of America's most eminent legal scholars" that "includes leading figures from all the top US law schools, as well as prominent names from other academic fields" — featuring "Laurence Tribe, a Harvard professor who is considered to be America's foremost liberal authority on constitutional law"; who "taught constitutional law to Barack Obama and was a key backer of his 2008 presidential campaign"; and "joined the Obama administration last year as a legal adviser in the justice department, a post he held until three months ago" — not only denounces Manning's detention but also the 2009 Nobel Peace Prize winner's personal responsibility for it:
[Tribe] told the Guardian he signed the letter because Manning appeared to have been treated in a way that "is not only shameful but unconstitutional" as he awaits court martial in Quantico marine base in Virginia. . . . Tribe said the treatment was objectionable "in the way it violates his person and his liberty without due process of law and in the way it administers cruel and unusual punishment of a sort that cannot be constitutionally inflicted even upon someone convicted of terrible offences, not to mention someone merely accused of such offences".The harsh restrictions have been denounced by a raft of human rights groups, including Amnesty International, and are being investigated by the United Nations' rapporteur on torture. . . .The intervention of Tribe and hundreds of other legal scholars is a huge embarrassment to Obama, who was a professor of constitutional law in Chicago. Obama made respect for the rule of law a cornerstone of his administration, promising when he first entered the White House in 2009 to end the excesses of the Bush administration's war on terrorism. . . .The protest letter, published in the New York Review of Books, was written by two distinguished law professors, Bruce Ackerman of Yale and Yochai Benkler of Harvard. They claim Manning's reported treatment is a violation of the US constitution, specifically the eighth amendment forbidding cruel and unusual punishment and the fifth amendment that prevents punishment without trial.In a stinging rebuke to Obama, they say "he was once a professor of constitutional law, and entered the national stage as an eloquent moral leader. The question now, however, is whether his conduct as commander in chief meets fundamental standards of decency."
Professor Benkler, echoing the point that I've repeatedly emphasized as I believe it to be the most important one, said "Manning's conditions were being used 'as a warning to future whistleblowers'." Indeed, Manning's treatment lacks even a pretense of justification; it — just like the Obama administration's unprecedented war on whistle-blowers — is clearly meant to threaten and intimidate future individuals of conscience who, like Manning, might consider exposing government deceit, corruption and illegality: one of the few remaining avenues for learning what the Government does. Aside from what conduct like this reveals about Obama, it also severely undermines the ability of the U.S. to exercise any shred of moral leadership in the world.


