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Cotai Casinos and Cotai Gambling - Macau
Cotai Casino Directory
Planning a Trip to Cotai?
Take advantage of some unbeatable lodging deals, book a room in Cotai
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Cotai Gambling News
Top 10 casinos by number of square feet
10 October 2016
Casino City has searched the globe for the casinos with the most square footage. Does bigger always mean better? We'll let you be the judge. read more
Top 10 casinos by number of table games
29 August 2016
With this top 10, Casino City takes you on a whirlwind tour around the globe to casinos that contain more table games than you can shake some dice at. read more
Wynn Resorts Ltd reports Q2 2016 results
29 July 2016
The company announced its net revenues from properties in Las Vegas, Macau and other locations. read more
Top 10 picks for the Global Poker Index American Poker Awards
19 February 2016
Casino City's Dan Podheiser tells us who he thinks should win in each category at this year's American Poker Awards. read more
Macau Studio City named 'Casino Resort of the Year' at International Gaming Awards
18 February 2016
This is the third time that a Melco Crown property has taken the top award, with City of Dreams Manila being named to the esteemed position in 2015, and City of Dreams Macau in 2013. read more
Macau gaming market settling, says Adelson
29 January 2016
Las Vegas Sands saw its Q4 earnings fall 19%, which turned out to be less than analysts had predicted read more
Sands opens Cotai Central final piece as Adelson predicts Macau turnaround
20 December 2015
During a celebration surrounding the opening of the $450 million, 400-room St. Regis hotel, Las Vegas Sands Chairman and CEO Sheldon Adelson said the Macau gaming market will turn around in 2016. read more
Steve Wynn buys 1 million shares of his company's stock
9 December 2015
Wynn spent roughly $63.8 million to acquire more than 1 million shares of Wynn Resorts Ltd. read more
Macau suffers 18th straight month of gaming revenue decline
2 December 2015
Casinos collected $2.1 billion from gamblers in November, 32.3% less than a year ago, Macau's Gaming Inspection and Coordination Bureau said Tuesday. read more
Inside Gaming: Macau adding casinos despite prolonged revenue slide
29 November 2015
Casino operators have budgeted almost $27 billion on new developments in Macau, despite the fact that Macau gaming regulators are expected to announce this week that November was the region's 18th straight month of revenue declines. read more
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What are we talking about? A new play, which imagines what goes on behind the closed doors of Buckingham Palace, where the Queen has held weekly meetings with 12 different Prime Ministers.
Elevator pitch Her Royal Highness will be seen now: Mirren dons the crown again for a right royal audience.
Prime movers It's written by Peter Morgan, returning to his fave subjects – HRH, and politicians – after his Oscar and Bafta nominated screenplays for The Queen, and Frost/Nixon. It's directed by Stephen Daldry, the man behind Billy Elliot, The Hours, and The Reader. Tony award-winning designer Bob Crowley is on designing duties.
The stars She's at it again: Helen Mirren, who impressed as the monarch in The Queen, winning an Oscar for her imitation, is reunited with Morgan to portray his version of Elizabeth once more. As for her PMs, Robert Hardy plays Churchill, Michael Elwyn gets Eden, Richard McCabe takes on Wilson, Haydn Gwynne is Thatcher, Paul Ritter becomes Major, Nathaniel Parker is Brown and Rufus Wright plays Cameron.
The Early buzz Much excitement; it featured on almost every look-ahead list, with The Independent calling it "a mouth-watering proposition", The Telegraph, an "intriguing new play", The Guardian musing that "presumably it'll be a battle of the handbags when it comes to those allegedly frosty encounters with Thatcher", and The Daily Mail concluding that The Audience "is bound to be one of the hottest tickets in town in years."
Insider knowledge Mirren isn't the only one returning to a previous role – Hardy will be playing Winston Churchill for the eighth time.
It's great that … although daunted by having to play the Queen ageing over 60 years, Mirren seems to have cracked the challenge by listening to how Elizabeth II's voice has modulated. She suggests that "she had a terribly posh voice when she was young [but now] there's a tiny bit of estuary creeping in there."
It's a shame that … there's a notable recent name missing from the list: where oh where is Tony Blair? Wouldn't his Iraq chat with the Queen have been rather interesting?
Hit potential You need to ask? Even with "premium" tickets going for the princely sum of £87, plenty of tickets have shifted already.
The details The Audience is at the Gielgud Theatre, London W1 (theaudienceplay.com), 15 February to 15 June.Reuse content

subset: commoncrawl


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Food Blog of the Day Archive
Welcome to the Featured Food Blog of the Day Archive! Look for great food blogs, get inspiration and discover new dishes. Want to nominate a great food blog to be featured? Contact us!
January 4, 2016
A good old fashioned Scottish soup perfect for winter dinners with crusty bread, Parsnip, Carrot & Lentil Soup. Low calorie, but very filling and suitable for vegans.
January 3, 2016
This recipe is a crowd pleaser…even my 3 year old couldn't put his spoon down. It is great in a bread bowl for an added element of fun!
January 2, 2016
This feel-good, healthy spinach salad is loaded up with plenty of roasted carrots and beets and doused in an unreal maple vinaigrette.Even all you beet nay-sayers are going to love this salad
January 1, 2016
Strawberry Caprese Pasta Salad is a twist on the traditional Caprese Salad. Instead of tomatoes, I used sweet Florida strawberries for a refreshing change to this classic flavor combo!
December 31, 2015
Hoppin John, a traditional southern dish enjoyed each year on New Year's Day, is made of black-eyed peas, rice, and flavored with pork.
December 30, 2015
Incredibly delicious stuffed mushrooms, made with a flavorful mixture of crispy bacon, spinach and Italian cheese mix.
December 29, 2015
It is seriously one of my favourite dishes and is so versatile. Nothing beats scooping into one of these dishes with the cheesy top and the creamy layers underneath. Rarely this dish will have any leftovers, everyone will go for seconds if there are some.
December 28, 2015
This spin on French Onion Soup puts the humble cauliflower on the map again. Flavourful broth, caramelized onions, roasted cauliflower, and some unique spices create a decadent soup that is perfect for this time of year.
December 27, 2015
These crispy waffles turned out delicious. Salty from the smoked salmon and cheese. Creamy from the use of cream cheese. Flavoured with dill and slightly sweet to contrast all the saltiness.
December 26, 2015
Risotto is like rice that got all dressed up to go to the Ball. It's savory and creamy and cheesy…and I could just eat it with a spoon straight from the pan.
December 25, 2015
A healthy, satisfying cheesy baked potato frittata with ham. An easy, classic frittata recipe that's perfect for any meal and a great way to use leftovers.
December 24, 2015
I'm suggesting you bring out winter's wonders and make a colorful beet and citrus salad that will brighten up your dinner table and your stomach!
December 23, 2015
Just look at this stack of Chocolate Blueberry Bread French Toast! The juicy blueberries, the drizzle of honey, the cinnamon sugar shell and the Nutella all work in harmony creating this decadent and indulging breakfast.
December 22, 2015
Alternating layers of red and white peppermint flavored cake with a dreamy peppermint marshmallow buttercream frosting. A great cake for the holidays!
December 21, 2015
The avgolemono, a Greek technique that involves adding an egg and lemon mixture to thicken hot broth, makes it thicker and more substantial than your average soup, without adding a lot of extra calories. With chicken, chickpeas, and brown rice, it's filling and warming and lovely.
December 20, 2015
Vegetarian cottage pie or shepherds pie, is a meal that I make fairly regularly as it is so simple, hearty and healthy. Lentils make a great (and very healthy) replacement for meat in a lot of recipes, particularly in warming Winter ones such as stews and pies.
December 19, 2015
We were in the mood for some cheesy Italian comfort food and boy did this HIT. THE. SPOT. The breadcrumb topping with fresh garlic makes this dish absolute heaven. This would be a great one to make for company.
December 18, 2015
I was big fan of persimmons already, but little did I know how fragrant these fruits would be once roasted.
December 17, 2015
My Sweet Potato and Kale Quesadillas are light yet satisfying and they're positively packed with important nutrients. Plus, it's also an economical dish as sweet potatoes are usually on sale at the market this time of year.
December 16, 2015
What I love about this dish is that in one mouthful you get sweet butternut squash and cranberries, earthy wild rice and kale, as well as the warm spices and the crunch of the pecans. What more could you want in a dish?


