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Tower Defence Warriors Outpost game is the best way feel the warriors' spirit! Start playing this amazing game and get into wonderful world of medieval kingdoms, castles and villages, thrones, skirmish, defence tower, dungeon, crusader, defence war, onslaught, defence heroes, fury and invasion! Do you remember movies about crusader, castle defence or defence tower heroes or another medieval community? Do you want to get to the same medieval empir
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Everyone loves Christmas and New Year holidays. And everyone waits for them decorating their houses inside and out with different ornamentation: tapes, toys, colored lights and, of course, Christmas candles! Feel the holiday atmosphere looking at winter scenes and Christmas will come to you at any time of the year, even in summer! Download our new Christmas candles screensaver and get the best desktop for your computer during the holidays.
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Halloween Adventure is one of the best our screensavers devoted to famous holiday. Halloween is the oldest holiday in the world. Celtic tradition of spirit celebration and Christian saints worship are mixed in this holiday. All sorts of evil come under the ground. Witches flying on the Sabbath, ghosts and vampires no longer shunned by men and appear before them in all its glory.
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POSTER is the award-winning program for creating big posters, signs, banners, murals, and enlargements, and printing them up to 100x100 feet on any printer. Get the best features of word-processing, graphics, and desktop publishing with features especially tuned for big posters and banners. This includes flexible graphics, a full set of drawing tools, and over 100 special text effects. Includes tutorial, extensive help, examples and templates.
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Dead Oil 1.6
This game is about a cube with a big heart who is in a closed, invisible maze. You can do nothing in this maze and still die, and the best way out is pure suicide! And the sooner the better! However, rumor has it that the Great Liberation Penetration is hidden in the labyrinth and maybe you will find it.
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Tipard Video Converter is able to convert any video to MP4, AVI, MOV, M4V, WAV, MKV and other general videos. Moreover, it can convert your videos to HD MP4, HD H.264 TS, HD MOV, HD AVI, HD H.264/MPEG-4 AVC, HD MKV and other 1080p HD video files. Meanwhile, it enables you to extract audios from your video, and then convert them to MP3, FLAC, WAV, WMA, MP2, AAC, AC3 and so on. Apart from that, this Video File Converter software supports NVIDIA� CUDA� technology that can accelerate you conversion speed. Besides, it owns powerful editing function like crop, trim and so on. After newly update, it is compatible with windows 10. Key functions: 1. Convert any video to MP4, AVI and more With the assistance of Video Format Converter, you can convert any video to general video formats like MP4, AVI, MOV, M4V, WAV, MKV and so on. Meanwhile, it can also convert your videos to HD MP4, HD H.264 TS, HD MOV, HD AVI, HD H.264/MPEG-4 AVC, HD MPEG-4, HD MKV and other 1080p HD videos. 2. Convert your videos to MP3, FLAC ...
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Tipard Mac iPhone Transfer Ultimate can help you transfer photos/videos/music and more from iPhone/iPad/iPod to Mac or from Mac to iPhone/iPad/iPod. It can also transfer files between any two iOS devices such as iPhone 6/6 Plus, iPhone 5S/5C, iPad mini 3, iPad Air 2, iPod and more. Meanwhile, it can also make a backup for your text message and contacts on Mac and it can delete the unnecessary contacts for you. Key functions: 1. Transfer files between iPhone/iPad/iPod and Mac This iPhone Transfer for Mac can help you transfer files such as photos, music, contacts, etc. from iPhone/iPad/iPod to Mac, so you can get your files make a backup on your Mac. Besides, you can also transfer photos /videos/music from your Mac to your iPhone/iPad/iPod. 2. Transfer files between iPhone/ iPad/ iPod iPhone File Transfer for Mac allows you to transfer files including photos, music, movie, contacts, between any two iOS devices like iPhone 6/6 Plus, iPhone 5S/5C, iPad mini 3, iPad Air 2, iPod and so on. 3. Backu ...
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text:
e longest he has ever made in one place. During his eight years there he was successful; but he finally antagonized the government, was arrested, and thrown into jail. He succeeded in escaping, fled to Salvador, and from there made his way to the United States, where, for a little time, he worked, unhappily, at San Antonio, Texas. A short time since, the Archbishop of Oaxaca was in Texas, met the padre, and promised him an appointment in his diocese. The padre was now on his way to Oaxaca to see the prelate and receive his charge.