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Decent special effects are the best reason to see this big-budget mess about the day that Los Angeles gets hit by the 'big one'.
Watch 'Earthquake' on Cinemax on xfinityTV.com
In The Wind Rises, Jiro (voice of Joseph Gordon-Levitt) dreams of flying and designing beautiful airplanes, inspired by the famous Italian aeronautical designer Caproni (voice of Stanley Tucci). Nearsighted from a young age and unable to be a pilot, Jiro joins a major Japanese engineering company in 1927 and becomes one of the world s most innovative and accomplished airplane designers, earning the respect of prominent industry greats, including Hattori (voice of Mandy Patinkin) and Kurokawa (voice of Martin Short). The film chronicles much of Jiro s life, depicting key historical events, including the Great Kanto Earthquake of 1923, the Great Depression, the tuberculosis epidemic and Japan s plunge into war. Jiro meets and falls in love with Nahoko (voice of Emily Blunt), and grows and cherishes his friendship with his colleague Honjo (voice of John Krasinski). Writer and director Hayao Miyazaki pays tribute to engineer Jiro Horikoshi and author Tatsuo Hori in this epic tale of love, perseverance, and the challenges of living and making choices in a turbulent world.
Trailer for Earthquake.
Construction Engineer Stuart Graff is estranged from his jealously possessive wife, Remy, and has an affair with Denise Marshall, the widow of a co-worker. Meanwhile, Remy tries to persuade her father, Sam Royce, who is Stuart's employer, to use his influence to stop Stuart from seeing Denise. Rogue policeman Lew Slade is suspended from the L.A.P.D. for having punched an obtuse officer from another jurisdiction. Embittered, Slade contemplates quitting the police force. Jody, a perverted grocery store manager, lusts after Rosa Amici, sister of Sal, the assistant to Miles Quade, an aspiring daredevil motor cyclist. The lives of all these people are devastated when a major earthquake rips through Los Angeles and reduces the city to ruins.
more Earthquake videos
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Explore The ITF
about ITFITF
World Tennis Day 2014 will take place on Monday 03 March 2014.
Anyone can get involved in World Tennis Day. Whether you are a regular tennis player playing once a week, have not played for many years, have never picked up a racket or simply wish to encourage your children, family and friends to try tennis, it is easy to do so. Simply grab a racket and a ball and have a go in a location convenient, it may be in your garden or in a local park. Check whether the local tennis club or sports / leisure centre is organising any activities. Schools, companies, social groups can all get involved and do some simple serving, rallying and scoring activities. Some example activities and events are provided in the World Tennis Day 2014 Guidance Document for CLubs and Organisations on pages 2-5 (download below).
World Tennis Day is a global initiative aimed at increasing participation among players. The event is centered around a series of high profile Showdown events featuring current and former professionals together in front of thousands of spectators. The inaugural World Tennis Day took place on Monday 04 March 2013 with 55 different nations involved across the world, with two BNP Paribas Tennis Showdowns in Hong Kong at the Asia World Arena and in New York at Madison Square Garden.
There are a variety of activities and specific events that can be organised for World Tennis Day 2014. In most cases, the National Tennis Association of each country will drive the activities and specific events organised, however tennis clubs, organisations and tennis enthusiasts can get involved too. If you are looking to organise your own activities and specific events, please get in contact with your National Tennis Association to find out their plans first. Some example activities and events are provided in the World Tennis Day 2014 Guidance Document for CLubs and Organisations on pages 2-5 (download below).
World Tennis Day is a global event and celebration of tennis for the world and anyone can take part. The ITF and StarGames Inc. remain the sole rights holders of the World Tennis Day brand, however all National Tennis Associations are encouraged to organise respective activities and specific events nationally.
The ITF are unable to subsidise any National Tennis Association's World Tennis Day activities or specific events with any financial assistance or equipment support. The ITF is aware that some activities and specific events are heavily reliant on financial assistance to deliver certain activities and encourage National Tennis Associations, clubs and organisations to utilise their existing resources or seek external funding or sponsorship for their activities and specific events linked to World Tennis Day.
Yes. World Tennis Day is non-exclusive and National Tennis Associations, clubs and organisations are able to seek their own specific sponsors or external funders to support their local events and activities. No sponsor should be credited as being a title or presenting sponsor, although national and local sponsors can be associated with World Tennis Day. The ITF and StarGames Inc. remain the sole rights holders of the World Tennis Day brand.
The ITF has produced a World Tennis Day marketing kit with materials that can be used by National Tennis Associations, clubs, organisation and tennis enthusiasts supporting World Tennis Day. A Poster, two-sided Postcard and Banner are available in English, French and Spanish languages. All available promotional materials can be downloaded from here.
Some examples of the style of images that should be shared on the official World Tennis Day social media channels related to World Tennis Day 2014 are shown within the World Tennis Day 2014 Guidance Document for CLubs and Organisations on page 10 (download below).
The ITF will be sharing content related to World Tennis Day throughout the days leading up to the event and in the aftermath too. The ITF would like to encourage images and video content to be shared via the official social media channels linked to the World Tennis Day on Instagram, Twitter and on Facebook, and using the hashtag #worldtennisday.
During World Tennis Day 2014, the ITF will be engaging in a social media campaign and will be asking for professional players, celebrities and participants to show their support for the event by posting a 'I support World Tennis Day' message on the official World Tennis Day Instagram, Twitter or Facebook pages and using the hashtag #worldtennisday. A specific 'I support World Tennis Day' poster (A4 Landscape) has been produced and will be made available to download from here.
© 2014 International Tennis Federation Powered by Umbraco Design by New Brand Vision


