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usually used in adjective form, cray- cray simply means, super crazy
"oh man in that party yesterday Johnny made out with a girl AND a guy! Only one word can describe that party... and it is.. cray- cray"
"That party was so cray-cray!"
"Angela is so cray-cray!"
"That party was so cray-cray!"
"Angela is so cray-cray!"
by SammiJ3000 March 06, 2006
Top Definition
meaning really crazy
damn homie, this party is cray cray
by Pint-O December 17, 2002
Steming from the term "Crazy", when Referring to someone as "Cray Cray", signifies their craziness to a whole other level. The ultimate second power of crazy. This person can either be insane in the brain. Or simply, TOO DOWN. To the point where its not even cool anymore.
by Chiquita Linda March 16, 2011
A desperate attempt to say "crazy" made by some adult trying to be cool.
Cray-cray lady: Omg, that's totes cray-cray. Yeah, i just like to abrev. all my words.
by Neva McNelly October 21, 2012
A person or individual who has gone completely mental, on an emotional or physical level. Abandoning all reason or good judgement.
-Melissa Wade is off her rocker!
-Yeah man, she's fucking Cray-Cray
-Yeah man, she's fucking Cray-Cray
by Your mother's mother's mother's father June 09, 2008
CrayCray - For when something is too crazy to just be crazy.
''Man, those guys are crazy!''
''Nah, they're way crazier than that- they're craycray!''
''Nah, they're way crazier than that- they're craycray!''
by ILikePandas April 16, 2010
A more interesting way of putting crazy.
That show was craycray, toast.
by ¡EVA! October 25, 2008
A describing word of someone who is out of their mind crazy. Normally spoken in a high pitched voice.
*Check out that guy trying to eat a duck - he is cray cray!
by holr517 October 02, 2013

subset: commoncrawl


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Ambros SubsMarch 25, 2014Sandwiches • San Dimas, United States
The diet sub with the sprouts is GREAT! Added turkey and it was excellent.
The diet sub with the sprouts is GREAT! Added turkey and it was excellent.
To conserve water, this building uses recycled water to flush toilets and urinals.
They have BIG cans of Coke!!! So much better than gross plastic bottles.
Love the "no tipping" policy. Everyone was very polite and nice. The cheese plate could have used some crackers. The mixed drinks were not as serious as I normally like. We'll be back, though!
Pinch yourself. This airport is actually in Los Angeles, not some cozy small Midwestern town. I love it so so so much.
You simply must do Hack The Met. #hackthemet
The pulled pork may change your life.
Dave O's drink is epic. Get on that.
LOVE this place - great happy hour and great sangria.
SOOOO GOOOOOD. you're taste-deaf if you don't love this place.
Friendly staff, beautiful tasting room, but rather dull wines - the Reisling is good though! Very sweet, like a moscato.
Desiree rocks my shaggy mop.
If you're not using the shuffle-board, you're doing it wrong.
Enjoy the awesome service - especially for a little hole-in-the-wall.
Don't miss the Wildlife Show! Seeing the owl and the falcon was freaking awesome. Also, the big cat they bring out is amazing. I WANT ONE IN MY HOUUSSEEE.
We usually have hidden Steaz. Hidden ... in the fridge.
Don't look Erik or Justin in the eyes. They will attack. Mercilessly.
This place was GREAT. amazing ciabatta bread, get the hawaiian pizza or sandwich and you'll be in heaven.
Sam Sneads is across the way. Expensive but nicer than eating at a food court.


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Skokie Tutors
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text: 09Feb Does SimCity 5 Really Need A Homeless Elimination Manual? Categories: Digital, Social Media and Web 2.0, UK, USA and Canada Tags: cc Comments: No by Drew Reed There's a new feature in the latest version version of SimCity that was completely absent in earlier ones: homelessness. And it's bringing out the best and worst in users. Read more


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Manufacturers working on making natural gas vehicles affordable
Chrysler this month began commercially selling its Ram 2500 compressed natural gas truck. Honda is offering a natural gas-powered Civic, and other manufacturers are working on natural gas vehicles.
Change takes time
To so dramatically change such a large industry takes time and many parts coming together at the same time, said Tod Hartje, head of market requirements for fleet operations at Chrysler Group.
"Creating a CNG market is like a puzzle," Hartje said. "You have to get everything to work together. If you pull one lever, you could have a great infrastructure, but if there is no product and people don't want it, it won't happen."
Chrysler and other manufacturers are working on the vehicles. Natural gas companies and retailers are working on fueling stations, and companies like General Electric are working on home fueling technology that would allow consumers to fill up their natural gas tanks in their own garages.
Both the refueling station and home refueling options are needed, Hartje said.
"Your vehicle needs to be able to handle your urban commute, but it also needs to take you to grandma's house and on vacation."


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If you have a sporting mindset and are looking for a great bunch to hang out with, join us at a training, match or event. We'd love to have you join us. We will teach you everything you need to know to have fun playing Australian Rules Football!!
Training time and location HERE
Get yourself ready for
We are asking all players to join us in Austin TX this October to compete at The USAFL National Tournament. Our push will begin with an 18-side match against Orange County on September 12 continue for the remaining 6 weeks leading up to nationals. There will be enough games to earn points to qualify for nationals. But you'll need to attend almost all of them.
Everything you need to know for attending Nationals is HERE
Surely you can commit to a 6-week season, rather than the 9-month commitment required in the past.
Sept 12 - Saturday - Match @ OC
11am start - South Lake Middle School, 655 W Yale Loop, Irvine
Sept 19 - Saturday - Metro Game
Sept 26 - Saturday - Metro Game CANCELED
Oct 2 - Friday - AFL Grand Final Night at McGregors
Oct 3 - Match with LA Dragons (afternoon/evening match in LA)
Oct 10 - Saturday - Metro Game - if needed
Oct 17-18 - Nationals in Austin, TX
Wanna get a head start?
TRAININGS CONTINUE EVERY WEDNESDAY AT 6pm at DOYLE ELEMENTARY


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Welcome to the Salem Garden Club of Salem, Massachusetts! We hope you enjoy browsing through this site to learn about our objectives, our programs, and our upcoming events! We hope you'll check in often as new information may be added on a regular basis.
Check the Seaside Garden Stroll 2015 page to see some photos of the lovely gardens featured this year!


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Craighaar Hotel
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Stirling, Perth, Dundee, Dunnotar Castle
... fear can come along at any time. I remember the phrase, "Feel the fear and do it anyway, I locked the house up and said good bye to comfort and luxury for the time being.
Passing Newcastle airport gave me a sense of being guided down another path! This comforted me. Heading up the A68, I had a very strong familiar feeling. Within two hours, I was taking photographs of the border view point. Scotland would be my home for a ...
Rattray head
We spent the day in the airport at Stockholm thankful to be off the ship and spent 5 hours in the airport. Despite the internet cutting out and paying what equated to $35 for a sandwich and beer, I took some airplane tablets early so I could drive when we landed... So it was a pretty smooth wait :p and I think we're really really used to waiting several hours for things. We picked up the camper ...
Going North!
... the Trump International Golf Links, north of Aberdeen. The sun shone, but the haar was still in evidence along the shoreline dunes. After elevenses, as we were thinking of leaving the club house, the golfer Justin Rose walked in! Further up the coast, we revisited a favourite haunt where the sticky toffee pudding was to die for. After a fine lunch (but without said dessert), a walk along the Ythan River to ...
... the blue and gave you something that would mean so much to you that you didn't know how to live without it? Something you would cherish forever because they are perfect, and they were given to you by your best friend?
Something that was so YOU.
Yes. I am indeed talking about Jarmy pants.
I, thanks to a gorgeous girl called Katie, now own my very own pair of jarmy pants. Not something most people would consider ...
Aberdeen and Dundee
... Some bloke was sitting on an old plot, swigging away from a 'tall brown' - by the look of his eyes and his massive gut, it wouldn't be long before he joined the souls he was now sitting on.
Walked out to the main 'resort' beach at Aberdeen - 'beautiful & bleak' is the kindest way I could describe it, with more emphasis on the bleak bit. Perhaps on a sunny day it would look ok, but today it didn't look too ...