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Cross-Cultural Competence
Theories, Tool-Kits and Applications
By (author) Slawomir Magala
Format: Hardback
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Cross-Cultural Competence by Slawomir Magala
Book DescriptionCross-cultural management is a crucial challenge for the successful development of international business, yet it is often badly understood and poorly implemented. Misunderstandings arise as culture affects both individuals and organizations, yet attempts to understand, explain and interpret these differences have often been hidden between a welter of conflicting theories and paradigms. This book is a much-needed guide to the theory and practice of cross-cultural management. It focuses on four key areas: * the language connection * the global connection * the management connection * the multimedia connection. Using an innovative approach combining theory, tool-kits and applications, it takes a fresh look at this complex topic, investigating the recognition of cross-cultural differences, accounting for them in managerial communications, and bridging them in a variety of negotiations, interactions and collaborative projects.
Buy Cross-Cultural Competence book by Slawomir Magala from Australia's Online Bookstore, Boomerang Books.
Book DetailsISBN: 9780415349659
(234mm x 156mm x 17mm)
Pages: 252
Imprint: Routledge
Publisher: Taylor & Francis Ltd
Publish Date: 25-Aug-2005
Country of Publication: United Kingdom
Other Editions...
Books By Author Slawomir Magala
Cross-Cultural Competence, Paperback (August 2005)» View all books by Slawomir Magala
Presents the guide to the theory and practice of cross-cultural management. Combining theory, tool-kits and applications, this book looks at this topic, investigating the recognition of cross-cultural differences, accounting for them in managerial communications, and bridging them in a variety of negotiations.
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Author Biography - Slawomir Magala
Slawomir Magala is Professor of Cross-cultural Management at the University of Erasmus, Rotterdam.
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More Videos...
1985 Porsche 928 S2 Auto 4 Speed Track Car
Don't let the automatic detour you from thinking this is a slow car. * For licensing / permission to use: Contact - firstname.lastname@example.com
Porsche 928 Racing at Road America. Amazing Lap.
Here is Mark Anderson in the White Zombie again at Road America behind a fellow 928. The two of them are ripping up Road America for about one full lap. (24 MB)
Porsche 928 S4 Murf level II SC drag race, Alastaro 2nd pull
Supercharged Porsche 928 S4 automatic at Alastaro Finland drag strip. 2nd pull of the day, 13.2XXs.
Pajen Rocker opp nabolaget med Porsche 928!
Pajen AKA the Mark paid me a visit a couple of weeks ago and couldnt resist taking my budget racer for a nice burnout after he choked it... Was it the plan all along to do dounuts, or was it due to the embarassing quelling of the engine..?!! Who knows... Hajen wont comment... My neighbour totally freaked and blamed me...! But I totally praise Hajen for making those lasting rubber marks in front of my mailbox... Respect! And special thx to Ketil for filming and especially for survivng...!!!!


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Results 1 to 3 of 3
- 05-12-2014, 04:54 PM Thread Author #1
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Sideload new app?
New Driod Maxx. Checked the allow unknown sources. I have been sent a prototype/beta APK file for a new App we are having developed. When I download it, it says it is downloaded to the SD Card as storage/emulated/0/filename.apk I have not found any sort of file app or widget I can use to get to this file. It isn't in the Downloads place. How do I find this? I also have a ZIP file with all sorts of stuff in it that I assume also needs to be made available to the app. How do I find it and do that?
Thanks very much for your help. I apologize, but I am a newbie at this.
- 05-12-2014, 05:20 PM Thread Author #2
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Re: Sideload new app?
I was just going to write use astro.
Sent from my Nexus 10 using AC Forums mobile app
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Caesar salad is a popular starter or side. Adding grilled salmon elevates it to a main dish rich in beneficial omega-3 fatty acids.
4 servings
Nutritional Information
Calories 340
Caloriesfromfat 36 %
Fat 13.6 g
Satfat 3.8 g
Monofat 5.2 g
Polyfat 3 g
Protein 34.3 g
Carbohydrate 20.9 g
Fiber 4.4 g
Cholesterol 73 mg
Iron 2.4 mg
Sodium 752 mg
Calcium 163 mg
1/4 cup fat-free mayonnaise
1/4 cup (1 ounce) grated fresh Parmesan cheese
2 tablespoons fat-free buttermilk
2 tablespoons fresh lemon juice
1 tablespoon water
1/2 teaspoon freshly ground black pepper
1/2 teaspoon Dijon mustard
2 garlic cloves, minced
2 canned anchovy fillets, drained and chopped
1/2 teaspoon salt
1/2 teaspoon paprika
1/2 teaspoon Spanish smoked paprika
Dash of ground red pepper
4 (6-ounce) salmon fillets, skinned
Cooking spray
8 cups torn romaine lettuce
1 cup fresh corn kernels
1 cup garlic-flavored croutons
1. To prepare dressing, combine first 9 ingredients in a mini chopper or blender; pulse until well blended. Cover and chill 1 hour.
2. To prepare salad, combine salt, paprikas, and red pepper; sprinkle evenly over top of fish.
3. Heat a large nonstick skillet over medium-high heat. Coat pan with cooking spray. Add fish, spiced side down, to pan; cook 4 minutes or until browned. Carefully turn fish over, and cook for 4 minutes or until fish flakes easily when tested with a fork or until desired degree of doneness.
4. Combine lettuce, corn, and croutons in a large bowl. Drizzle dressing over lettuce mixture; toss gently to coat. Arrange 2 cups salad on each of 4 plates; top each serving with 1 fillet.
May 2008


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Professional resources — The best place to find relevant and up-to-date information about professional conference interpreting.
You've heard about conference interpreting but you're not sure exactly what it involves, what studies to pursue, or what opportunities may be available. Here are some questions to consider.
Choosing a school is one of the most important steps you will take on your path to becoming a trained conference interpreter.
Resources and pointers for budding and junior interpreters.
Conference interpreters work for businesses, government and international organisations. Most interpreters are self-employed and have variable schedules.
An ongoing series on major city and national markets – from the practioners' mouths.
Insider tips for interpreters working their first day for an international organisation.
Practitioners share their professional experience.
Tips and tricks for interpreters freelancing on the private market and their clients
What sort of professional development is available and useful for practising conference interpreters.
Agreements governing the employment conditions of conference interpreters paid by the day between AIIC and international organisations.
More about interpreting booths, remote conferencing, sound quality and applicable standards
A reminder of the main points, plus a few tips drawn from interpreters' experience.
Seminars and guidance for trainers of conference interpreters.
Views, research findings, and guidelines on remote interpreting - what it is, how it works, and what is needed for it to work well.
Articles of interest for interpreters employed by international organisations and government
Looking back at the early years of conference interpreting.
Insights into interpreting – the process, the work environment, and the interplay between the two.
The technical conditions of simultaneous interpretation work are important because they have repercussions on interpreters' health.
Insights into interpreting – the process, the work environment, and the interplay between the two.


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There is nowt more we love here at HuffPost towers than seeing a celebrity stacking it.
And after Kate Moss' tumble last week, it was Kim Kardashian's turn to give us a LOL.
Kimmy was heading out to a hair salon in LA yesterday when she came a cropper.
Well, she will wear those towering stilettos.
We could soon be seeing a lot less of the star than we're used to though as KK is set to leave Instagram following their change in policy.
Kim tweeted her frustrations at the new terms of use, and now a source has added that she is thinking of taking her 5.7m followers elsewhere. Lucky them.
"Kim is telling friends she's considering leaving unless its new policies are drastically revised, ASAP," reports TMZ. "She's thinking about shutting down her Instagram account, going to a rival photo-posting company ... and taking all of her followers with her."
The star unveiled a new fringe earlier this week, but it has since proved to be a clip in.