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Annual 5K, 10K and kids' runs are Thursday at Dana Point Harbor. You can save money on your entry fees if you register online by today.
It's almost that time again, so break out your running shoes and get ready for the Dana Point Turkey Trot, a Thanksgiving festival featuring 5K, 10K and 1-mile Kids' Gobble Wobble runs that annually draw 10,000 and more to the scenic harbor.
For openers: The event kicks off from 10 a.m. to 5 p.m. Wednesday with the first day of the Aviir Health and Wellness Expo, featuring products from health-industry vendors. The expo continues the next day.
Racing: Starts at 7 a.m. on Thursday, Thanksgiving
What's new: Organizers from the Dana Point Chamber of Commerce promise some surprises along the course, including photo opportunities and sampling of food and beverages from some of the sponsors.
Registration: If you register at www.turkeytrot.com/register.shtml by today, entry fees are:
• Both races: $55
• Kids' Gobble Wobble (ages 5-12): $12
After Monday, the 5K, 10K and 5K/10K fees are $10 more. You can register in person from 10 a.m. to 5 p.m. Wednesday or beginning at 6 a.m. the day of the event at the Dana Point Harbor parking lot on the northwest corner of Golden Lantern and Dana Point Harbor Drive.
Events schedule:
• 7 a.m.: 10K (6.2 miles)
• 8:30 a.m.: 5K Masters (40 and older)
• 9:10 a.m.: Costume contest
• 9:30 a.m.: 5K Open (3.1 miles)
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Keep it civil and stay on topic. No profanity, vulgarity, racial slurs or personal attacks. People who harass others or joke about tragedies will be blocked. By posting your comment, you agree to allow Orange County Register Communications, Inc. the right to republish your name and comment in additional Register publications without any notification or payment.


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TARTA will hold a job fair on Thursday, June 6 at the TARPS Paratransit Facility, 130 Knapp Street, in Toledo. There will be two sessions, from 10 a.m. to 11 a.m. and from 6 p.m. to 8 p.m.
TARTA is looking to hire multiple paratransit drivers and repair mechanics, along with one maintenance supervisor.
Applicants must be at least 21 years old, have a high school diploma or GED, and a "background worthy of public trust" according to a press release. Other requirements include five years of experience driving any vehicle and a safe driving record.
More information about the positions can be found on TARTA's website.
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Michelle Keegan
A thumbnail gallery of the British actress Michelle Keegan. She is best known for playing the part of Tina McIntyre in Coronation Street. Before taking up the role she worked in the department store Selfridges and as a check-in agent at Manchester Airport. In late-2007, in only her second-ever audition, she was offered the the part of Tina. Click the thumbnail pictures for full size images.


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Items where Author is Killick, D.
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Number of items: 1.
Salter-Dvorak, Hania (2002) Changing consciousness of EFL learners through project work in the community. In: Cormeraie, S. and Killick, D. and Parry, M., (eds.) Proceedings of the First Annual Conference of the International Association for Languages and Intercultural Communication, December 2000. Leeds Metropolitan University, Leeds, UK, pp. 185-195.


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Journal of Studies on Alcohol and Drugs
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Neuropsychological Characteristics of Young Children from High-Density Alcoholism Families: A Three-Year Follow-Up
Montserrat Corral, Socorro Rodríguez Holguín, Fernando Cadaveira
Objective: We performed a follow-up study of a group of young children from high-density alcoholism families (HD children), who were first assessed about 3.5 years ago, with the aim of evaluating verbal span and visuospatial abilities (which differed significantly between HD and control [C] children at the first assessment), as well as other neuropsychological measures. Method: In this second assessment, 22 boys and girls were evaluated. They were comparable in family income and parents' level of education. The 12 HD children had an alcoholic father and at least two other alcoholic relatives, whereas the 10 C children had no family history of alcoholism in either the first or second generation. A neuropsychological battery was set up with standardized tasks to measure attention, memory, visuospatial and executive functions. Results: Analysis revealed significant Group × Assessment interactions in the digit span subtest where high-density children increased their performance until it reached that of the control children, and in the Wisconsin Card Sorting Test (WCST) where high-density children did not show the same improvement as the C children with maturation. A main effect was also observed for group factor in perseverative responses of the WCST. Conclusions: High-density children attain the same level of performance as control children for verbal span, but differences between groups increase over time for executive functioning as measured by the WCST. These results are considered in the context of the developmental delay hypothesis. The small sample size, however, means further studies will be necessary to confirm our findings. (J. Stud. Alcohol 64: 195-199, 2003)


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It's similar in size to my old one but sits slightly lower which works well. And the pale grey of the veining ties in nicely with the paint colour in here too.
So what do you think of the new addition? Have you had to make any happy compromises lately?