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Ford Motor will invest 11.4 billion yuan ($1.8 billion) to expand research and development in China, Chief Executive Mark Fields said on Monday.» Read More
Wall Street looked set to rally Monday following a series of measures and cash injections by governments and central banks designed to prop up the banking sector and avoid a global meltdown.
After a few days of tracking the latest talks between GM and Chrysler, I'm more convinced than ever before that these two companies will not merge. It's an idea that ultimately creates more headaches than solutions for GM.
After trading in a 1,000-point range for the first time ever, stocks ended the day with a whimper, closing slightly lower amid hopes that the holiday weekend could bring good news.
If you think GM is just a short drive from steering into bankruptcy, think again. This morning, while everyone says this company is on the verge of collapsing, a GM spokeswoman emphatically said "NO!"
Ford Motor is not considering bankruptcy protection as an option, CNBC reported Friday, citing company executives. The unidentified Ford executives said bankruptcy is not even under discussion, and that the company has sufficient liquidity.
Stocks opened aggressively higher Thursday as Wall Street sought to break a dismal six-day losing streak.
General Motors' shares hit their lowest level in almost 60 years as the U.S. automaker said its year-to-date sales in Europe slid almost 2 percent.
Stocks opened aggressively higher Thursday as Wall Street sought to break a dismal six-day losing streak.
If you are GM CEO Rick Wagoner, what do you do? The man in the top job at the struggling automaker is pulling every move possible to keep his company from collapsing. And by all accounts, he's done a hell of a job.
Stocks closed lower after swinging wildly all day as a coordinated global rate cut failed to reassure investors.
Want a sign of just how screwed up this economy has become? Auto repo companies are finding business has slowed down because banks and lenders are reluctant to take back cars and trucks people can no longer pay for.
U.S. stock index futures turned positive after coordinated action to cut rates across the globe to fight the danger of the world economy being hit by a depression.
The new fed facility to buy commercial paper is a HUGE move in increasing liquidity in the marketplace. Also important: they are buying 3-month paper, a longer term than most commercial paper, so less rollover pressure.
These are gut check times for Ford & GM investors. Shares of the two automakers slid to lows not seen since the early 80's for Ford and mid 50's for GM. As one Wall Street veteran told me, "These are dire times for Ford & GM."
Could this finally be the big breakthrough diesel fans have been clamoring for? Could this be the start of Americans getting over their lack of interest for diesel cars? Audi certainly hopes so. Audi is on a cross country publicity push spreading the word about clean diesel.
Stocks declined Wednesday as disappointing economic data added to the weight on investors shoulders over the strained credit market and haggling on Capitol Hill.
This is for all of you who e-mail and call me "Toyota Phil" and for those of you who think I favor the Japanese automaker and never write anything critical.
Over the last two weeks I've done several reports on TV and written in this blog about tighter credit hurting auto sales. For the industry, September sales dropped 27% and nearly everyone in the industry admits that a big reason for the plunge has been the deteriorating credit markets.
Stocks ended lower Wednesday amid concerns about strained credit markets and the economic slowdown. Banks rallied as investors were encouraged by progress on bailout talks on Capitol Hill. GE got a vote of confidence -- to the tune of $3 billion -- from Warren Buffett.
GE's announcement of a $15 billion capital raise ($12 b in common, $3 b in preferred to Warren Buffett with a 10 percent dividend) is difficult news for shareholders, but everyone agrees that two things need to be done:


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Youth Sports
Tryouts and announcementsThu., Oct. 8 | 09:14 AM - Check out these opportunities among sports teams, leagues and camps.
Photos: Central Loudoun Youth Football League Fun FestWed., Aug. 26 | 04:00 PM - Central Loudoun Youth Football League held its annual Fun Fest on Aug. 22 at Freedom Park in Leesburg. Times-Mirror photographer Rick Wasser was on hand to catch the action on and off the field.
D1SA Spartan Elite swish championship at national eventTue., Aug. 25 | 04:03 PM - D1 Sports & Athletics 15U Spartan Elite Boys won the Gold Elite Championship among a pool of 158 teams at the Bigfoot Hoops Las Vegas Classic on July 26 in Nevada. The Loudoun-based Spartan Elite shot past Drive Bounce Elite (Canada) 80-66 in the championship game to claim the title in the five-day tournament.
LGSL Freedom sit atop softball diamondMon., Aug. 24 | 01:23 PM - Leesburg Girls Softball League's 14U Freedom team placed first at the USSSA Hickory Sting Fest, contested Aug. 2 in Bel Air, Md. The Freedom defeated Delaware's Midway All-Stars 8-6 in the championship game.
A historic run for CLLL National All-StarsSun., Aug. 23 | 10:08 AM - For the first time in the 51-year history of Central Loudoun Little League, an All-Star team from the Majors division advanced to the state championship game. Already district champions, Central Loudoun National won its first five games by a combined score of 113-33 to reach the state final before falling to the Mechanicsville All-Stars in the championship game.
Ready for next ride: Stone Bridge alum earns spot on Auburn equestrian teamWed., Aug. 19 | 08:00 AM - It wasn't a particularly great day for Casey Schmitz. Earlier in the day, the recent Stone Bridge High School graduate was involved in an auto accident that left her unharmed, but the door of the car damaged. Little did Schmitz know that 30 minutes later, she would receive a phone call that would make the day significantly better.
Baseliners place fifth at PONY NationalsMon., Aug. 17 | 11:40 AM - The Baseliners finished fifth out of 45 teams in the 16U age division at the PONY Nationals East Zone softball tournament. The team features players from Potomac Falls, Dominion, Tuscarora, Broad Run, Stone Bridge, Patriot, Westfield and Holton-Arms high schools.
Newly formed Loudoun Legacy Track Club starts fastSat., Aug. 15 | 06:50 PM - The Loudoun Legacy Track and Field club hit the ground running in its first season this year. Established in March, Loudoun Legacy qualified 14 athletes through the Virginia State meet for the 2015 AAU Junior Olympics. Legacy head coach Chris Wanza notes "our goal for this season and this special group of athletes was to commit to individual successes and cultivate an environment of highly competitive athletes in sprints, distance, field events and life."
Loudoun South All-Stars excel among elite competitionTue., Aug. 11 | 01:42 PM - Loudoun South Little League National 9/10 All-Star team recently completed an impressive postseason run with a runner-up finish in the Tournament of State Champions in Greenville, N.C.
Tryouts and announcementsTue., Aug. 11 | 10:12 AM - Check out these opportunities among sports teams and camps.
D1SA Spartan Elite swish championship at national event Next level: Bailey to become first Husky to play NCAA Division I hoops More Basketball
Loudoun's Varsity Football Schedule—Week 7 Tuscarora's Burnett receives Redskins' coaching honor More Football
Group of Wolverines ready to excel at next level Panthers' Griffith to take mat for Maryland More Wrestling
All-stars wrap up ODSL season on high note Photos added: Swimmers strike gold at state meets More Swimming
APEX gymnasts participate in Relay for Life APEX qualifies 18 gymnasts for regionals More Gymnastics
Soccer: Golan signs with Brighton & Hove Albion F.C. Tiernan named to MAC Hermann Award watch list More Soccer
Play ball: Purcellville is new home for Valley Baseball League team A historic run for CLLL National All-Stars More Baseball
LGSL Freedom sit atop softball diamond Loudoun Special Olympics softball goes national More Softball
Loudoun's Varsity Sports Rewind-Oct. 7 events Loudoun Valley wins 4A West Region golf title More Golf
Vikings, Huskies motor to LCPS cross-country team titles LCPS Cross-Country Championship results More Cross Country
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Various pathways impinge on the actin-myosin pathway to facilitate cell migration and invasion including members of the Rho family of small GTPases and MAPK. However, the signaling components that are considered important for these processes vary substantially within the literature with certain pathways being favored. These distinctions in signaling pathways utilized are often attributed to differences in cell type or physiological conditions; however, these attributes have not been systematically assessed.
To address this question, we analyzed the migration and invasion of MDA-MB-231 breast carcinoma cell line in response to various stimuli including lysophosphatidic acid (LPA), hepatocyte growth factor (HGF) and epidermal growth factor (EGF) and determined the involvement of select signaling pathways that impact myosin light chain phosphorylation.
LPA, a potent stimulator of the Rho-ROCK pathway, surprisingly did not require the Rho-ROCK pathway to stimulate migration but instead utilized Rac and MAPK. In contrast, LPA-stimulated invasion required Rho, Rac, and MAPK. Of these three major pathways, EGF-stimulated MDA-MB-231 migration and invasion required Rho; however, Rac was essential only for invasion and MAPK was dispensable for migration. HGF signaling, interestingly, utilized the same pathways for migration and invasion, requiring Rho but not Rac signaling. Notably, the dependency of HGF-stimulated migration and invasion as well as EGF-stimulated invasion on MAPK was subject to the inhibitors used. As expected, myosin light chain kinase (MLCK), a convergence point for MAPK and Rho family GTPase signaling, was required for all six conditions.
These observations suggest that, while multiple signaling pathways contribute to cancer cell motility, not all pathways operate under all conditions. Thus, our study highlights the plasticity of cancer cells to adapt to multiple migratory cues.
Keywords:Rho GTPases; RhoA; RhoC; ROCK; Rac1; MAPK; MLCK; Breast carcinoma; Chemotaxis; Invasion
The motility of a cell is determined by its ability to coordinately regulate a dynamic organization of the cytoskeletal architecture to create polarity, rigidity and contractile forces necessary for movement. At the core of a cell's ability to migrate is the interaction between actin and non-muscle myosin II, whose activation states cycle in a systematically regulated manner (reviewed in [1,2]). Actin polymerizes and depolymerizes on a continuous basis and typically forms a meshwork with protrusions at the leading edge of the cell, pushing the plasma membrane forward. At the rear of the cell, long, unbranched actin-myosin filaments mediate contraction that pulls the rear of the cell forward and retraction of the trailing edge to facilitate cell polarization that promotes directed cell migration. During these coordinated processes, myosin II and its regulatory myosin light chain (MLC) undergo cycles of phosphorylation and dephosphorylation; these changes affect the conformational state of myosin, allow it to interact with actin, and move actin fibers relative to each other. In concert with the directed polymerization of actin, the motor activity of myosin results in cell propulsion.
Numerous well-studied signal transduction pathways converge to control the activity of actin and myosin II (Figure 1) and, hence, cytoskeletal architecture and movement. Among the most influential are the Rho GTPases, Rho and Rac (reviewed in [3,4]) but also include the MEK/Erk mitogen-activated protein kinase (MAPK) pathway [5]. Rho promotes both actin polymerization and myosin II contractility. Rho-induced actin polymerization is mediated by the Rho effector mammalian homologue of diaphanous (mDia) [6], a member of the formin family, while myosin II activity is promoted through Rho-associated coiled coil kinase (ROCK) control of myosin by inhibiting myosin phosphatase [7,8]. Preventing myosin phosphatase from dephosphorylating MLC prolongs MLC and thus myosin activity. Rac, on the other hand, can inhibit myosin light chain kinase (MLCK) to reduce myosin II activity while simultaneously promoting actin polymerization; both of these functions can be attributed to p21-activated kinases (PAK) [9,10]. Recently, PAK was shown to be central to the flow of actin in the lamella and the localization of myosin II at the leading edge to facilitate cell migration [11]. The Rho and Rac pathways converge on LIM-kinase (LIMK) downstream of ROCK [12] and PAK [13], respectively, which leads to the phosphorylation and inactivation of the F-actin depolymerizing protein cofilin, thereby stabilizing actin filaments [14]. MAPK has been shown to limit activation of LIMK, subsequent phosphorylation of cofilin, and migration of primary human T cells in a three-dimensional (3D) environment [15]. The MAPK cascade also regulates myosin II activity by phosphorylating and enhancing the activity of MLCK [16]. Therefore, control of actomyosin dynamics results from cooperation of multiple signaling pathways that have independent effects on both actin and myosin which must be balanced appropriately to allow cell movement.
Figure 1. Signaling pathways important for the control of actin dynamics and myosin activity. Key signaling pathways that converge on actin and myosin to control cell motility are depicted and include Rho, Rac, MLCK, MAPK/MEK. The inhibitors for each of these pathways used in this study are indicated in italics.
The pathways presented above, however, have been pieced together from data obtained using a wide variety of cell types subjected to a myriad of conditions and all have been implicated in one way or another with metastasis of carcinoma cells. However, the signaling components that are considered important for these processes vary substantially in the literature with certain pathways being favored. One could effectively argue that distinctions in the signaling pathways utilized are a result of variations in cell types or handling by investigators. However, they might also arise from differences in physiological conditions, which have not been systematically evaluated.
Here, we dissect the pathways used by highly metastatic breast carcinoma cell line MDA-MB-231, which are able to migrate and invade toward LPA, HGF and EGF [17-19]. We find that partially overlapping subsets of signaling pathways are employed by these cells depending on the environmental context. This observation has important consequences for cancer therapy and rational drug design.
Cells treatments and reagents
The metastatic MDA-MB-231 breast carcinoma cell line was cultured in low glucose DMEM (Invitrogen), 10% Fetalplex (Gemini Bio-Products, West Sacramento CA), 1% penicillin-streptomycin, 1% L-glutamine (Invitrogen) to 70% confluence. For experiments, cells were trypsinized and rinsed with DMEM plus 250 μg/ml fatty acid-free BSA (Gemini Bio-Products cat# 700-107P) (DMEM/BSA). For pharmacological inhibitor studies, cells were treated in suspension for 30 min at 37°C with the following inhibitors: 10 μM ML-7 (MLCK inhibitor, Calbiochem cat# 475880), 10 μM U0126 (MEK1/2 inhibitor, Calbiochem cat# 662005), 50 μM PD98059 (MEK1/2 inhibitor, Calbiochem cat# 513000), 10 μM Y-27632 (ROCK inhibitor Cayman Chemical cat# 10005583), or 100 μM NSC23766 (Rac inhibitor, Tocris Bioscience cat#2161). To inhibit Rho directly with C3 exotransferase, cells (3×106) were electroporated in serum-free DMEM with 5 μg glutathione-S-transferase (GST; control) or GST-C3 purified bacterial-expressed protein as done previously [20,21] just prior to use.
Cell migration and invasion assays
For migration assays, transwell chambers were coated with 15 μg/ml collagen I (BD Biosciences cat# 354249) as previously described [18]. For invasion assays, transwells were top-coated with 5 μg Matrigel (BD Biosciences cat# 354234), dried overnight, and rehydrated in 50 μl DMEM for 30 min at 37°C prior to assay; bottom wells were coated with 15 μg/ml collagen I. Chemotaxis or chemoinvasion was stimulated by adding to the bottom chamber 100 nM oleoyl-L-alpha-lysophosphatidic acid sodium salt (LPA, Sigma cat# L-7269), 50 ng/ml HGF (PeproTech cat# 100–39) or 5 ng/ml EGF (PeproTech cat# AF-100-15) diluted in DMEM/BSA, in the absence or presence of inhibitor. Cells (5×104) were allowed to migrate or invade at 37°C for 3 hours in the presence of inhibitors, as noted. Data are presented as the mean cell number migrated per mm2 from triplicate wells and plotted with the standard deviation. Statistical significance was calculated using a two-tailed unpaired t-test assuming equal variances. For all experiments, data presented are representative of a minimum of three independent assays. In some cases, controls (cells not treated with chemoattractant or inhibitor) are reported more than once in a figure if multiple conditions for the same experiment were represented for consistency of the presentation.
MAPK, Rho and Rac activity assays
Cells were plated onto collagen-coated dishes for 3 hrs. Cells were then treated with 10 μM U0126 or 50 μM PD98059 before stimulation with 100 nM LPA, 50 ng/ml HGF or 5 ng/ml EGF. The activity of the MAPK pathway was determined by immunoblot analysis of p44/p42 MAPK (Erk 1/Erk2) for total Erk (3A7, mouse Ab, Cell Signaling) and the phosphorylated form (197G2, rabbit Ab, Cell Signaling).
Rho assays were assessed using a Rhotekin RBD affinity assay as described previously [18,21,22]. For Rac assays, cells were serum starved overnight, treated with or without 100 μM NSC23766 compound for 3 hrs and then treated with chemoattractant as noted for 5 minutes prior to harvesting. Cell lysates were then assessed for Rac activity using a Pak1 Rac Binding Domain assay, as we have performed previously [21,23].
MLCK is involved in migration and invasion of MDA-MB-231 cells
For these studies, we utilized chemical inhibitors of select signaling molecules (Figure 1) and performed short-term (3 hrs) migration and invasion assays. This approach permits assessment of the immediate downstream impact of select signaling pathways without substantially altering transcription or proliferation that could affect our interpretation. Myosin activation by phosphorylation of the MLC is essential for its interaction with actin and actin-myosin contractility. MLCK is the primary kinase that controls MLC phosphorylation. To determine if MLCK plays a central role in the migration and invasion of MDA-MB-231 cells, we performed transwell migration assays and Matrigel invasion assays using LPA, HGF, or EGF as chemoattractants in the presence of the MLCK inhibitor ML-7. As shown in Figure 2, there was a significant decrease in the number of ML-7 treated cells that migrated or invaded compared to untreated cells, including both basal and growth factor stimulated conditions. The effect was stronger on invasion than migration with a greater than 50% reduction in number of cells that were able to invade in the presence of inhibitor. Therefore, these data demonstrate that MLCK is a key mediator of both migration and invasion in response to a variety of chemotactic agents for MDA-MB-231 cells.
Figure 2. MLCK is required for cell migration and invasion in response to LPA, HGF and EGF. MDA-MB-231 cells were allowed to migrate across a collagen-coated transwell (A) or invade through Matrigel (B) toward LPA, HGF or EGF for 3 hours in the presence or absence of the MLCK inhibitor, ML-7 (inhib.), as noted. The numbers of cells migrated or invaded per mm2 were graphed with their standard deviations for triplicate wells within a single experiment. For simplicity of presentation, statistically significant differences between stimulated and stimulated plus inhibitor-treated cell conditions only were determined using a t-test (*p < 0.02). Data are representative of a minimum of three independent assays for each condition.
MAPK pathway in migration and invasion of MDA-MB-231 cells
MAPK directly phosphorylates and activates MLCK, thus facilitating the activation of myosin II in vitro[16]. To determine if MAPK influences chemotactic migration or invasion of MDA-MB-231 cells, we used two inhibitors of MEK1 and MEK2, U0126 and PD98059, in migration and invasion assays. We found inhibitor- and chemoattractant–specific effects for both migration and invasion. Both inhibitors significantly reduced the number of cells that migrated or invaded toward LPA (Figure 3). When HGF was used to stimulate cells, U0126 did not affect either migration or invasion while the PD98059 inhibitor reduced both; however, there was a trend toward inhibition with the U0126. Neither inhibitor reduced migration toward EGF while PD98059 was effective in reducing invasion of these cells. The concentration of both of the inhibitors used here were equally effective at reducing ERK phosphorylation, which reflects the MEK1/2 activity, in these cells as analyzed by immunoblot (Additional file 1: Figure S1). Further experiments were performed using 50 nM PD901, a more potent and specific MEK inhibitor. These experiments gave the same results as the PD98059 compound for cell migration and for U0126 for invasion assays (data not shown). These data suggest that the MAPK pathway acts to finely tune migration and invasion responses to different stimuli, but is not required under all conditions.
Figure 3. MAPK pathway has distinct effects on migration and invasion in response to LPA, HGF and EGF. MDA-MB-231 cells were treated with one of two MEK1/2 inhibitors, U0126 or PD98059, and then assessed for either migration (A) or invasion (B) toward the indicated chemoattractant. Cells migrated or invaded were then quantified, and results graphed as described in Figure 2. Data are representative of a minimum of three independent assays for each condition. Statistically significant differences between stimulated and stimulated plus inhibitor-treated cell conditions only were determined using a t-test (*p < 0.02).
Additional file 1: Figure S1. The Mek inhibitors U0126 and PD98059. MDA-MB-231 cells were plated onto collagen coated dishes for 3 hrs and then either left untreated or treated with 10 μM U0126 or 50 μM PD98059 30 mins, as noted. Cells were then stimulated with 100 nM LPA, 50 ng/ml HGF, or 5 ng/ml EGF for 5 mins before lysis. Cell lysates were then analyzed for phospho p44/p42 MAPK (Erk 1/2; upper bands) and total p44/p42 MAPK by immunoblot analysis.
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Rac and Rho GTPase pathways in migration and invasion of MDA-MB-231 cells
Rac and Rho are both major mediators of cell migration and invasion, and are thought to have distinct functions in the migration and invasion of carcinoma cells [3,4]. Here, we utilized electroporation of C3 protein (which ribosylates and inhibits RhoA, B and C; effectiveness shown in Additional file 2: Figure S2) and the ROCK inhibitor Y27632 to assess the Rho-ROCK pathway; Rac activation was inhibited by NSC23766 [24]. We find that MDA-MB-231 cells had opposing requirements for the Rho and Rac pathways for cell migration. LPA–stimulated cells used Rac but not Rho for migration (Figure 4). In fact, inhibition of Rho with C3 exotransferase and inhibition of Rho's downstream effector ROCK with Y-27632 tended to increase migration (Figure 4A) suggesting that the Rho pathway normally serves to limit this process in these cells. In accordance with this concept, inhibition of the Rho-ROCK pathway tended to increase membrane ruffling and lamellae formation in response to LPA (data not shown). Notably, Rho/Rock pathway is essential to invasion in all conditions (Figure 4B and C) suggesting that Rho is important mediator of tumor cell invasion. HGF and EGF, in contrast, employ Rho but not Rac for migration. During invasion, however, both Rho and Rac pathways were necessary for EGF, while HGF required only Rho. These data are summarized in Tables 1 and 2. Notably, the Rac inhibitor, NSC23766 effectively blocked Rac activation in response to all three chemoattractants (Additional file 3: Figure S3). Therefore, these observations demonstrate that the chemoattractant and migration/invasion condition dictate which GTPases are utilized.
Additional file 2: Figure S2. Confirmation of C3 treatment on RhoA inhibition. MDA-MB-231 cells were electroporated with bacterially expressed GST or GST-C3, plated on collagen coated plates for 2 hrs and then stimulated with 100 nM LPA for 5 mins. Cell lysates were then analyzed for RhoA activity using a GST-Rhotekin RBD binding assay (upper bands; active) and total RhoA (10% total; bottom bands) by immunoblot analysis.
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Figure 4. Rac and Rho GTPase inhibitors have differential effects on migration and invasion in response to LPA, HGF and EGF. MDA-MB-231 cells were treated with inhibitors of the Rho pathway using C3 or Y-27632 (A, B, C), or the Rac pathway with NSC23766 (D, E) as described in the Methods section, and assayed for their ability to migrate (A, D) or invade (B, C, E) toward various growth factors as described in Figure 2. Data are representative of a minimum of three independent assays for each condition. Statistically significant differences between stimulated and stimulated plus inhibitor-treated cell conditions only were determined using a t-test (*p < 0.02).
Table 1. Summary of pathways used for growth factor-stimulated migration
Table 2. Summary of pathways used for growth factor-stimulated invasion
Additional file 3: Figure S3. NSC23766 effectively inhibits Rac in response to LPA, HGF or EGF stimulation. MDA-MB-231 cells were serum starved overnight and then treated with 100 μM of the Rac inhibitor NSC23766 for 3 hours, as noted. Cell were then stimulated with BSA (control), 100 nM LPA, 50 ng/ml HGF, or 5 ng/ml EGF for 5 mins. before lysis. Cell lysates were then analyzed for Rac activity using a GST-Pak RBD binding assay (upper bands; active) and total Rac (10% total; bottom bands) by immunoblot analysis. Numbers below the blots represent fold activity compared to untreated control cells.
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Discussion and conclusions
The metastatic process requires cells to leave their native site in response to environmental cues and move to a different location where they proliferate to form new tumors. The cellular mechanisms used in this aberrant migratory response are fundamentally similar to those used during normal developmental migration and boil down to the ability of the cell to organize its actin cytoskeleton in a polarized manner and to activate the myosin motor function to move that cytoskeleton in the direction of polarization [25]. These basic functions can be mediated by a variety of apparently redundant signaling pathways that converge on the polymerization of actin and the activation state of the myosin II. However, we have shown here that in a single cell type context specific motility can signal through different subsets of pathways, as summarized in Tables 1 and 2, despite the fact that they all converge on the activity of a relatively small number of proteins (see Figure 1). Not surprisingly, MLCK is an essential player in both migration and invasion in response to all of the stimuli tested here, as it is central to the control of myosin II phosphorylation and subsequent activation. Beyond that, while capable of employing several pathways to drive actomyosin-mediated movement, these cells utilize specific subsets of pathways to achieve motility in different environments and toward distinct growth factors. These observations demonstrate a surprising versatility and plasticity in carcinoma migration and invasion.
In development and leukocyte navigation, it is well accepted that different chemoattractants will stimulate specific pathways such that patterning and precise navigation can be achieved [26]. Certainly if all cells responded to a stimulus in a similar manner, it would not be conducive to precise navigation or organismal development. However, the concept that tumor cells might utilize multiple growth factor signaling pathways for dissemination in different ways is not generally discussed. Rather the responses to specific growth factors or cocktails of factors (such as fibroblast conditioned medium) are reported in such a way that these conditions likely apply to all cancer cells, or at least a particular subtype of cancer. Furthermore, modes of migration can vary substantially among tumor cells [25,27]. Considerable attention has been given to the role of the extracellular environment, its matrix composition, and matrix tension in mediating the differences in cancer cell invasion. However, how select signaling events from distinct growth factors and other chemoattractants might facilitate these differences has received noticeably less scrutiny. One exception is the roles of Rac and Rho pathways. Rac is generally attributed to the formation of lamellae, which are used to propel cells forward. These large fan-shaped lamellae are advantageous for two-dimensional migration but may in fact be inhibitory for movement through a 3D environment where space is at a premium, especially when matrix metalloprotease activity is low [27]. In the 3D condition, a smaller pseudopodial-like protrusion might be more advantageous. Importantly, RhoA has also been implicated in membrane ruffling and lamellae formation [6,22,28] where it can play a major role in 3D invasion [7,17,29,30]. Notably, the utilization of RhoA in the formation of lamellae can be in cooperation with [21] or independent from Rac1 [22]. The types of protrusions formed by Rac, Rho or the cooperation of Rac and Rho are expected to be functionally redundant, but could in fact be fundamentally different in structure or their function altered by the 3D environment. Certainly more research is needed in this regard with careful attention to the fact that the role of these GTPases in invasion may be multifaceted.
We further find that the MAPK pathway is an important mediator of LPA chemotaxis and invasion, but is dispensable for EGF-mediated migration. On the other hand, the MAPK pathway plays a less definitive role in the migration and invasion of these cells toward HGF. The inconsistences observed in the migration and invasion behavior of MDA-MB-231 cells in response to different inhibitors of MEK, specifically in invasion toward EGF and migration and invasion toward HGF, raises some question as to how the MAPK pathway contributes to these events. While PD98059 and U0126 are MEK1/2 inhibitors, these two inhibitors work by distinct mechanisms. Furthermore, U0126 inhibits both MEK1 and MEK2 while PD98059 has a more potent effect on MEK1 than on MEK2 [31,32]. The discrepancy in the results using the two inhibitors could indicate differences in utilization of MEK1 versus MEK2, or that simply off target effects of the inhibitors alter the interpretation. Previous studies have noted similar differences between the two compounds where PD98059 inhibits preferentially [33], thus suggesting MEK2 might counteract the function of MEK1. Certainly more definitive experiments will be required to fully elucidate the role of the MAPK pathway, including substrate specificity and individual contributions of each kinase.
This study was not meant to be a comprehensive analysis of signaling pathways in response to the conditions assessed here. But rather we sought to demonstrate that migration of carcinoma cells, even a single cell line, is more versatile than previously recognized. Here, we chose to use pathway specific inhibitors and short term assays rather than genetic analyses to distinguish the immediate signaling effects of these pathways from the effects on transcription or proliferation that might alter our interpretation of the results. Accordingly, our results do not conclude, as an example, that Pak is unimportant to select migration or invasion conditions where the Rac inhibitor shows no effect. Pak could be stimulated by cdc42 or Rac3, which are not reported targets of the Rac inhibitor [24]. Notably, transcriptomes vary from cell to cell. And with these variations come differences in how pathways are activated, spatially localized, and utilized during specific signaling contexts. Since we use a single cell line for this study, we find that a cell can use specific combinations of pathways to achieve migration or invasion in response to different stimuli that goes beyond cell-to-cell variations in transcriptional profiles. The use of some but not all of the possible pathways to control actin reorganization has been seen in other cell types in response to particular environments. Clone A colon carcinoma cells use MAPK signaling (unpublished observation) and Rho, but not Rac, to drive migration on laminin [22]. In contrast, MDA-MB-435 cells use Rac [23] and Rho [21] but not MAPK (unpublished observation) to migrate toward LPA, which differs from the MDA-MB-231 cells.
To determine which signaling pathways govern the motility and invasion of a particular cell type, the physiological conditions including matrix composition, matrix compliance, and growth factors utilized to stimulate these processes need to be considered. This concept becomes particularly important when screening genes and compounds for their impact on tumor invasion. As an example, fetal bovine serum (FBS) is a common stimulant for migration and invasion assays. The major pro-migratory growth factor in FBS is LPA, which is found in concentrations as high as 20 μM [34]. We have found previously that these high levels of LPA (1 μM and higher) can actually inhibit the migration of breast carcinoma cells [18]. In this study, we find that LPA does not require Rho signaling for chemotaxis, but does for invasion. Therefore, the use of FBS in migration or invasion would have low potential to yield important insight into the breast cancer invasion process. Furthermore, if screens utilize FBS in migration assays to represent the tumor invasion process, important compounds might be discarded in the in vitro screening process, thus eliminating potentially effective drugs in lieu of ones that ultimately may be ineffective in vivo. Consequently, our study helps to highlight the importance of physiological context when assessing pertinent signal transduction pathways, which has notable implications for the effective development of cancer therapeutics and rational drug design.
EGF: Epidermal growth factor; FBS: Fetal bovine serum; GST: Glutathione-S-transferase; HGF: Hepatocyte growth factor; LPA: Lysophosphatitic acid; mDia: Mammalian homologue of diaphanous; MAPK: Mitogen-activated protein kinase; MLC: Myosin light chain; MLCK: Myosin light chain kinase; PAK: P21-activated kinases; ROCK: Rho-associated coiled coil kinase; 3D: Three-dimensional.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
SMWH and KLO designed and wrote up the current study. MC was involved in the study design, validation of Rho and Rac inhibition, and editing the manuscript. TK and SMWH performed all experiments and analyzed all data. All authors read and approved the final manuscript.
This work was supported by the National Institutes of Health Grant R01 CA109136.
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Pre-publication history
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The Fresca Bellezza 59-inch Modern Bathroom Vanity provides beauty and functionality to any bathroom setting. It features a contemporary design with modern fixtures and smooth-closing doors and drawers. A middle shelving unit offers open-air storage while lower cabinet offers additional storage. Available in a rich espresso finish. Faucets included and also available with finish options.About Fresca BathFresca Bath believes that the bathroom is the most important room in the home. This is why they have crea