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News By Tag
* Devices
* Test
* Modular
* Instrument
* More Tags...
Industry News
News By Location
Industry News
Increasing Complexity of Devices under Test Drive Demand for Modular Instruments. Frost & Sullivan
Modular instrumentation continues to gain ground over its traditional counterpart, with the European market expected to reach €265.5 million in 2017
In addition, the decelerating manufacturing growth rates in key countries such as Germany, France and the United Kingdom are expected to continue driving the industry shift from traditional instrumentation to modular instrumentation in Europe.
New analysis from Frost & Sullivan, European Modular Instrumentation Markets, finds that the VXI- and PXI-based test and measurement equipment markets earned revenues of €111.5 million in 2010, and estimates this to reach €265.5 million in 2017. Market expansion will be mainly due to increasing demand from the automotive industry and growth of contract manufacturing in Eastern Europe, as well as to demand from the telecom design industry in Scandinavia.
"There is a large automotive footprint in Europe, particularly in Germany, that is driving demand for modular instrumentation,"
While modular instrumentation is predominantly used in manufacturing applications, it has made significant inroads in R&D applications as well, especially in design verification and validation in the recent past. Germany is the European leader for R&D spending, due to the presence of key players in the automotive, aerospace, pharmaceuticals and energy industries.
However, the economic downturn in Europe is of concern to many industries. "During times of economic hardship, capital expenditures in test and measurement equipment can be severely affected," remarks Cavazos. "On the other hand, this situation has caused customers to re-evaluate their test strategy so as to identify the best way to lower their cost of test, favouring modular instrumentation over traditional instrumentation."
Modular instruments vendors need to keep educating the market about the benefits of modular instrumentation. This includes educating buyers on how it may lower the cost of test and accelerate time to market through case studies and other means.
If you are interested in more information on this study, please send an e-mail with your contact details to Anna Zanchi, Corporate Communications, at anna.zanchi@
European Modular Instrumentation Markets is part of the Test & Measurement Growth Partnership Service programme, which also includes research in the following markets: European General Purpose Test and Measurement Equipment Markets, World Semiconductor ATE Markets and European Signal Generators and Arbitrary Waveform Generators Markets. All research included in subscriptions provide detailed market opportunities and industry trends that have been evaluated following extensive interviews with market participants.
About Frost & Sullivan
Frost & Sullivan, the Growth Partnership Company, enables clients to accelerate growth and achieve best-in-class positions in growth, innovation and leadership. The company's Growth Partnership Service provides the CEO and the CEO's Growth Team with disciplined research and best-practice models to drive the generation, evaluation, and implementation of powerful growth strategies. Frost & Sullivan leverages 50 years of experience in partnering with Global 1000 companies, emerging businesses and the investment community from more than 40 offices on six continents.
Anna Zanchi
Corporate Communications – Europe
E: anna.zanchi@
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G.V. Prakash
G.V. Prakash Kumar teams up with Amy Jackson for 'Ketta Payada Indha Karthi'
The film, which will mark Prakash's fourth outing as an actor, will be directed by debutant directors Guna and ShankarJune 21, 2015, 3:30 pm explore: Movies
Telugu music composer GV Prakash to marry Saindhavi
Composer G V Prakash Kumar, nephew of Oscar-winning musician AR Rahman, will marry Saindhavi, a popular playback singer.April 21, 2013, 3:52 pm explore: India
Tamil movie 'Thalaivaa' to hit the screens soon
Directed by filmmaker AL Vijay, the movie has a total of seven tracks.February 11, 2013, 6:41 pm explore: India
Thaandavam: Vikram's role inspired by Daniel Kish
Actor Vikram's role in 'Thaandavam' is inspired from Daniel Kish, a blind American expert in human echolocation.September 6, 2012, 6:31 pm explore: India
Paradesi: GV Prakash tries something unique
Adharva Murali plays the protagonist, while Vedhika and Dhanshika are the leading ladies in the film.August 13, 2012, 11:42 am explore: India
'Thaandavam': Vikram uses human echolocation
Vikram underwent special training from Daniel Kish, an internationally renowned expert of human echolocation.test sharma, August 3, 2012, 12:16 pm explore: India
Anushka Shetty does a cameo in Karthi's 'Saguni'
According to sources, she appears as a funny police officer and scenes involving her will bring the roofs down.test sharma, June 12, 2012, 12:35 pm explore: India
First Look: Karthi, Pranitha in Tamil film 'Saguni'February 27, 2015, 2:46 pm explore: Movies
Rajinikanth unveils the music of Kuselan in Chennai
The film is all set to release in Tamil and Telugu in July.Smriti Advani, July 1, 2008, 5:07 pm explore: India
Mind it! It's Daler singing in Tamil for Kuselan
Daler has recently recorded the title track of Rajinikanth starrer Kuselan.Reshil Charles, April 24, 2008, 4:49 am explore: India
Anu Malik in another musical war
Anu Malik is accused of taking credit for the song, Sabko Maloom Hai, which was reportedly not composed by him.Urvashi Yadav, October 24, 2006, 6:23 pm explore: India
Rahman nephew set to rock music world
Music runs in the family of most music composers but GV Prakash has none other than AR Rahman as his uncle and mentor.Pratibha Parmeshwaran, September 28, 2006, 6:33 pm explore: India
StarGaze: Shraddha Kapoor Parties With Farhan Akhtar, SRK Attends OK Jaanu Special Screening
Kishwer Merchant- Suyyash Rai Wedding: Look Who All Attended the Reception Party
Hollywood Friday: Ryan Gosling, Emma Stone Starrer La La Land Releases This Week


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Andy Murray will arrive in a Volkswagen Polo but a nation will be hoping that he leaves in a blaze of glory. The 25-year-old Scot, who sold his red Ferrari last year because he felt "a bit of a prat" when driving it, has been travelling to the All England Club each day for the past fortnight in a friend's Polo. He has no intention of changing his routines as he readies himself for the biggest match of his life in this afternoon's Wimbledon final against Roger Federer.
Murray will be the first British man to play in a Wimbledon singles final for 74 years and will be aiming to become the first home champion since Fred Perry in 1936, but the world No 4 will prepare for his moment of destiny by treating it like any other match.
He was planning to watch a film at home yesterday evening – "I normally try to watch something funny, something that is relaxing, not something that is tough to watch" – and said he planned "a decent lie-in" before getting up around 9am. "I've slept perfectly so far," he said. "I've been having porridge for breakfast on the days of my matches. I'll have a few yoghurts and get some energy drink down me."
Murray said he would try not to let the enormity of the occasion get to him. "All of the Grand Slam matches I've played have been important to me, all of them," he said. "This is my next match and I focus on it like any other one. If I look upon it as the Wimbledon final and no Brit has won it for however long and there's this many people watching, I'm going to play crap.
"I need to focus on it as a tennis match against Roger Federer, somebody I have won against before, how I'm going to win that match and what am I going to do to win it. That's really the plan."
But for the hordes of cameramen, Murray's practice session at Aorangi Park yesterday was much like any other. Oliver Golding, Britain's US Open junior champion, was his hitting partner again, while the key members of the Scot's entourage – Ivan Lendl, his coach, Dan Vallverdu, his closest friend, Andy Ireland, his physiotherapist, and Jez Green, his physical trainer – watched from the sidelines.
Murray has lost in all three of his previous Grand Slam finals without winning a set, two of them against his opponent this afternoon. "I know how tough that feeling is, so I don't want to let thinking about winning it or getting ahead of myself ruin my chances," he said. "It's exciting and it's a great position to be in, but I'm not going to get ahead of myself as I know that's counter-productive."
Nobody has felt more at home on Centre Court over the past 10 years than Federer, who has won the All England Club title six times and will be appearing in his eighth final, more than any other player. Murray, nevertheless, has also grown to love the world's most famous tennis arena.
"The more matches you play on a court you get used to the surroundings," he said. "You know the wind, where the shadows are on the court and the sun, where everybody is sitting in the box. I know how the court plays, the speed of the court, I do feel a lot more comfortable on that court than all of the other courts in the Slams."
While Murray said he would need "all the support I can get", he also expects plenty of backing for Federer, as there was in their previous two meetings on British soil, at the year-ending World Tour Finals at London's O2 Arena. "I'm not expecting silence when he wins points at all. He deserves support wherever he goes, because of what he has achieved of course, but I always say that having the crowd behind you, in any sport but especially in tennis, makes a big difference."
Federer said he hoped to have some support but welcomed the chance to play "the local hero – and Andy is exactly that at Wimbledon". While it would be impossible to imagine a bigger occasion for Murray, this is also a big moment in the career of the 30-year-old Swiss.
He has not added to his record-breaking collection of 16 Grand Slam titles for two-and-a-half years, needs one more victory to match Pete Sampras's seven Wimbledon titles and will reclaim the world No 1 ranking, which he last held more than two years ago, if he wins here. The Swiss would also become only the third man (after Rod Laver and Arthur Ashe) to win the Wimbledon title in his thirties.
Federer, who appears to have made a full recovery from the back problem which forced him to leave the court for treatment during his fourth-round victory over Xavier Malisse, said: "Of course there's a lot on the line for me. I'm not denying that. I have a lot of pressure as well. I'm looking forward to that. That's what I work hard for."
Murray admitted that as a boy he did not appreciate the importance of Wimbledon, but there is no danger of that now. "This is the reason you put your body through the work-outs and training," he said. "In the last few years I have thought about it more and come to understand how important it is."
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International Edition
February, 26, 2017
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Military's upgraded IDF jet fleet photos go public
By Joseph Yeh ,The China Post May 22, 2014, 12:03 am TWN
TAIPEI, Taiwan -- The R.O.C. Air Force yesterday made public the photographs of a first batch of upgraded, locally developed Indigenous Defense Fighter (IDF) jets taken at an air base in the southern city of Tainan.
The photographs taken by the Military News Agency (軍聞社) and made public by a military spokesman on his Facebook page yesterday showcase the trainings of the pilots and ground crew of the 443rd Tactical Fighter Wing at the Tainan air base with the newly introduced IDF C/D aircraft.
The 443rd Tactical Fighter Wing is the first fighter wing in the R.O.C. Air Force featuring the upgraded IDF fighters.
The fighter wing in Tainan received the first batch of upgraded IDF jets during a ceremony this January.
The ceremony was attended by President Ma Ying-jeou and Defense Minister Yen Ming (嚴明), marking the upgrading of the 71 IDF fighters at the Tainan air base by Taichung-based Aerospace Industrial Development Corp (AIDC, 漢翔).
The locally built IDF "Ching-Kuo" (經國號) fighters were developed and manufactured by the AIDC in 1988. The aircraft was named after the late President Chiang Ching-kuo (蔣經國).
In a move to upgrade these fighters, Taiwan military decided to spend NT$17 billion to upgrade 71 IDFs as part of a four-year project that began in 2009. The Air Force currently has 127 IDFs.
According to the Air Force, the upgrade program was mainly to strengthen the air-to-land strike capacity of the jets.
All of the IDF C/D fleet at the Tainan base is now capable of carrying the Wan Chien long-range air-to-surface missile system (萬劍飛彈), which was researched and produced by the military-run Chung-Shan Institute of Science and Technology (中山科學研究院).
According to ruling Kuomintang (KMT) lawmaker Lin Yu-fang (林郁方), the R.O.C. military is scheduled to start mass production of the locally developed Wan Chien system in 2015.
The weapon can be launched at a distance from targets, enabling Taiwan's fighter jets to avoid risking defensive anti-aircraft fire from mainland China when launching the new armaments, Lin said.
The long-range missiles could also cause significant damage to mainland Chinese troops, harbors, missiles and radar installations located at the opposite side of the Taiwan Strait, he said.
According to the Air Force, Wan Chien missiles have a maximum range of 200 kilometers or more.
The long range means R.O.C. fighter jets will not need to launch the missiles in mainland Chinese airspace.
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May 22, 2014 blairjames@
Nine armored troop carriers seized by Hong Kong on the way back to Singapore
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South Korean rep positive about tourism in Taiwan
As bird flu threat rises, pass on the eggs Benedict
Year of the Monkey gives Taiwan dollar an unusual boost
Asus will 'cooperate fully' with antitrust probe