He was full of hope for a happy future. When he learned that we were bound for the ruins of Mitla, he was fired with a desire to accompany us. At Oaxaca we separated, going to different hotels. My party was counting upon the company of Mr. Lucius Smith, as interpreter and companion, to the ruins, but we were behind our appointment and he had gone upon another expedition. This delighted the padre, who saw a new light upon the path of duty. The archbishop had received him cordially
Cara Devon has always suffered curiosity and im... Read more
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subset: commoncrawl


text:
Hotel Atlantis
No prices found through our partners. Please contact the business directly or check some of our recommended alternatives.
How has this hotel rated in the past?
- Spa
- Suites
- Shuttle bus service
- Microwave in room
- Heated pool
- Swimming pool
Travelers also recommend:
TripAdvisor Reviews Old Colonial Motel Old Orchard Beach
Travel Blogs from Las Terrenas
Las Terranas & Playa Rincon
... Samana from as high as 1,500 feet. Unfortunately, the heavy rain overnight made me skip the area's top natural attraction, the Salto de Limon, a waterfall that's either an hour hike each way along a steep and usually very muddy trail or a guided horse ride trip, and those things scare me. I always think of Christopher Reeve whenever I ride a horse; if a horse could do that to Superman, imagine what one could do to a chubby middle-aged guy like ...
Samana Peninsula - Tropical Beach Paradise
... but there aren't many ways to
make even a pretty basic living. The settlements all look a little
hardscrabble, but maybe in a warm climate you don't need much more to survive
than a roof over your head and enough income to buy food. The peninsula is
actually one of the main growing areas for the D.R.'s significant production of
organic cocoa, but growing agricultural commodities usually doesn't provide
much income for too many people.
Headed back to the States
... we've started. We are excited to see more pictures of the finished results. Please continue to pray for safe travels. Our little crew is tired and a few are not feeling well. Nothing too bad ... Just the culmination of a week of work , sun, sand and more sun! We are sad to be leaving but excited to come home and to serve in new and tangible ...
At the Work & Witness House
After many tears, we left Nagua around 1:00 and headed to Santo Domingo. We arrived safely and have spent the rest of the evening hanging out and playing cards. After many hours in the son working and building relationships, it was good to take a break for a while. We will be headed out first thing in the morning to do some sports ministry and sight seeing before checking into the hotel for the last leg of the ...
Work Day #2
It is very late but I wanted to update everyone a bit on our trip. It has been an amazing two days. Yesterday, we worked from 8:30 to 6 pm, painting the windows and bars throughout the upstairs of the church in El Factor. This was very time consuming because we had to clean every bar, paint them with a red anti rust paint and then go back over everything with multiple coats of white paint. We also painting all ...


text:
BY: Laura Machell
I am a self-taught... MORE
I am a self-taught baker/cook. Ironically enough I was lead down... MORE
- Prep5 Mins
- Cook10 Mins
- Total15 Mins
- Yield3 Servs
About this recipe
Between the crunchy texture and all the complementing flavors- salty, spicy, AND sweet, they just hit every note with your taste buds. Plus they are so simple and quick to make- just roast the nuts and toss with the other ingredients immediately out of the oven. Done. Couldn't be easier.
- 2 1/4 cups (18 oz.) assorted unsalted nuts, including peeled peanuts, cashews, Brazil nuts, hazelnuts, walnuts, pecans and whole unpeeled almonds
- 2 tbsp. coarsely chopped fresh rosemary leaves
- 1/2 tsp. cayenne pepper
- 2 tsp. dark brown sugar
- 2 tsp. sea salt
- 1 tbsp. unsalted butter, melted
- Preheat the oven to 350 F.
- Toss the nuts in a large bowl to combine and spread them out on a baking sheet. Toast in the oven until light golden brown, about 10 minutes.
- In a large bowl, combine the rosemary, cayenne, sugar, salt and melted butter.
- Thoroughly toss the toasted nuts in the spiced butter and serve warm.
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text:
Ratings based on 7,775 Verified Reviews
They paid and stayed. We double-checked.
4.7 Room cleanliness
4.6 Service & staff
4.8 Room comfort
4.7 Hotel condition
They paid and stayed.
We double-checked.