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Iceland's Grand Canyon by johnfreeman (2274)
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Hi john! Beautiful dreamy photo. The different levels that exist in this photo are wonderful. The rocks, the water, the cloudy sky. Impressive photo!
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by Kathy Baldock on 8:14 am in 5. RESOURCES, 6. STRAIGHT ALLIES, TOPICS IN BLOG
"What does the Bible say about loving, same-sex relationships?" Nothing. Not a thing. And in that absence of Biblical direction of support for or condemnation of these relationships, Christians need to follow the general principles of the Bible: love, justice and kindness. This was the point Matthew Vines wanted to emphasize at his recent presentation at […]
"Traditional Family Values" | Which Traditions? Whose Families? What Values?
by Kathy Baldock on 3:47 pm in 6. STRAIGHT ALLIES, 8. MARRIAGE EQUALITY
Traditional family values is a packed cliché. The (ab)use of the term "family values" began in 1976 when it was introduced into the Republican Platform. It became a rally cry at the 1992 GOP Convention when Vice President Dan Quayle bemoaned the collapse of the family because the then-popular show, "Murphy Brown," portrayed the main character […]
Edie Windsor vs The People of the United States in DOMA | Edie (4), US (0)
by Kathy Baldock on 2:20 pm in TOPICS IN BLOG
UPDATE: On Wednesday, March 27th, the Supreme Court will hear the plaintiff, Edie Windsor, in her case to struck down DOMA. When I spoke with Edie in January, 2012, she thought it might be 5 to 6 years before her case got to the Supreme Court. Now, just 14 months later, her case will be […]
President Obama Seeks to Include as a Minority (21%) of Registered NC Chooses to Exclude
by Kathy Baldock on 4:57 pm in 6. STRAIGHT ALLIES, TOPICS IN BLOG
On May 9, 2012, President Obama became the first sitting United States President to support same sex marriage. There are at least 8 million adult gay Americans. Although they are still a minority, this is equivalent to the entire population of the state of North Carolina who on May 8th voted by in majority at the […]
The 61% in North Carolina Miss the Message of Christ and Civil Rights on Amendment 1 Voting
by Kathy Baldock on 11:49 am in 6. STRAIGHT ALLIES
Amendment 1 passed in the State of North Carolina. The definition of marriage as one man and one woman is now codified in that state's constitution. Discrimination is now codified in that state's constitution. Christians did this. Christians who believe they have the right to deny equality to minority groups; Christians who believe they have […]
Pastor Sean Harris Continues the "Apology" on the Day of Prayer
by Kathy Baldock on 8:30 pm in 8. MARRIAGE EQUALITY, 9. THE LIES & LIARS
Pastor Sean does not understand apology. He just does not get it. I taught my children at a very young age how to apologize appropriately . It requires honesty about your actions and the humility to accept responsibility. Pastor Sean believes he offered such words after his intensely offensive rant about gay people and gay kids […]
The Bible and Homosexuality | A Biblical Presentation with Matthew Vines
by Kathy Baldock on 7:45 am in 1. VERSES, 2. RESOURCES FOR PARENTS, 3. LGBT YOUTH, 5. RESOURCES, 8. MARRIAGE EQUALITY
Matthew Vines, 22, of Wichita, KS attended a conservative Presbyterian church growing up. He excelled in school and went to Harvard in 2008, and in that less restrictive social and academic environment, Matthew came to understand and accept that he was gay. In conservative denominations, there are only a few options for gay, lesbian, bisexual […]
Ten Things I've Learned About Gay People in Ten Years | A Christian Perspective
by Kathy Baldock on 4:15 pm in 2. RESOURCES FOR PARENTS, 3. LGBT YOUTH, 4. SEXUAL ORIENTATION & GENDER IDENTITY, 6. STRAIGHT ALLIES, TOPICS IN BLOG
In 2001, if you had asked me, "Kathy, can you be gay and Christian?" I would have hedged a bit and fallen on the side of "No". I did not have any close relationships with gay people nor had I ever studied the issue in the Bible. I did not even know one gay Christian, […]
"Loosen the chains of injustice, untie the cords of the yoke, set the oppressed free and break every yoke. Then you will be called Repairer of the Breach." Isaiah 58
The mission of Canyonwalker Connections is to repair the division that exists between social and Christian conservative and the lesbian, gay, bisexual, and transgender (LGBT) community through education, training, and dialogue in both secular and religious environments.
Canyonwalker Connections is a 501c3 tax deductible organization.
"Walking the Bridgeless Canyon" book (2014)
Contact Me Via Post
Canyonwalker Connections
PO Box 19017
Reno, Nevada 89511
Kathy at CanyonwalkerConnections dot com
Subscribe to Canyonwalker Newsletter
- Alan Chambers' My Exodus — A Book Review October 6, 2015
- Untangling the Mess Presentation in Sacramento, October 17th September 28, 2015
- Ron Belgau, Celibate Gay Catholic, to Present at World Meeting of Families During Papal Visit September 16, 2015
- The Davis Case is About Defying the Rule of Law NOT About Religious Liberty September 3, 2015
- The Creation of Another Christian Martyr — County Clerk Kim Davis September 1, 2015
- The Tipping Point of Christian Love at Charlotte Pride August 26, 2015
- Ray Comfort's Audacity — Nothing Says — I Have No Respect for You — Like Giving a Copy to a Gay Person August 21, 2015
- Michael Brown's "Outlasting the Gay Revolution" Continues His Non-Academic Anti-Gay Rantings August 20, 2015
- Kevin DeYoung's Book — Another Author Lacking Academic Integrity But Telling Us What God "Really Says" Anyway August 2, 2015
- Sisters of Thunder Podcasts with Kathy and Yvette July 30, 2015