text:
Baby sloth video goes viral
This baby sloth video has caught the attention of 600,000 people.
The rescued sloth hands a flower to a tour guide, and does so with what seems to be a smile.
Reaching this many views after only being online for a couple weeks the cuteness factor must be at play.
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text: Cavendish Mall, a retail center in a small city outside of Montreal called Cote St. Luc, is targeting young families as part of a larger strategy by the city and local businesses to accommodate changing demographics. Close to half of the 400,000-square-foot center is being converted into housing for young families. The resulting retail space will include an indoor playground.


text:
With Instructables you can share what you make with the world, and tap into an ever-growing community of creative experts.
It's Christmas season once again and that means its time to get together with all of your friends and family to share in the joys of the holiday ...
You will need: - (x2) Arduino Uno - (x2) Wireless SD shield - (x2) XBee transceivers - 8 x 6 x 3 project enclosure - Laser cut panel ...
Place the wireless SD shield onto the Arduino. Next, place the XBee transceiver into the socket of the the wireless SD shield such that the antenna is closer ...
Attach a 12 gauge wire to each power terminal of the power sockets. Don't worry about attaching the socket's ground terminal to anything since standard stranded Christmas lights ...
Fasten your power sockets to the front panel using nuts and bolts.
Drill a 5/8" hole for the lamp cord cable centered on the lower edge of one of the shorter side's of the case. In other words, copy what ...
Pass the lamp cord cable and tie an overhand knot to prevent it from being pulled back through the hole. When you finally commit to tying the knot, ...
Bundle together a corresponding wire from each of the power sockets. In other words, they should all come from the identical terminal of each of the power sockets. ...
On the inside of the case, place your perfboard and make a mark inside each of its mounting holes. Next, place the Arduino in a position in which ...
The Arduino operates at 5V, but the relays operate at 9V. To be able to use the Arduino with the relay, it is necessary to use transistors as ...
Attach the sockets to the N.O. pins on the relay. This is the pin that is not connected when no power is applied to the relay. Make sure ...
Pass your 6-32 x 1/2" bolts up through the bottom of the circuit board. Inside of the case, place the 1/4" spacers onto the bolts. Put the circuit ...
Pick one of the outer terminals pairs to solder the power connection to. Solder the red and black wires from the 9V plug respectively to each of the ...
On the side of the case opposite to where the circuit board and Arduino is suppose to mount, mark and drill a 3/4 " hole using a spade ...
Mount the Arduino to the inside of the case using the 1-1/2" bolts and corresponding 4-40 nuts.
Lastly, drill a hole in the bottom of the case in a spot where there is a lot of free space using a 1/8" drill bit. Fasten the ...
Plug in your USB cable, make sure that the switch on the Wireless SD board is toggled to "USB" and program the Arduino with the following code: /* ...
Plug in the wires from the relay board into the female headers on the Arduino board as follows: Relay/Socket 1 --> Pin 3 Relay/Socket 2 --> Pin 4 ...
Plug the M-type connector into the Arduino and connect the 9V snap to a 9V battery. Place the battery snugly into the battery clip. If the light on ...
Fasten the socket panel firmly in place to close the case.
A nice finishing touch to the controller box is to add an adhesive rubber in each corner on the bottom of the case.
Before you can go any farther, you need Python. If you are using a Mac with a recent version of OS X, you should have Python already. Open ...
In order for the python script to be able to talk to Twitter and read from the serial port, you are going to need to download and install ...
The next step is to get authorized to use the Twitter API. Go to the Twitter app developer page and enter the account you have created for you ...
Plug in the other Arduino into the computer. Don't worry about programming it. It functions mainly as a pass-through for transmitting serial data. It is important to make ...
Attached below is the python script that checks twitter and sends serial commands to the tree. Download and open this script in a basic text editor. Once downloaded, ...
Plug the Christmas lights into the controller box. Make sure you have the right colors plugged into the right sockets. You may want to label them so you ...
To change the colors tweet at the tree. You can currently control the tree by tweeting the following color commands: #red #green #white
Tweeting Christmas Tree receiver code
Controls the color of Christmas tree lights
'a' turns red on
'b' turns red off
'c' turns green on
'd' turns green off
'e' turns white on
'f' turns white off
'g' turns other on
'h' turns yother off
int sentDat;
void setup() {
pinMode(3, OUTPUT);
pinMode(4, OUTPUT);
pinMode(5, OUTPUT);
pinMode(6, OUTPUT);
void loop() {
if (Serial.available() > 0) {
sentDat = Serial.read();
//red control
if(sentDat == 'a'){
digitalWrite(3, HIGH);
}else if(sentDat == 'b'){
digitalWrite(3, LOW);
//green control
if(sentDat == 'c'){
digitalWrite(4, HIGH);
}else if(sentDat == 'd'){
digitalWrite(4, LOW);
//blue control
if(sentDat == 'e'){
digitalWrite(5, HIGH);
}else if(sentDat == 'f'){
digitalWrite(5, LOW);
//other control
if(sentDat == 'g'){
digitalWrite(6, HIGH);
}else if(sentDat == 'h'){
digitalWrite(6, LOW);
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text:
Women's Skechers Bobs, Doily Slip On Fun fashion meets cool style with the bobs doily shoe Soft Eyelet fabric upper in a feminine espadrille design Openwork fabric makes for a breathable and light...More
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text:
We Support; Saeler-Solkvony Memorial Poker Run
Saturday, August 15th will be the annual Saeler-Solkovy Poker Run. This annual event is held in memory Of Steve Saeler, Jessica Saeler and John Solkovy. Each year, a beneficiary is chosen from the community for the proceeds of the event to go to. This year, Lucretia […]Read More


text:
3.8 Education Core The Education Core will coordinate the Center's innovative outreach and training programs. Dr. Randy Smith, Director of Educational Programs at Jackson, will lead the Core and supervise its two Education Outreach Developers. Members of the Core will meet with the Center Director once a month to report program progress. Detailed information about the Center's outreach and education programs are described in the Outreach Plan, Education and Training Plan, and Recruitment and Retention Plan for Diversity.
|Carmody, Rachel N; Gerber, Georg K; Luevano Jr, Jesus M et al. (2015) Diet dominates host genotype in shaping the murine gut microbiota. Cell Host Microbe 17:72-84
|Kelada, Samir N P; Carpenter, Danielle E; Aylor, David L et al. (2014) Integrative genetic analysis of allergic inflammation in the murine lung. Am J Respir Cell Mol Biol 51:436-45
|Cheng, Wei; Zhang, Xiang; Guo, Zhishan et al. (2014) Graph-regularized dual Lasso for robust eQTL mapping. Bioinformatics 30:i139-48
|Mazrouee, Sepideh; Wang, Wei (2014) FastHap: fast and accurate single individual haplotype reconstruction using fuzzy conflict graphs. Bioinformatics 30:i371-8
|Tyler, A L; McGarr, T C; Beyer, B J et al. (2014) A genetic interaction network model of a complex neurological disease. Genes Brain Behav 13:831-40
|Huang, Yuan; Caputo, Christina R; Noordmans, Gerda A et al. (2014) Identification of novel genes associated with renal tertiary lymphoid organ formation in aging mice. PLoS One 9:e91850
|Philip, Vivek M; Tyler, Anna L; Carter, Gregory W (2014) Dissection of complex gene expression using the combined analysis of pleiotropy and epistasis. Pac Symp Biocomput :200-11
|Noordmans, Gerda A; Huang, Yuan; Savage, Holly et al. (2014) Genetic analysis of intracapillary glomerular lipoprotein deposits in aging mice. PLoS One 9:e111308
|Baker, Christopher L; Walker, Michael; Kajita, Shimpei et al. (2014) PRDM9 binding organizes hotspot nucleosomes and limits Holliday junction migration. Genome Res 24:724-32
|Gatti, Daniel M; Svenson, Karen L; Shabalin, Andrey et al. (2014) Quantitative trait locus mapping methods for diversity outbred mice. G3 (Bethesda) 4:1623-33
Showing the most recent 10 out of 70 publications