We double-checked.
for Everyoneby A verified traveler from JAPAN
やっぱりLASは面白いPosted Oct 9, 2015
Pros: MGMGRANDに泊まるより静かだと思います。でも歩くねぇ
Cons: 無し
Location: ロケーションは文句なし。
4泊しました。MGMに泊まろうかと思いましたがキッチンがあるほうが良いかと思いシィグネチャーにしました。 この料金なら圧倒的に良いです。ただ我々はただのギャンブル好きなので基本カジノに入り浸って風呂の変わりに プールとジャグジーに入ってましたので良く考えるとほとんどベッドに入っていることはなかったので、勿体なかったと思いますが設備等は中の上で問題もありませんでした。 ただ辛かったことは、部屋からMGMカジノまで体感2Kmぐらいあるように感じましたねWWWでも動く歩道もあるし。 それとキッチネット付でしたがコーヒーメーカーと紙コップしかなくフォークナイフお皿湯沸しポットがなく 大勝利の日ドンぺりを買ってきて紙コップでのみました。WWその辺はさすがLASのホテルのポリシーだったんでしょう。 ストリップは毎日お祭りのようににぎやか。 日本にたとへカジノができてもLASのほうが良い。楽しい楽しい旅行でした。
for Couplesby A verified traveler from Takapuna, Auckland, New Zealand
Tower 3Posted Oct 8, 2015
Pros: Location to the MGM Grand and the Strip, ease of access, quiet yet close to the action.
Cons: The pool was closed and no deli/restaurant in the Tower
Location: Great location, easy walk to the action
A one bedroom suite was exactly as advertised, spacious, clean and very comfortable. The kitchen was adequate for our simple breakfast needs, cutlery and crockery were delivered without fuss. A very pleasant and quiet suite on the 22nd floor.
for Everyoneby A verified traveler from somerset
Love this hotel so muchPosted Oct 8, 2015
This is the third time we've stayed at The Signature and this time was extra special as we were married in Vegas and stayed on for our honeymoon. We were up graded to a one bedroom suite and it was fantastic!
for Everyoneby A verified traveler from uk
Really nice hotel stayed twice nowPosted Oct 7, 2015
Second time staying at this hotel. Stayed in a balcony suite, very clean, very spacious, huge balcony. Staff as always very friendly and polite. What we like about this hotel is the signature is away from the noise of the strip but close enough to get to. Also each tower has its own private pool which are generally always quiet which is an added bonus and not a pool party atmosphere!
for Everyoneby A verified traveler
Wonderful Stay!Posted Oct 6, 2015
We loved the Signature at MGM Grand! Beautiful 1 Bedroom Suite. Excellent Service from the staff. Covered walkway to MGM Grand with moving sidewalks made the walk easy and quick. We highly recommend this hotel and we will book there again!
for Familiesby A verified traveler from Smiths Falls, Ontario
Very nice hotel connected to the Vegas stripPosted Oct 6, 2015
Pros: Liked the location and the service of all.
Cons: I did not see anything that required improvement.
Location: The location and proximity to the strip, casinos, and the tram was great. Shopping was also convenient.
Family oriented hotel without all the noise from the strip, but connected to the strip. Liked the no smoking policy and the kitchenette in the suite. Very close to the Miracle Mile shops and the tram. The Housekeeping staff were some of the best I have seen, and anything that you required was supplied right away. The Front Desk staff were equally friendly and professional. Would definitely stay there again.
for Everyoneby A verified traveler from nz
Good facilities.Posted Oct 5, 2015
Great family friendly hotel with ac walkway to strip.
for Everyoneby A verified traveler from London
Great views of the StripPosted Oct 4, 2015
Pros: The views, having a full sized fridge, clean and comfy room.
Cons: It's a shame that pool no.3 is only open at the weekend. Often housekeeping wouldn't come until around 4pm.
We couldn't fault the hotel. The bed was comfy, the room was clean, and the views of the Strip were brilliant - literally!
for Everyoneby A verified traveler from 日本・さいたま
とても満足です。Posted Oct 4, 2015
Pros: 清潔さ、ホスピタリティ
とても満足です!文句ありません。なにもかもすべて思った以上のホテルでした。 ラスベガスに行くときは、ぜひまた泊まりたいホテルです。
for Everyoneby A verified traveler from new zealand
Posted Oct 4, 2015
Check in was fast and easy. The room was amazing! Stayed on the 29th floor facing Las Vegas strip. The view was awesome. Would 100% recommend.