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Dec 23, 2014 Bob Buskirk Gaming, Input Devices, Reviews 0
Cougar is a company that we have known for mainly power supplies and cases. With the popularity of gaming and eSports it seems they want it get it on it and they have started producing gaming peripherals. From the looks of it they are taking it very seriously with some pretty impressive keyboards and mice. Today we will be taking a look at their new flagship gaming keyboard the 700K. This keyboard has a ton of great features some of them include an aluminum chassis, Cherry MX mechanical keys, 6 programmable G-keys, three different profiles and some pretty sweet backlighting. Will this keyboard get you thinking about Cougar when it comes to gaming peripherals? Read on as we find out.
Dec 11, 2014 Bob Buskirk All News, Gaming News, Press Releases 0
COUGAR, a leading player in the computer gaming hardware market announces today the release of a breakthrough product: the COUGAR 500K Gaming Keyboard. The 500K is the most recent addition to COUGAR's series of gaming peripherals.
Dec 03, 2014 ThinkComputers News All News, Gaming News, Hardware News 0
COUGAR announces today the release of a breakthrough product: the COUGAR 600K Gaming Keyboard. Sharing design with the award-winning COUGAR 700K that already conquered the desktops of thousands of players, the 600K offers a radically different approach with the same quality. While the COUGAR 700K satisfied the needs of those gamers who crave for extended functionality and full customization, the 600K caters for the purists, those people for which the most important is that nothing gets in the way.
Nov 05, 2014 Bob Buskirk All News, Gaming News 0
Tesoro Technology USA Inc., a manufacturer of high-tech gaming products, today unveils the Tesoro Excalibur RGB LED backlit mechanical keyboard with a 16.8 million color palette. Named after the legendary sword of King Arthur, Tesoro Excalibur RGB lets gamers choose virtually any backlight color, 16.8 million.
Oct 29, 2014 Bob Buskirk All News, Gaming News, Hardware News, Press Releases 0
Cooler master has just announced a brand new gaming combo that they are calling Octane. Following the overwhelming success of the Devastator gaming mouse and keyboard combo, Cooler Master is introducing a new package for those looking to get their game on their way.
Oct 07, 2014 Bob Buskirk All News, Gaming News, Hardware News 0
QPAD has just announced a brand new gaming keyboard, the MK-70. The MK-70 is more or less an upgraded version of QPAD's MK-50 that features Cherry MX key switches and blue back-lighting. QPAD is looking to give gamers the best bang for their buch with the MK-70.
Sep 23, 2014 Bob Buskirk All News, Hardware News 0
Cooler Master, a leading developer of PC and electronic components and accessories, today announces the NovaTouch TKL, a hybrid capacitive keyboard designed for high speed, extreme accuracy, and total comfort in the ultimate typing experience.
Sep 17, 2014 Bob Buskirk All News, Gaming News, Hardware News 0
Logitech today announced the Logitech® G910 Orion Spark RGB Mechanical Keyboard. The keyboard features Logitech's exclusive new Romer-G™ mechanical switches, offering 25 percent faster actuation than any other mechanical switch, improved durability and intelligent Illumination.
Sep 17, 2014 Bob Buskirk All News, Gaming News, Hardware News 0
COUGAR, leading eSports and computer peripherals brand has launched a cutting-edge aluminum keyboard which has already managed to win the 2014 iF International Design Award. COUGAR has invested two years of intense work in designing what is arguably the best gaming keyboard of the market, the 700K.
Aug 07, 2014 Bob Buskirk All News, Gaming News, Hardware News, Mobile News, Press Releases 0
Mad Catz announced today the shipping of the S.T.R.I.K.E. M Wireless Keyboard. Designed around a compact tablet sized footprint, the S.T.R.I.K.E. M is designed for home or mobile use and can pair with up to four devices simultaneously.
Oct 09, 2015 0
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text:
- ITV Report
- ITV Report
Teenager dies during police chase
- ITV Report
Meet Hampshire's new Chief Constable
Live updates
Baby born after high speed motorway police chase
A Hampshire woman gave birth of the side of the motorway after the police stopped her 100mph dad as he drove her to hospital.
Tiffany Ellmore on the M275 motorway at 10.15pm on Friday evening after the police pursuit.
Four unmarked police vehicles surrounded the family car as the baby's head started to appear, in which Tiffany's dad Colin delivered the baby.
The officers present phoned an ambulance which took mother and baby to Queen Alexandra Hospital in Cosham, Portsmouth.
Tiffany, who has three other children, was 38-weeks pregnant and had started having contractions around 4pm.
Baby Lola Mia Rose weighed a healthy 6lb 4oz and was discharged home on Saturday.
Police said no action would be taken over the M275 drama.
Dorset police officer abused his position
A Dorset police officer has been convicted of five counts of fraud. Adam McLean, 38, pleaded guilty at Bournemouth Crown Court. He was sentenced to a community service order to carry out 150 hours of unpaid work for each offence – to run concurrently.
Following his conviction he was dismissed from Dorset Police. PC McLean was arrested on 12 June 2013 following an investigation by the Dorset Police Anti-Corruption Unit and the Major Crime Team. Police say he let down his colleagues and the service.
He met a 52-year-old Sherborne man, in 2006 when he dealt with an incident in the town while on duty and subsequently they became friends. PC McLean went on to abuse his position, and in 2012 he used the victim's bank account to pay off his own personal debts.
Four cars involved in car crash in Weymouth
Police are appealing for witnesses after four cars were involved in a crash in Weymouth.
At around 1pm on Sunday 6th April, police were called to the collision at the junction of Chickerell Road and Lynch Road.
A grey Renault Laguna was travelling along Chickerell Road heading towards the Granby Industrial Estate when it collided with a silver Honda CR-V and a black Vauxhall Agila. The Honda then struck a grey Volkswagen Touareg.
Police Constable Nick Gravenor, of Weymouth Police, said: "The road was closed for about an hour and a half in order for officers to investigate the scene and for paramedics to treat the slight injuries of all motorists involved.
Anyone who has information is asked to call 101, quoting 6:197.
Dorset Police unveil Tardis-style box
They disappeared from our streets in the late sixties, although a certain Time Lord has continued to make use of one for his travels. Today, a 21st century police box was unveiled in the main shopping precinct at Boscombe in Dorset.
The police hope it will reduce crime and anti-social behaviour in the area. But, as Martin Dowse reports, the launch felt rather more like a Dr Who convention.
Bournemouth FC player at launch of functioning 'tardis'
AFC Bournemouth's @stevefletcher33 at the unveiling of the #boscombepolicebox this morning http://t.co/8045uWM46m
Police proudly unveil Doctor Who-inspired box
Police reveal Tardis box in Boscombe
Dorset Police have unveiled a new police box that resembles the time-travelling tardis used in Doctor Who.
The box has been revealed in Boscombe town centre today to crowds of people and police hope its 'magical' design will help raise police presence in the area.
Crowds gather to get a glimpse of Doctor Who police box
A police box with a twist has been revealed in Dorset today.
The Tardis-style police box has been made to resemble the iconic time-travelling machine in Doctor Who.
Dorset Police hope it will create a more visible police presence in the area and bring down the levels of crime.
- David Johns (@davidjohns_itv)
Sussex MP gets apology from police
Sussex Police has been forced to apologise to an MP and former Government minister, after wrongly threatening him with prosecution. A Parliamentary committee had condemned Sussex Police for making a serious mistake.
Now Tim Loughton, the MP involved, has told us he's furious with the wasted time and costs of the police action. David Johns reports, speaking to Tim Loughton MP and Sussex Police & Crime Commissioner Katy Bourne.
Police on the move
It's one of the things people often ask for from their police force - more bobbies on the beat. But a report on a trial of mobil police stations shows that they have been so poorly attended that sometimes - no one turned up at all.
Kent Police Commissioner Ann Barnes launched the scheme last summer, saying they would increase police visibility. And she insists the the programme is working. Nashreen Issa reports.