text:
List Criteria: Vote for your favorite
If you think the best Jake Abel role isn't at the top, then upvote it so it has the chance to become number one. The greatest Jake Abel performances didn't necessarily come from the best movies, but in most cases they go hand in hand.
With films ranging from Go Figure to Percy Jackson & the Olympians: The Lightning Thief, this is a great starting point for a list of your favorites.
"This list answers the questions, "What are the best Jake Abel movies?" and "What are the greatest Jake Abel roles of all time?"
- 1+ 16- 0
The Host Diane Kruger, Saoirse Ronan, Emily Browning
- 2+ 19- 1
Percy Jackson: Sea of Monsters Alexandra Daddario, Logan Lerman, Jake Abel
- 3+ 22- 2
Percy Jackson & the Olympians: The Lightning Thief Uma Thurman, Pierce Brosnan, Rosario Dawson
- 4+ 11- 5
I Am Number Four Dianna Agron, Teresa Palmer, Alex Pettyfer
- 5+ 6- 1
Go Figure Jordan Hinson, Jake Abel, Brittany Curran
- 6+ 10- 5
The Lovely Bones Rachel Weisz, Mark Wahlberg, Susan Sarandon
- 7+ 4- 1
Tru Loved Jane Lynch, Alexandra Paul, Jasmine Guy
- 8+ 4- 1
Strange Wilderness Jonah Hill, Ernest Borgnine, Ashley Scott
- 9+ 4- 1
Hollywood Takes a Stand Against Planking Sara Paxton, Jake Abel, Kyle Gallner
- 10+ 4- 2
Angel of Death Rawle D. Lewis, Ed Brubaker, Lucy Lawless
- 11+ 2- 1
18 Jake Abel, Nolan Gerard Funk, Portia Doubleday
- 12+ 2- 1
Good Girl Jake Abel, Carrie Armstrong, Melissa Hunter
- 13+ 4- 5
Flash of Genius Lauren Graham, Alan Alda, Tatiana Maslany


text:
Around the Farm: July 15
|Jason Donald
(photo: Columbus
Around the Farm takes a quick look at some of yesterday's performances by Indians prospects throughout the system. The positions listed below are where the player was playing in yesterday's game.
Jason Donald: 3B, Columbus: 3-5, 1 R, 1 2B, 2 K:
Holy cow, Donald is absolutely on fire right now, and it does directly correlate with Luis Valbuena's call-up. Donald has had multi-hit games since July 8th, the day that Valbuena was called up ahead of him. During that stretch, the middle infielder has gone 11-19, with three runs, three doubles, two homers and five home runs. While his hit streak goes back five games, if you extend his stats back seven, he's 13-26, with seven runs scored. I'm not sure where Donald fits on this team with so much talent in Columbus at the middle infield positions, but it's hard to overlook a guy that hitting over .500, who's a steady infielder at second, short and third, over any measurable stretch. While I doubt that Donald is going to continue at this torrid a pace, it's distinctly possible that something has clicked on for Donald, who may be playing for his major league life right now.
- Jerad Head: LF, Columbus: 3-5, 2 R, 2 2B, 2 K: Head's been an offensive constant in the Columbus lineup throughout the season, and he has always peppered his statistics with big games like this. I'm not saying that Head is a long-term answer in the Tribe's outfield, but I do feel that he could give the Indians a short term, right-handed answer. Of course, if you think Austin Kearns' .212 with a homer and five RBI is, well, then nevermind.
- Chad Huffman: RF, Columbus: 0-4, 1 RBI, 1 BB: You start to wonder what a team is thinking when you sign a journeyman outfielder to perhaps to give your team depth and he struggles mightily throughout the season. You REALLY start to wonder what another team is thinking when they intentionally walk a guy who hasn't hit a thing in a long...long...time.
- Zach Putnam: RP, Columbus: 2 IP, 1 H, 3 K: Perhaps the all-star break did some good for Putnam, who was rocked for five runs in 2 2/3 innings pitched in his two games leading to the break. He used to be the first option out of Columbus because of his talent and performance, but that's teetering on the brink. More outing like this though, and Putnam can solidify his spot as most likely to join the bullpen mafia.
- Josh Judy: Closer, Columbus: 2 IP, 1 H, 1 BB, 2 K, W (3-2): I like seeing these two inning performances from Judy, who will likely become a set-up man for Cleveland when he eventually makes to move permanently. While he gave up a run in Cleveland, with Columbus, he hasn't given up a run in 11 games.
- Ben Copeland: RF, Akron: 2-4, 1 R, 1 BB, 1 K, SB (5): Cleveland made a bunch of free agent, minor league signings, in particular, in Akron, and all the players, including Copeland, have paid off. Copeland brings a nice blend of plate discipline and speed to the Aeros, and could be a nice fill in as a veteran presence in Columbus should they need one.
- Beau Mills: 1B, Akron: 1-3, 1 R, 1 2B, 1 RBI, 1 BB, 1 K: Beau Mills, power hitting corner outfielder, likely future major leaguer. That all sounds really good for a kid that has come off the DL in 2011 and finally started to hit the ball the way a first round pick should. He's 8-16, with five runs, three doubles, two homers and six RBI in his last five games.
- Chun Chen: C, Akron: 2-4, 1 R, 1 RBI: Chen rested his back during the all-star break, and it's clearly paying off, as he's gone 3-8, with a run, a double and two RBI in his last two games.
- Karexon Sanchez: 2B, Akron: 1-4, 1 R, 1 HR, 1 RBI, 2 K: Sanchez has been a bucket full of struggle from the offensive side of the plate, but can play every infield position, so is a viable option in Columbus...if THEY weren't so loaded with potential major league talent.
- Drew Pomeranz: SP, Akron: 4 2/3 IP, 3 H, 1 R/ER, 1 BB, 5 K, 1 HR: Pomeranz went over his 90 pitch threshold in the fourth inning, so while his numbers were solid in his debut, you can see there was some struggle there. Of course, a third of his outs were K's, and his debut double A ERA is 1.93, so it only gets better for the Tribe's top pitching prospect.
- Matt Langwell: RP, Akron: 1 2/3 IP, 1 H, 1 BB, 3 K, W (3-1): Langwell rebounds with a solid outing after getting lit up prior to the break. There's promis there, but he needs to get past a roller coaster ride in June and early July.
- Cory Burns: Closer, Akron: 1 1/3 IP, 2 K, S (26): Burns leads the league with 26 saves (by 9), and is the organizational saves leader. You have to like the depth at this position with Josh Judy at Triple A, Burns at Double A and Guilmet in Single A. Throw in several flame-flowers in between, and you have a bunch of potential closers should the Indians ever need them.
- Brett Brach: SP, Kinston: 6 1/3 IP, 8 H, 3 R/ER, 5 K, 1 HR, L (6-6): This wasn't Brach's best performance, but with an offense that only gave him four hits and a run of support, well, welcome to Kinston.
- Rob Bryson: RP, Kinston: 1 IP, 2 K: Bryson is liking winding down his time with the K-Tribe. He's been nothing short of dominant since his return, giving up only six hits, three walks and a run, while striking out an impressive 20 batters in 14 innings of work. He may be the most talented, strictly bullpen arm in the system, if he can stay healthy.
- Carlos Moncrief: RF, Lake County: 3-5, 1 R, 1 K, 1 SB (15): I really love the part of my job when you see a kid really start to figure things out. Moncrief is in that boat right now, as he's really started hitting the ball from the lead-off spot in Lake County's offense. He's 11-27, with three runs, two doubles, a triple and an RBI in his last six games.
- Jesus Aguilar: 1B, Lake County: 2-3, 1 2B, 1 RBI, 2 BB: Jump on the Aguilar bandwagon now. While his power numbers certainly impress, what has to make the Tribe brass absolutely giddy are games like this one. Why? He walked twice without a strikeout. Aguilar has struck out 87 times this year, with only 30 walks. If he starts showing this type of plate discipline, his star goes up another notch. Wow, a big, power-hitting righty in the system. Who'd have thunk it.
- Bryce Stowell: RP, Lake County: 1 1/3 IP, 1 H, 1 BB, 4 K: While I mentioned Bryson as the best pure reliever arm in the system, he may have taken that title away from Stowell. While it's true, he took a major step backwards this year, start taking notice. Stowell is starting to pitch like the guy from last year.
- Kyle Petter: RP, Lake County: 2 IP, 1 H, 4 K: Petter was the 34th round pick for the Tribe in 2010, and he's starting to show some solid stuff. His ERA at Mahoning Valley was 0.00 in six games, and he made the jump to Lake County. While he got touched up in his first two outings, he's been rock solid in his past three, going 4 2/3, with one hit and eight K's. Looks like we have another solid reliever on our hands.
- Jordan Smith: 3B, Mahoning Valley: 2-4, 2 RBI: Smith has gotten lost a bit in the shuffle in Mahoning Valley, but has ben the most consistent hitter on the team, since Bryson Myles has been out.
- Alex Lavisky: DH, Mahoning Valley: 2-4, 1 R, 1 K: What is this? Is Alex Lavisky hitting the ball? He has a modest (for him, not so much) five-game hitting streak, and is 7-17. The youngster has to be feeling good right now, and just might be turning the corner.
Follow Tony and the Indians Prospect Insider on Twitter @TonyIPI. Also, his latest book the 2011 Cleveland Indians Top 100 Prospects & More is available for purchase for $20.95 to customers in the US (shipping and handling extra).
Jim is currently the senior editor and Columnist, as well as the host of IBI's weekly online radio shows, Smoke Signals and Cleveland Sports Insiders. You can follow Jim on Twitter @Jim_IBI, or contact him via e-mail at email@example.com.