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Reader comments are listed below. Comments are currently closed and new comments are no longer being accepted.
The Republican party has not yet hit bottom and until it does, a significant segment will remain in denial about the abject failure of its policies and the hopelessness of its electoral position. Since Reagan, the party has depended on an odd mix of fiscal hawks and religious nut-jobs obsessed with inserting their own neurotic brand of repression into everyone else's lives. By promoting simplistic messages the party attracted people whose thinking is equally simplistic, which in turn led to candidates whose caliber might charitably be described as "uncertain." Not surprisingly, such repellent politicians tend to repel most voters while attracting criticism from the more rabid wing of the party for being insufficiently bigoted, hysterical, and nonsensical.
Meanwhile the Democratic party avoids, for the most part, essential internal reforms of its own because it rightly senses the Republicans are a diminishing threat. The overall result is political stagnation, which the USA absolutely does not need at this time of great change and challenge.
It would be nice to think that the Republican party can purge itself of the inadequate, ineffectual, and intolerant in the space of a few years but in reality the party will either totally implode and be replaced (this does happen, after all) or lurch in a semi-conscious way towards reform over the course of a generation. For the short term the outlook is very, very bleak.
How does the GOP, with a straight face, wish to increase minority outreach while supporting voter registration/ID policies that inherently target minorities? Or increase "women's outreach" while continuously attacking Roe Vs Wade, especially at the state level? Or shake off their "we only support the wealthy" tag while calling half of the population moochers?
Then again, if you believe that 'tax cuts increase revenue' and 'corporations are people', logic may not be your strong suit....
The Republicans are more afflicted by difficulties now, but the Democrats have faced them in the past. It is a matter of having brought the lunatic fringe into the mainstream of the party. This is difficult to undo, because the Yahoos will not go away quietly and the center will be slow to trust. Rest assured that so long as Yahoos make up a significant part of their base, non-Whites will not trust the Republicans, either. Thank Boy Genius Rove and his 50%+1.
"...many minorities wrongly think that Republicans do not like them or want them in the country."
I recently heard Rush Limbough, often referred to as a leader in the party, say: "Democrats like Mexicans because they've aborted all their voters".
So, Hispanics get the impression that the GOP doesn't like them? Naaawww...
That the party should stand up and punch back is one thing, unfortunately it is punching back against its own as long as it holds to its hypocritical social values anti-women, anti-gay, anti-libertarian agendae. Among the young and educated, that train has left the station years ago, so the old guard leadership are actually standing up and shooting themselves in the foot by not embracing a fiscally conservative, socially libertarian platform (along the lines of Preibus's recommendations). I don't get it, if your opposition is supporting your taking certain positions and not fighting you for taking them then obviously they know that those positions are poison for the vast majority of voters, so it's time to swallow hard and support abortion rights, gay marriage, birth control in all employer health insurance packages, an end to the war on drugs, equal pay for work of equal value, etc. Are the fiscal conservatives so afraid ofthe social conservatives' power as to render them unable to present a sensible, electable, libertarian platform?
Eric Cantor, the Republican House majority leader, told Ryan Lizza of the New Yorker in a perceptive March 4th article ("The House of Pain")that there was nothing wrong with the CONTENTS of the GOP package, just the package needed a bit of re-doing.
As the guy who admittedly torpedoed the Obama-Boehner Grand Bargain in 2011 and may even continue to call its major shots, redemption is a couple of mirages away. Extinction looms
The GOP will only be taken seriously again when it ditches its current hysterical and senseless rhetoric, and dump the deranged Tea Party together with its clownish mouthpieces: Sarah Palin, Michele Bachman, Donald Trump and others. When I turned the TV on the other day and I saw Palin and Bachman BSing(which is nothing new, it must be said) at the CPAC convention, I asked myself: and they(the GOP) still wonder why they are getting their fingers burnt?
The elephant in the room (pun intended) is the pair of unmistakable trends which the report misses (as do most Republicans, and still too many Democrats). They ignore, as if refusing to countenance, the trends in favor of gay marriage and legalizing recreational marijuana use.
The GOP simply will not be able to get around these issues, much less get in front of them. The Dems, who should be more tolerant and humane (right?), are currently still too old-fogeyish to do much better on that score, but they probably feel they don't have to as their competition is so weak, and will naturally stick to maintaining power over promoting principle. Meanwhile, we the people will keep charging ahead, at local and state levels, in favor of personal liberty. (I wish I could say the same for economic liberty, but it might be too late for that anymore.)