text:
The 2015 fee schedule &
admission policies
were approved by
the Authority Board
on 20 Nov 2014.
2015 Swimming Pool Fees
for Park Forest Community Pool (814) 238-4515
and Wm. L. Welch Community Pool (814) 237-3964
The two outdoor pools opened for the
2015 season
on Saturday, 23 May 2015.
How do I purchase season pool passes?
2015 Pool Admission & Season Pass Fees
• These fees apply to General Swims, Adult Fitness / Toddler Time Swims and to CRPR Special Events.
• All entrants (swimmers, non-swimmers, chaperones, sunbathers, babysitters, etc.) are subject to admission charges via season pass, daily admission or the Group Admission Policy.
Age Daily Admission Season Pass**
3 & Under*........$3....................$38
After 5 PM.......................$7 (ages 4+)
Residents must reside in State College Borough or
in the Township of College,
Harris, Ferguson or Patton.
Proof of residency may be required.
Age Daily Admission Season Pass**
3 & Under*..........$2...................$25
After 5 PM............$5 (Ages 4+)
• 5th+ family member passes are available for $40 per person. Not available online.
• Resident passes purchased through April 30 2015 are eligible for a $10 discount on each pass.
* Each toddler must wear a swim diaper and be
accompanied by an in-water chaperone.
**Each season pass requires a Photo Card with a $5 fee for new and replacement cards. Cards may be re-used from year to
year. Cards that are unreadable, excessively worn, or with an outdated photo may be exchanged for a new card free of charge.
Please note:
The CRPR Authority is a publicly-funded, municipal agency serving 5 municipalities.
© 1999-2015 All rights reserved.
The Centre Region Parks & Recreation Authority
2643 Gateway Drive #1
, State College, PA. USA 16801 (814)231-3071 Fax 814.235.7832