text:
The tumour-associated glycoprotein podoplanin is expressed in fibroblast-like synoviocytes of the hyperplastic synovial lining layer in rheumatoid arthritis
DOI: 10.1186/ar3274
© Ekwall et al.; licensee BioMed Central Ltd. 2011
Received: 10 September 2010
Accepted: 7 March 2011
Published: 7 March 2011
Activated fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) share many characteristics with tumour cells and are key mediators of synovial tissue transformation and joint destruction. The glycoprotein podoplanin is upregulated in the invasive front of several human cancers and has been associated with epithelial-mesenchymal transition, increased cell migration and tissue invasion. The aim of this study was to investigate whether podoplanin is expressed in areas of synovial transformation in RA and especially in promigratory RA-FLS.
Podoplanin expression in human synovial tissue from 18 RA patients and nine osteoarthritis (OA) patients was assessed by immunohistochemistry and confirmed by Western blot analysis. The expression was related to markers of synoviocytes and myofibroblasts detected by using confocal immunofluoresence microscopy. Expression of podoplanin, with or without the addition of proinflammatory cytokines and growth factors, in primary human FLS was evaluated by using flow cytometry.
Podoplanin was highly expressed in cadherin-11-positive cells throughout the synovial lining layer in RA. The expression was most pronounced in areas with lining layer hyperplasia and high matrix metalloproteinase 9 expression, where it coincided with upregulation of α-smooth muscle actin (α-sma). The synovium in OA was predominantly podoplanin-negative. Podoplanin was expressed in 50% of cultured primary FLSs, and the expression was increased by interleukin 1β, tumour necrosis factor α and transforming growth factor β receptor 1.
Here we show that podoplanin is highly expressed in FLSs of the invading synovial tissue in RA. The concomitant upregulation of α-sma and podoplanin in a subpopulation of FLSs indicates a myofibroblast phenotype. Proinflammatory mediators increased the podoplanin expression in cultured RA-FLS. We conclude that podoplanin might be involved in the synovial tissue transformation and increased migratory potential of activated FLSs in RA.
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease predominantly affecting joints, leading to tissue destruction and functional disability [1, 2]. Both genetic and environmental factors are believed to contribute to the dysregulated immune responses seen in this heterogeneous autoimmune disease [3]. Today, treatment strategies involve traditional disease-modifying antirheumatic drugs as well as biologic agents targeting proinflammatory cytokines (tumour necrosis factor α (TNFα), interleukin (IL)-1 and IL-6), B cells or the activation of T cells [4]. Despite this arsenal of drugs, at least 30% of the patients are resistant to the available therapies, suggesting that yet other mediators must be important.
The most prominent feature of RA is the progressive destruction of articular cartilage and bone, which is orchestrated by activated RA fibroblast-like synoviocytes (RA-FLSs) [5, 6]. RA-FLSs not only mediate tissue destruction but also are considered to play a major role in initiating and driving RA in concert with inflammatory cells [7]. In the healthy synovium, one to three layers of synoviocytes, the macrophage-like type A and the more abundant fibroblast-like type B (also referred to as synovial fibroblast), form the synovial lining layer separating the synovial sublining layer of loose connective tissue from the joint cavity [8, 9]. The synoviocytes are interconnected with adherens junctions containing cadherin-11 [10, 11] and E-cadherin [12, 13] and are embedded in a lattice of extracellular matrix (ECM) resembling an epithelium but lacking a discrete basal membrane as well as gap junctions and desmosomes. Apart from being a marker of FLSs, cadherin-11 has been shown to be essential for the formation of synovial lining structures in vitro and for the development of inflammatory arthritis in mice [14, 15].
The morphological hallmarks of RA include activation of FLSs; infiltration of inflammatory cells such as T cells, B cells and macrophages in the sublining; hyperplasia of the synovial lining layer; fibrotic deposition; and subsequent formation of the "pannus" [16]. This tissue mass expands and attaches to and invades the adjacent cartilage and subchondral bone [17]. The major cell type accounting for the thickened lining layer as well as for pannus formation is believed to be activated FLSs [18, 19]. These aggressive cells share many characteristics with tumour cells, with upregulated expression of proto-oncogenes and promigratory adhesion molecules, increased production of proinflammatory cytokines and matrix-degrading enzymes [7], as well as increased resistance to apoptosis [20, 21]. There are data indicating that the transformed phenotype of RA-FLS is stable and maintained even in the absence of stimulus from inflammatory cells [22]. In high-inflammation synovial tissue, RA-FLSs show a gene expression profile characteristic of myofibroblasts, and cells of the synovial lining in RA have been found to express α-smooth muscle actin (α-sma) and type IV collagen [13, 23]. Thus, it has been suggested that RA-FLSs can undergo a process resembling epithelial-mesenchymal transition (EMT), a phenomenon known from early developmental processes, tissue repair, fibrosis and carcinogenesis [24, 25]. Recently, it was also suggested that migrating RA-FLSs might be responsible for spreading the disease to distant joints [26].
Podoplanin (identical to human PA2.26, aggrus and T1α-2), is a small, 38- to 40-kDa, mucin-type transmembrane glycoprotein normally expressed on human lymphatic endothelia, basal epithelial keratinocytes, myoepithelial cells and myofibroblasts of certain glandular tissues, follicular dendritic cells and fibroblastic reticular cells of lymphoid organs and alveolar type I cells [27, 28]. We demonstrated strong podoplanin expression on subepithelial interstitial cells in human endolymphatic tissue of the inner ear [29]. The physiologic function of podoplanin is to a large extent unknown, but knockout (KO) studies showed that it is crucial for the development of the lung and deep lymphatics in mice [28]. The podoplanin-KO mice died at birth as a result of respiratory failure and generalised lymphoedema. Overexpression of this glycoprotein in epithelial cells induced a dentritic cell morphology and increased cell adhesion and migration [27]. Interestingly, increasing data show that podoplanin is upregulated on the invasive front of human cancers [27, 30]. The expression of podoplanin is correlated with metastasis and a bad prognosis. In addition, podoplanin (or aggrus) induces platelet aggregation of tumour cells [31] and has been associated with both EMT-dependent and EMT-independent tumour cell invasion [32]. There are a few studies indicating increased podoplanin expression in fibroblasts in reactive tissues, such as in chronic pleuritis, in cancer-associated fibroblasts [33] and in cultured fibroblasts [34]. However, little is known about the potential role of podoplanin in inflammation and tissue repair. In this study, we were interested to see whether podoplanin is expressed in FLSs in RA and could be associated with the fibrotic transformation of the synovium in this disease.
Materials and methods
Human synovial tissue and cells
Characteristics of patientsa
RA (n= 18)
OA (n= 9)
Age, mean yr
Sex, F/M
Disease duration, mean yr
Seropositiveb, %
Larsen scorec (mean ± SD)
2.9 ± 0.6
DMARDs, %
Steroids, %
Biologic drugs, %
Paraformaldehyde (PFA)-fixed (Histolab, Göteborg, Sweden), paraffin-embedded (4 μm) or acetone-fixed (Histolab) frozen sections (6 μm) were rehydrated in Tris-buffered saline for 10 minutes. Antigen retrieval was performed when required in a pressure chamber (2100 Retriever; Histolab). Unspecific binding was blocked using serum-free protein block or normal rabbit serum (Dako, Glostrup, Denmark). After incubation with mouse monoclonal antihuman podoplanin (clone D2-40; AbD Serotec, Oxford, UK), mouse monoclonal antihuman cadherin-11 (clone 5B2H5; Invitrogen) or mouse monoclonal antihuman CD90 antibodies (clone AS02; Dianova, Hamburg, Germany), respectively, the specimens were incubated with a biotinylated rabbit antimouse immunoglobulin G F(ab')2 fragment (Dako) followed by streptavidin-conjugated alkaline phosphatase (Dako). Fast Red Naphthol (Sigma) was used as a substrate, and the specimens were counterstained with Mayer's haematoxylin (Histolab) and mounted in Aqua-Mount mounting medium (VWR International Ltd, Leicestershire, UK). The same staining protocol was used for immunocytochemistry of primary FLS seeded onto chamber slides (Lab-Tek; Nunc, Rochester, NY, USA) and fixed in PFA. Normal mouse IgG1 (Dako) was used as a negative control. The podoplanin staining was scored by two independent observers blinded to the procedure according to the following scoring method: 0 = negative staining, 1 = positive staining of single or limited groups of cells in the lining layer, 2 = continuous positive staining of the cells of the synovial lining layer and 3 = same as 2, but with the addition of positive staining of cells in the sublining layer.