The GOP is talking about switching from caucuses to primaries? Primaries are, I believe, the chief reason our political system is dominated by extremist crackpots at both ends of the political spectrum. To get to the general election, candidates must first run the gauntlet of the "true believers", the registered party members who vote in the primaries. This leaves the general electorate with choices who have spent the past year polishing their credentials as bulwarks against moderation. I would argue for a two stage general election and runoff which would favor moderate candidates rather than those at either wing of their parties. California has recently switched to this system, and there is some evidence (Economist Articles)that this has brought a measure of sanity to state politics there.
As long as there is discontent (with the present administration and situation) to leverage (and there is plenty on many fronts), the GOP will have legs. Simply by being the "other" they get credence. It matters little that their policies make no sense. Negativism and obstructionism have traction, an unfortunate fact of American politics. This is grim, because there is no dislodging the red state block in the house.
It all spells a very happy 2014, 2015 and 2016 for Barack Obama. If the Tea Party keeps up their ramble, the party will remain split and Democrats will reap the benefits.
pet peeve here: the 'corporations are people' thing dates back to the late 18th century when at the time it was considered that only people could file lawsuits and enter into contracts. Therefore courts took to looking at corporations, charities, organizations in general, and later UNIONS, as "persona ficta" for simple legal purposes so that they could enter into contracts with each other and regular citizens, etc... It has been a couple hundred years since original precedence was set so most people don't realize that any organization that intends to have legal representation is treated as a 'persona ficta' (literally fictional person) before the court and don't get why you would ever treat corporations as people. Recent rulings that have increased the number of rights and protections afforded to legal entities other than living breathing human beings has benefited unions as well as any other organization of people that intends to involve itself in society. It is rather absurd that the Democratic party has suddenly decided that the last 200+ years of legal precedence is no longer politically correct and needs to be overturned.
In other words you think it's just a phase the party will be going through?
People say the Republican Party must change and be more inclusive if it is to survive. Have you ever considered what you are saying? There are things I don't like about the Republican Party (birth control position), but please name a political group about which you like everything. Even if you could find one, should their planks change later just to include a few more voters? What would they stand for then?
Ultimately, it must come down to individuals and their positions on matters that are important to you. If you want someone in office that agrees with you on everything, it must be you.
People don't see the bigger picture which is nothing less than people trying to control other people. Toward this end, they support bigger government and Parties that advocate what they like. They are advocating nothing less than a modern form of slavery.
Let the Democrats and Republicans be what they are, but beware a government big enough to make you be what the ruling party wants.
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by @Jason_Silva – Follow him on Twitter!
… A Universe Of Possibilities
… Grey Infused By Color
… The Invisible Revealed
… The Mundane Blown Away By Awe
Dedicated to: Carl Sagan, Ray Kurzweil, Timothy Leary, Buckminster Fuller, Stewart Brand, The Imaginary Foundation, Chris Anderson from TED, Linda Mishkin, Richard Feynman, and all the curious and the wonderful…
Watch More related to Human Condition:
THE HUMAN CONDITION - vimeo.com/34416826
ECSTASY - vimeo.com/34358027
LOVE - vimeo.com/34415843
BEAUTY - vimeo.com/34416532
More Technology and Philosophical Espresso:
The Beginning Of Infinity - vimeo.com/29938326
You are a RCVR - vimeo.com/27671433
To Understand Is To Perceive Patterns - vimeo.com/34182381
Abundance - vimeo.com/34984088
Camera: Michael Marantz
Audio: Drew English
Edited with Drew English and Pete Demas
Color Correction: Jason Goodman
Music: A Kaleidoscope of Mathematics from a Beautiful Mind soundtrack, and the track "Primavera".
Buy them on iTunes!
Still Images courtesy of Imaginary Foundation:
Other images courtesy of Transcendent Man
Also including images by:
/Aaron Koblin


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- Asa Akira brings you a hot update with Marie Luv in this gonzo style shoot. Nothing but the best.


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Everyone knows that aluminum iPhone 6 cases are the most protective type of cases on the market. Signal loss however has always been a draw back until now. Our aluminum iPhone case was designed with form and function in mind. While you will still receive the ultimate in protection you will not have to worry about any signal loss. Since our aluminum iPhone 6 case does not require any tools or screws to take on/off we are able to offer the sleekest of design profiles. Get all the protection without any bulk or signal loss.
The Rokform Rokbed Fuzion is CNC machined from 6061 T-6 aircraft grade aluminum with an impact resistant inner TPU shell. The new case is available in a variety of anodized colors to fit almost any taste. Compatible with all iPhone carriers. Designed, engineered and machined in the USA.
Love it
(Posted on 11/29/14)
there's not to many cases on the market right now that offer the protection this case has. When I put it on I could instantly tell it would be my go to case
(Posted on 10/29/14)
I'm so glad I purchased this product! I drop my phone all the time!! This thing is durable!! I'm loving the wrist lanyard! I don't always carry my purse, so this is a great feature!
(Posted on 10/16/14)