text:
- 22 Resorts
- Consistent Snow
- Diverse destinations
- Resorts open before those of many other states
- Home to Vail, Beaver Creek, Copper Mountain
From the biggest, snowiest and steepest to the quietest, car-free, family-friendly choices. Full Article
Which type of ski accommodation suits you best? You'll find plenty of inspiring ideas and practical info inside. Full Article
Dancing on tables in ski boots or a more laid-back shopping, dining and spa experience? Full Article
Our guide to the chicest ski spots, most elegant lodging and sophisticated apres-ski. Full Article
7th April 2014
Find the best ski resorts and accommodation to fit your family profile. Full Article
7th April 2014
Expert tips on the cheapest and most stress-free ways to travel to the Alps. Full Article
7th April 2014
OnTheSnow's year-round ski guide brings you the top spots for skiing in spring, summer and autumn. Full Article
8th April 2014
Steep verticals, big jumps, deep powder - whatever your fix, we can help you find it. Full Article
7th April 2014
Read our Ski Resorts in Focus guide to get inspiration for your next winter getaway. Full Article
18th April 2013
Get inspired with new ideas on where to ski this winter. Full Article
12th December 2012
Skiing in autumn means uncrowded slopes and cheaper lift passes. Full Article
6th August 2015
Best resorts for freeriders, families, après-ski and snow-sure slopes on the other side of the world. Full Article
27th July 2015
For waist-deep powder and crowd-free slopes, embark on a South American adventure. Full Article
19th April 2015
Drop your beach towels and grab your shells as here's our guide to the coolest summer ski resorts in Europe and North America. Full Article
14th April 2015
Few hot tubs can compare to the scenic beauty of these ones, located in the finest ski resorts spanning the globe. Full Article
5th April 2015
Miles of untamed wilderness with lakes and mountains as far as the eyes can see. Full Article
1st April 2015
Ski resorts can be anywhere between 7 and 13 hours' drive from Calais. Full Article
29th March 2015
Beat the lift queues, choose a high-altitude hotel with powder on your doorstep. Full Article
28th March 2015
Five resorts deliver holiday fun with activities on and off the slopes.... More


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They are lovely, interesting looking carvings, Lily.
It was quite a nice day yesterday, I put a tablecloth on the line, then forgot it, now it's very wet and still on the line! It hasn't really been dry enough to put washing out for weeks.
Been having internet problems, couldn't use laptop this morning. Hope all your winds are dying down. It's been pouring here.
Red sky at night didn't work, it's pouring and I've left a tablecloth on the washing line
We had super sunset, on Camera thread, but now it's really p.....g down.
Stacey, do you know that if you click on someone's pic it will tell you about them - if they've written something, that is. Pentillie is near Marlow.
The sky tonight is fantastic. It's been a nice day.
Just had coffee and carrot cake Before that I was finishing laying the paving stones on the 2 side paths in the veggie garden. If I do the main path I must get another 50 pavers. They are so heavy!
Before that I was painting my new shelf, for over the radiator under the sitting room window, with varnish. It's oak. Will be temporary home for my seedlings as French houses don't have window sills. Now going off to do 2nd coat.
Pea and bean seeds keep for several years. Parsnips and carrots don't!
Artjak, what a great idea, what a lovely person you must be.
Wish I could help, but not very practical living where I live, France.
I haven't started mine yet, usually raining too hard. Ok until well into March to prune.


text:
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Subject to exceptions, Debenhams is happy to exchange or refund your purchase within 28 days of delivery. Please check here for more details on our returns policy and exceptions.