Immunofluorescence and confocal microscopy
Paraffin-embedded synovial sections were subjected to a double-staining procedure: incubation with rabbit antihuman cadherin-11 (Invitrogen), rabbit anti-matrix metalloproteinase (MMP)-9 (AB805; Millipore, Billerica, MA, USA), rabbit antihuman E-cadherin (clone H-108; Santa Cruz Biotechnology, Santa Cruz, CA, USA) or rabbit anti-α-sma (PA1-37024; Thermo Scientific, Rockford, IL, USA) antibodies followed by addition of Alexa Fluor 555-conjugated goat antirabbit IgG (Invitrogen) or, in one step, Alexa Fluor 647-conjugated mouse antihuman CD68 (clone KP1; Santa Cruz Biotechnology). Second, mouse antihuman podoplanin (clone D2-40) incubation was followed by Alexa Fluor 488-conjugated goat antimouse IgG (Invitrogen). Alternatively, biotinylated mouse antihuman podoplanin (Acris Antibodies GmbH, Herford, Germany) and Alexa Fluor 488-conjugated streptavidin were added prior to mouse antihuman cadherin-11 (clone 5B2H5) and Alexa Fluor 555-conjugated goat antimouse IgG (Invitrogen). Slides were placed in ProLong Gold antifade reagent mounting medium with 4',6-diamidino-2-phenylindole (Invitrogen). Normal mouse IgG1 or normal rabbit serum (Dako) was used as negative controls. Images were collected using a confocal microscope (LSM700; Zeiss, Oberkochen, Germany). The background fluorescence level was set with the negative controls, and images were analysed using Zen image analysis software 2009 (Zeiss).
Western blot analysis
Membrane proteins from tissue and cell pellets were prepared by sodium carbonate treatment [37]. In brief, lyophilized material was resuspended in 0.1 M sodium carbonate before sonication. After removal of cell debris, the membrane fraction was collected by ultracentrifugation at 115,000 g for 75 minutes. The membrane proteins were solubilised with 7 M urea, 2 M thiourea, 40 mM Tris, 1% C7 detergent (wt/vol) and 4% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate buffer (wt/vol) and kept at -80°C before use.
Samples, together with recombinant unglycosylated human podoplanin core protein (ProSpec, Ness-Ziona, Israel), were separated by 20% sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions with 10 mM dithiothreitol. After being transferred onto polyvinylidene fluoride membrane, the blots were probed with mouse antihuman podoplanin (1:50; D2-40) and detected with a horseradish peroxidise-conjugated rabbit antimouse antibody (1:2,000; DakoCytomation) and chemiluminescence (SuperSignal West Femto Maximum Sensitivity Substrate; Thermo Scientific).
Flow cytometry
Primary synovial cell cultures from patients with RA (n = 6) and patients with OA (n = 5) were trypsinised, resuspended in fluorescence-activated cell sorting buffer (5% HIFBS, 0.09% sodium azide and 0.5% ethylenediaminetetraacetic acid in PBS) and transferred onto a 96-well plate. For intracellular staining (CD68; α-sma), cells were PFA-fixed and permeabilised with 0.1% Triton X-100 in PBS. Unspecific binding was blocked using 1% HIFBS in PBS or Beriglobin P (human IgG; Apoteket, Sweden). Staining was performed with allophycocyanin (APC)-conjugated mouse antihuman CD90, phycoerythrin (PE)-conjugated mouse antihuman CD68, PE-conjugated mouse antihuman CD29 (BD Biosciences, San Jose, CA, USA), mouse antihuman podoplanin (clone D2-40), mouse antihuman cadherin-11 (clone 5B2H5), rabbit antihuman α-sma (PA1-37024) and isotype controls (BD Biosciences). The unconjugated antibodies were incubated with secondary PE-conjugated rat antimouse IgG1 (BD Biosciences) or APC-conjugated goat antirabbit IgG (Santa Cruz Biotechnology) in a second step. Fluorescence was measured using the FACSCanto II system (BD Biosciences) equipped with DIVA 6.2 software (BD Biosciences), and data were analyzed using FlowJo 8.7.3 software (Tree Star Inc., Ashland, OR, USA). The isotype controls were used to set the gates for positive and negative populations.
Stimulation experiments
Primary FLSs from one OA patient were seeded into complete DMEM in triplicates in six-well plates (100,000 cells/well) and incubated until confluence. The cells were serum-starved in DMEM supplemented with 2% heat-inactivated foetal calf serum for 6 hours before the different human recombinant cytokines were added: 10 ng/ml TNFα (Sigma), 1 ng/ml IL-1β and 1 ng/ml TGF-β1 (R&D Systems, Minneapolis, MN, USA). The cells were harvested by trypsinisation after 12, 24 and 48 hours, and podoplanin expression was measured using flow cytometry with antipodoplanin antibody (clone D2-40). The experiment was repeated four times with different primary cell cultures, including RA-FLSs, with similar results.
Statistical analysis
Differences in protein expression between the patient groups detected by immunohistochemistry (IHC) and flow cytometry were evaluated using the Mann-Whitney nonparametric test.
Podoplanin is expressed in the human synovial lining layer in RA
Podoplanin is expressed on cadherin-11-positive synoviocytes of the lining layer in RA
α-sma is upregulated in podoplanin-expressing synovial lining layer cells
Next, we were interested to see whether podoplanin could be involved in EMT-like transdifferentiation of RA-FLSs. We therefore investigated the expression of α-sma and E-cadherin in relation to podoplanin in RA synovia. We found that α-sma was expressed in the cytoplasm of podoplanin-positive synovial lining cells in hyperplastic areas (Figure 3I). In addition, α-sma was expressed in vessel walls and on a few dispersed cells in the sublining. E-cadherin could be detected in some areas of the synovial lining layer in both RA and OA specimens. Interestingly, the expression of E-cadherin was very low or absent in podoplanin-expressing lining layer cells (Figure 3G and overview in Figure 3H).
Different MMPs (especially MMP-1, MMP-3, MMP-9 and MMP-13) are upregulated in the RA synovium and are responsible for the degradation of ECM and cartilage [5, 38]. We used MMP-9 as an indicator of inflamed synovium and of the presence of matrix degradation. MMP-9 is reportedly expressed in synovial lining cells, in leukocytes and in endothelia of the RA synovium [39]. In agreement with this, we found high expression of MMP-9 in the synovial lining, in sublining ectopic lymphoid structures and in vessels in RA synovial tissue (Figure 3J). Double-staining of podoplanin and MMP-9 showed that the podoplanin-positive lining layer cells expressed MMP-9 (Figure 3J).
Podoplanin is expressed in cultured CD90-positive FLSs
The podoplanin expression was further evaluated in six RA-FLS and five OA-FLS primary cell cultures using flow cytometry, showing an average expression of 52 ± 24% and 64 ± 6%, respectively. The variation in RA-FLS compared to OA-FLS was evident. Furthermore, 99 ± 6% of RA-FLSs expressed the fibroblast marker CD90, 97 ± 1% of RA-FLSs expressed CD29 (β1-integrin) and less than 0.6 ± 0.5% of RA-FLSs expressed the macrophage marker CD68. A percentage of 95 ± 0.7% OA-FLS expressed CD90, 98 ± 1% expressed CD29 and less than 0.8 ± 0.4% expressed CD68 (Figure 4C). The mean expression of cadherin-11 was low in OA-FLSs (2.3%) and slightly increased in RA-FLSs (up to 21%) (Figure 4D). Interestingly, one RA-FLS cell line had a more dendritic phenotype (Figure 4E) and was growing without contact inhibition. This cell line had a 100% expression of podoplanin on the basis of flow cytometry.
Cultured fibroblasts upregulate α-sma (up to 100% by passage 5) in culture [40, 41]. We were interested to see whether this is true also for primary FLSs. Using flow cytometry, we found that nearly 100% of both OA-FLSs and RA-FLSs express α-sma by passage 6. About 60% (58.2% for RA-FLSs and 61.7% for OA-FLSs) were double-positive for podoplanin and α-sma. All podoplanin-positive cells expressed α-sma (Figure 4F).
Podoplanin expression in vitrois increased by proinflammatory cytokines
IL-1β and TNFα are known to activate RA-FLSs. TGF-β1 is a key mediator of EMT and promotes the differentiation of fibroblasts into myofibroblasts in wound healing and fibrosis.
In this study, we investigated the effects of IL-1β, TNFα and TGF-β1 stimulation on podoplanin expression in primary FLSs. We found a more than twofold increase in podoplanin expression in OA-FLS culture after stimulation with 1 ng/ml IL-1β and 10 ng/ml TNFα. This culture had a low baseline expression of podoplanin (30%), which increased to 72% after 48 hours of IL-1β stimulation (Figure 4G). Using two different primary RA-FLS cultures, we found an early increase in podoplanin expression from, on average, 50% at baseline to about 90% after 12 hours of IL-1β stimulation. These effects were maintained after 36 hours of stimulation (data not shown). TGF-β1 (1 ng/ml) had a moderate effect (+1.7-fold) on podoplanin expression evident at late time points (48 hours) (Figure 4G).
In this study, we have shown that the tumour-associated proinvasive glycoprotein podoplanin is highly expressed in synovial lining layer cells in RA but is rarely found in OA synovial specimens. The expression of podoplanin was most pronounced in areas with signs of inflammation (that is, the presence of leukocyte infiltrates and ectopic lymphoid structures) and synovial transformation (indicated by lining layer hyperplasia, MMP-9 expression and upregulation of cadherin-11 and α-sma). Furthermore, the podoplanin-expressing lining layer cells expressed cadherin-11 but not the macrophage marker CD68, suggesting that these synoviocytes were FLSs rather than synovial macrophages.
All included RA patients had progressed to erosive disease (Larsen index score >1), and all except one had a high podoplanin expression score (IHC score >1) of the synovial tissue from the replaced joint (Table 1). However, without the rarely available tissue specimens from nonerosive and early RA joints to compare these tissues with, we could not analyze whether there is a correlation between erosive disease and podoplanin expression.
The function of podoplanin is far from elucidated. On one hand, this small glycoprotein is constitutively expressed on the apical surface of lymph endothelia as well as on specialised epithelia (for example, podocytes) facing fluid compartments [28, 42, 43]. On the other hand, podoplanin is crucial for processes involving cell migration, such as the specific embryologic development of deep lymphatics [28] and the invasion and metastasis of certain tumour cells or tissues [32]. Podoplanin has been shown to bind ezrin, an actin filament membrane linker protein, on the inside of the cell in vitro [30, 44]. It has therefore been suggested that podoplanin is involved in directing actin polymerisation, thereby forming the cellular protrusions needed for migration.
In our study, the marked and widespread expression of podoplanin in lining layer cells in RA was not restricted to the apical cell surface. Instead, it resembled the strong whole cell surface-staining pattern of podoplanin in tumour tissues [30]. It has been shown that RA-FLSs of highly inflammatory synovial tissue show a gene expression profile characteristic of myofibroblasts [23]. We detected coexpression of podoplanin and α-sma of FLSs in areas of synovial transformation and found that the expression of E-cadherin was low or absent in the podoplanin-expressing lining layer cells. We know from earlier studies that podoplanin can promote EMT of epithelial Madin-Darby canine kidney cells in vitro [44]. EMT is a biologic process in which polarised epithelial cells undergo sequential changes into a mesenchymal cell phenotype with increased migratory potential and the production of ECM components [24]. Loss of E-cadherin and gain of α-sma expression constitute examples of such changes. We therefore hypothesise that podoplanin is involved in an EMT-like transdifferentiation of RA-FLSs into myofibroblasts.
Podoplanin has been observed in interstitial fibroblasts in different inflammatory environments in vivo and in vitro [33, 34]. In agreement with this observation, we found a locally increased expression of podoplanin in interstitial cells of the sublining connective tissue in specimens from patients with RA. However, it is difficult to determine whether upregulated podoplanin expression in the sublining in some RA specimens was a result of general inflammation or whether this phenomenon was part of a specific activation and transdifferentiation of FLSs in RA.
To confirm the specificity of the D2-40 antibody and the expression of podoplanin in RA synovial tissue, we performed SDS-PAGE and Western blot analysis of protein extracts showing a distinct band of about 45 kDa. The mature glycosylated form of podoplanin has been estimated to be about 38 to 40 kDa [27]. The difference in approximated molecular weight could be explained by the reported heterogeneity of podoplanin in SDS-PAGE, which arises as a result of heavily O-linked glycosylation of the core protein [27] as well as a slightly unspecific migration of the used molecular weight markers.
Characteristics of RA are the phenotypic changes and hyperplasia of FLSs of the lining layer. Conventional isolation of FLSs from synovial tissue yields homogeneous fibroblast cultures [45], but the interindividual morphological variation is large, and cultures presumably arise from both the synovial lining and sublining layers.
We established primary cultures of FLSs from human synovial tissues by enzyme digestion and found that the cells had typical fibroblast morphology. Nearly all of the primary FLSs stained positive for the fibroblast marker CD90/Thy-1 and most expressed β1 integrins. However, the IHC staining of human synovia using the anti-CD90 antibody revealed positive expression in the sublining, but not in the lining layer cells (Figures 3A and 3B). Fibroblasts possess a remarkable phenotypic plasticity [41] as well as a positional identity [46]. The synovium (lining layer versus sublining layer) of both healthy and RA patients harbour phenotypically different (by morphology and expression of surface markers) populations of fibroblasts. CD90 might therefore be a good marker for interstitial tissue fibroblasts, but not for the FLSs forming the epithelium-like lining of the synovium. In addition, fibroblasts change the expression of several surface molecules in vitro and acquire an "active" phenotype with prominent stress fibres and focal adhesions [47] when cultured on plastic. We therefore concluded that most of the established primary FLS cultures in this study originated from the sublining connective tissue or acquired a sublining fibroblast phenotype (with respect to CD90 expression) in culture. Using IHC, we found that cadherin-11 was expressed both in the lining layer and in cells of the sublining tissue in reactive areas, but when using flow cytometry, we found it on average in only 10% of the isolated primary FLSs. These data support the assumption that the isolated primary FLSs in these experiments originated from the sublining rather than from the lining layer.
Fibroblasts have been shown to upregulate podoplanin in culture [34]. In this study, we did not observe any significant difference in mean podoplanin expression between the RA-FLS and OA-FLS cultures. Only one culture, derived from an RA patient, was growing without contact inhibition, a characteristic of activated FLSs in RA. All cells of this culture were expressing podoplanin. Taken together, our results suggest that cultures of the lining layer FLS phenotype are hard to establish by using this technique and that primary FLSs, like other fibroblasts, probably upregulate podoplanin in culture. The observed upregulated expression of α-sma of the primary FLSs constitutes another example of an acquired feature of cultured fibroblasts.
Finally, we found a more than twofold increase in podoplanin expression in primary FLSs after stimulation with IL-1β and TNFα compared with controls. Interestingly, we also detected an increase in podoplanin expression in response to TGF-β1 stimulation. TGF-β1 is a key mediator of EMT and promotes the differentiation of fibroblasts into myofibroblasts in wound healing and fibrosis. Furthermore, TGF-β1-induced podoplanin in human fibrosarcomas [48] was found to be increased in arthritic joints in RA [49] and promoted EMT of FLS in vitro [13]. The fact that proinflammatory cytokines and growth factors, known to be present in high concentrations in the RA joint, stimulate podoplanin expression in primary FLSs in vitro supports our finding that podoplanin is upregulated in the synovium of RA patients and might be involved in the transdifferentiation of FLSs in RA.
We can now add podoplanin expression as a shared characteristic of activated RA-FLSs and tumour cells that possibly affects common features of RA and carcinoma-like fibrotic tissue transformation and tissue invasion. Podoplanin might therefore be an important target not only in cancer therapy but also in the treatment of RA.
- α-sma:
α-smooth muscle actin
- DMARDs:
disease-modifying antirheumatic drugs
epithelial-mesenchymal transition
fluorescence-activated cell sorting
fibroblast-like synoviocyte
- IL-1β:
rheumatoid arthritis
- TGF-β1:
transforming growth factor-1β
- TNF-α:
tumour necrosis factor-α.
We thank Ing-Marie Jonsson, Sofia Andersson and the late Berit Ertmann-Ericsson for skillful technical assistance with paraffin embedding and sectioning. This work was supported by grants from The Göteborg Medical Society, The Swedish Rheumatism Association and The Rune and Ulla Amlöv Foundation.
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13 Comments
Simple but cool +1
Do check mine: http://www.designbyhumans.com/vote/detail/64407?page=1
cocoooo +1 :)
this is great, beautifully rendered.
rafaelsencebe Artist
ApathyDinosaur Artist
nice! +1
great….illustration ++
Great!!!really nice!!
PandaPouye Artist from France
just beautifull
playground Artist
oooh nice. Quite odd, I like it! +1
Andyoflove Artist
AWESOME!!! voted
check out http://www.designbyhumans.com/vote/detail/67470
niiice +1
great job +1
zeitgeistein Artist
Love it!


text:
Category:Frederick Stark Pearson
|Authority control
English: Frederick Stark Pearson (July 3, 1861 – May 7, 1915) was a United States electrical engineer and entrepreneur.
This category has only the following subcategory.
- ► A Pearson (15 F)
Media in category "Frederick Stark Pearson"
The following 3 files are in this category, out of 3 total.