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Injectable Fillers Q&A
Skin + Injectable Fillers
Fillers for Under Eye Hollowness and Dark Circles?
I'm a 27 year old model. Since my teenage years I've suffered from under eye tear throughs problem. I also have some puffiness in the lower eyelid... READ MORE
Are There Benefits to Having Fillers As Early As 28 Years Old?
Hey all, I am 28 years old, and I am aging poorly. This is very frustrating because I don't smoke, I try to eat right, and I work out 5 times a... READ MORE
What to Do for Upper Lip Smile Line?
I noticed this a few years ago and it drives me crazy. When I smile, now I have a smile line on the skin above my upper lip. I don't know what... READ MORE
Can Fillers Actually Stimulate One's Own Collagen Production?
I am 28 years old and considering getting a filler for a deep smile line I have on the right hand side of my face. I have heard that fillers can... READ MORE
Why Do Some People Get Fillers in the Temple Area?
What does this do to enhance the face? Or maybe it gives a little lifting effect to the skin? That's one area I never considered. Just curious. Thanks. READ MORE
Can Migration of Filler Cause Skin Necrosis?
I am wondering if it is possible for migration of filler to "migrate" and put pressure on an artery causing skin necrosis? Has this ever... READ MORE
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I had a skin graft on my nose for skin cancer, and stitches were pulled out and now my one nostril is irregularly shaped and makes me look loopy,... READ MORE
Dermal Fillers and Botox: Plastic Surgeon or Dermatologist?
Since these treatments are not surgery, a dermatologist who only treats the skin would be more specialized at these kinds of treatment. Who wants a... READ MORE
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Don't know if this is a turkey neck but I want to get rid of the fat + skin under my chin. I wouldn't do a facelift but something to take care of this... READ MORE
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During the procedure of injecting a filler in the under eye area a vein was hit in my upper cheek. It was bruised for several months. The skin is... READ MORE


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- 800.878.7323
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Used Hardcover
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The Principles of Uncertaintyby Maira Kalman
Synopses & Reviews
Publisher Comments:
Maira Kalman paints her highly personal worldview in an inimitable combination of image and text.
The Principles of Uncertainty is an irresistible invitation to experience life through the psyche of Maira Kalman, one of this country's most beloved artists. The result is a book that is part personal narrative, part documentary, part travelogue, part chapbook, and all Kalman. Her brilliant, whimsical paintings, ideas, and images — which initially appear random — ultimately form an intricately interconnected worldview, an idiosyncratic inner monologue. Kalman contends with some existential questions — What is identity? What is happiness? Why do we fight wars? And then, of course, death, love, and candy (not necessarily in that order).
The tremendous success of Kalman's 2005 illustrated edition of Strunk and White's The Elements of Style established her as an original, inspirational voice, and the quirky, hilarious, heartbreaking style of The Principles of Uncertainty reveals Maira Kalman for what she truly is: a national treasure.
In July 2008, illustrator and designer Christoph Niemann began Abstract City, a visual blog for the New York Times. His posts were inspired by the desire to re-create simple and everyday observations and stories from his own life that everyone could relate to. In Niemannandrsquo;s hands, mundane experiences such as riding the subway or trying to get a good nightandrsquo;s sleep were transformed into delightful flights of visual fancy. The struggle to keep up with housework became a battle against adorable but crafty goblins, and nostalgia about New York manifested in simple but strikingly spot-on LEGO creations. This brilliantly illustrated collection of reflections on modern life includes all 16 of the original blog posts as well as a new chapter created exclusively for the book.
Praise for Abstract City:
andldquo;Everyday experiencesandmdash;from looking at leaves to riding city subwaysandmdash;are funny and fresh and often a source of wonder when depicted by this brilliant graphic designer.andrdquo; andmdash;Readers Digest
andldquo;I will call Christoph when anything awful happens to me. And he will make me laugh like crazy about the whole thing. Because he is insanely funny and completely tenderly true. I love every column he did and will do.andrdquo; andmdash;Maira Kalman, author/illustrator of And the Pursuit of Happiness
andldquo;Christoph Niemann is the best illustrator alive. Every single time I come across a piece of his work, which is often as he either works all the time, or worse, draws incredibly fast, it is wonderful. While the rest of us are lucky to get a proper piece out here and there, Christoph produces hit after hit after hit. If he wasnandrsquo;t such a genuinely sweet man, weandrsquo;d surely hate his ass a lot.andrdquo; andmdash;Stefan Sagmeister, author of Things I Have Learned in My Life So Far
andldquo;Few books have more probingly and humorously gotten inside the mind and day-to-day experience of an artist.andrdquo; andmdash;NPR.org
andquot;Whatandrsquo;s terrifying (to me, certainly, and possibly to many of his peers) is that nearly every idea he has seems to be equally well formed . . . once again, performing neat, virtuosic circles around the rest of us, to our delight.andquot; andmdash;PRINT magazine
andquot;Irresistible.andquot; andmdash;Very Short List
andldquo;A masterpiece of sophisticated humor, this is a brilliant one-of-a-kind work.andrdquo; andmdash;Library Journal, starred review
Maira Kalman paints her highly personal worldview in this inimitable combination of image and text
An irresistible invitation to experience life through a beloved artist?s psyche, The Principles of Uncertainty is a compilation of Maira Kalman?s New York Times columns. Part personal narrative, part documentary, part travelogue, part chapbook, and all Kalman, these brilliant, whimsical paintings, ideas, and images?which initially appear random?ultimately form an intricately interconnected worldview, an idiosyncratic inner monologue.
About the Author
In her own words: "born. bucolic childhood. culture-stuffed adolescence. played piano. stopped. danced. stopped. wrote. discarded writing. drew. reinstated writing. married Tibor Kalman and collaborated at iconoclastic yet successful design studio. wrote and painted children's books. worried. took up Ping-Pong. relaxed. wrote and painted for many magazines. cofounded the Rubber Band Society. amused. children: two. dog: one."
Table of Contents
The Principles of Uncertainty May 2006
Sorry, the Rest Unknown
June 2006
Celestial harmony
July 2006
Cherubim and Seraphim
August 2006
Heaven on Earth
September 2006
October 2006
Collecting Myself
November 2006
December 2006
Ich Habe Genug
January 2007
February 2007
The Impossibility of February
March 2007
One Thing Leads To Another
April 2007
Map of USA by Sara Berman
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text: Nicki Minaj - "Freedom" (Music Video) by Hilton Hater at November 20, 2012 10:40 am. Comments Nicki Minaj has come out with the official video for "Freedom." Sit back and watch now! Share Tweet Email Edit Delete Follow Nicki Minaj? Facebook Disqus Star: Nicki Minaj Tag: Music Related Videos: Nicki Minaj Videos, Music Videos Related Post: Nicki Minaj Releases Music Video for "Freedom" Uploaded by: Hilton Hater Uploaded: November 20, 2012 Duration: 300 seconds


text:
Failed to discover domain details for '' Error: 1702
Created: 12 Feb 2014 • Updated: 14 May 2014 | 2 comments
This issue has been solved. See solution.
"2/12/2014 2:27:27 PM","Failed to discover domain details for '' Error: 1702","Altiris.NS.Discovery.DiscoverMachines.GetComputerDomain","AeXSvc","82"
Source: Altiris.NS.Discovery.DiscoverMachines.GetComputerDomain
Description: Failed to discover domain details for '' Error: 1702
I recently updated my 7.1 SP2 MR1.1 to Rollup 8 and now when I try to push an agent to a machine from the web interface I get this error in the logs. Prior to the rollup I would get a status for the install and the feature worked. Now with the error above nothing will attempt to start once I highlight the machine, choose install, and enter my credentials for that domain.
I see several changes to the agentpush page and some of the tables in the various rollup release notes, but nothing specific to the error I am now getting. Has anyone else seen this or been able to resolve it? I suspect the computer name sholdn't be blank between the tick marks. I have deleted the entry and re-run AD import with the same results. Thank you.
Operating Systems:
Comments 2 Comments • Jump to latest comment
seems like here is a solution for your problem:
- Don't forget that, first you can find an answer for your question in Knowledge base
- If answer solves your question, then please mark as solution to close a thread


text:
A Complete HealthCare Program for Clermont
Clermont Medical Center
is proud of our tradition of providing a complete family healthcare program from Pediatrics through Geriatrics for the families of Clermont and the surrounding communities. This website is produced to give you a better understanding of our family practice services and also introduce you the our network of medical specialists that enable us to provide a complete healthcare program for you. Our on-staff family medicine services include:
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Family Counseling
Patient Education
Food Allergies
Power Operated Vehicle Assessment
Genova Testing
Referral Coordination
Hearing Testing
School and Sports Physicals
Heavy Metal Screening
Hormonal Evaluation
Traveller Health Evaluations
Vision testing
Individual Counseling
Women's HealthCare
Infant Care and Child Care
HealthCare Team Chart
will acquaint you with some of the medical specialists we use to respond to your special medical needs. You will also find helpful patient articles for improved healthcare and wellness.
Clermont Medical Center | 1135 Lake Avenue, Clermont, Florida 34711 | 352-394-4035