text:
On "Wild Man", the first single from Kate Bush's winterized 10th album, the singer tells of an expedition searching for the elusive Abominable Snowman. "They want to know you," she coos, "They will hunt you down, then they will kill you/ Run away, run away, run away." Of course, when it comes to modern popular figures-- who often court fame and adulation with an obsessiveness that can be fascinating or just plain sad-- Bush herself is something of a mythical beast. 50 Words for Snow is only her second album of original material in the last 17 years, and she hasn't performed a full concert since her groundbreaking and theatrical Tour of Life wrapped up its six-week run in 1979. So it's no surprise that she readily sympathizes with the misunderstood monster at the center of "Wild Man": "Lying in my tent, I can hear your cry echoing round the mountainside/ You sound lonely."
50 Words for Snow is teeming with classic Bush-ian characterizations and stories-- fantasies, personifications, ghosts, mysteries, angels, immortals. As quoted in Graeme Thomson's thorough, thoughtful recent biography Under the Ivy, she explained her attraction to such songwriting: "[Songs] are just like a little story: you are in a situation, you are this character. This is what happens. End. That's what human beings want desperately. We all love being read stories, and none of us get it anymore." She's onto something; in our postmodern era, the idea of a tale can seem quaint and simple.
But Bush continues to infuse her narratives with a beguiling complexity while retaining some old-school directness. Because while most of this album's songs can be easily summarized-- "Snowflake" chronicles the journey of a piece of snow falling to the ground; "Lake Tahoe" tells of a watery spirit searching for her dog; "Misty" is the one about the woman who sleeps with a lusty snowman (!)-- they contain wondrous multitudes thanks to the singer's still-expressive voice and knack for uncanny arrangements. And mood. There's an appealing creepiness that runs through this album, one that recalls the atmospheric and conceptual back half of her 1985 masterpiece Hounds of Love. Indeed, when considering this singular artist in 2011, it's difficult to think of worthy points of reference aside from Bush herself; her onetime art-rock compatriots David Bowie and Peter Gabriel are currently MIA and in rehash mode, respectively. And while current acts including Florence and the Machine are heavily inspired by Bush's early career and spiritual preoccupations, none are quite able to match their idol's particular brand of heart-on-sleeve mysticism. In an interview earlier this year, the 53-year-old Bush told me she doesn't listen to much new music, and after listening to the stunningly subtle and understated sounds on Snow, it's easy to believe her.
The album's shortest song, the gorgeous closing piano ballad "Among Angels", clocks in at almost seven minutes. "Misty" rolls out its brilliant, funny, and bizarrely touching tale across nearly a quarter of an hour. It's not one second too long. During the 12-year gap between 1993's The Red Shoes and 2005's Aerial when she was raising her son Bertie, Bush gained a new level of compositional patience. She's now allowing her songs to breathe more than ever-- a fact reinforced by this year's Director's Cut, which found her classing-up and often stretching out songs from 1989's The Sensual World and The Red Shoes via re-recordings. So while "Misty" is an eyebrow-raiser about getting very intimate with a cold and white being with a "crooked mouth full of dead leaves," it hardly calls attention to its own eccentricities. Propelled by Bush's languid piano and the jazzy, pitter-pattering drums of veteran stick man (but relatively new Bush recruit) Steve Gadd, the song is about as appealingly grown-up as a song about having sex with a snowman can possibly be. In her early career, Bush sometimes let her zaniness get the better of her, highlighting her tales of sexual taboo and bizarre yarns with look-at-me musical accompaniment and videos. Those days are long gone. And her heightened sophistication works wonders here. So when the song's titular being is nowhere to be found the following morning-- "the sheets are soaking," she sings-- there is nothing gimmicky about her desperation: "Oh please, can you help me?/ He must be somewhere."
The ending of that song brings up another common thread through Snow, aside from its blizzard-y climate. This is an album about trying, oftentimes futilely, to find connections-- between Bush and her characters, reality and surreality, love and death. "Snowflake" is a duet with her 13-year-old son, where he plays the small fleck of white falling down from the sky, his high-pitched, choir-boy voice hitting the kind of notes his mom was originally famous for. On the track, Bush encourages her son-- "The world is so loud/ Keep falling/ I'll find you"-- and yet the plaintive piano that steers things is seemingly aware that, once the flake arrives, it'll either melt or disappear among millions of other icy bits. Similarly, while the lake-bound ghost of "Lake Tahoe" is overjoyed to find her long-lost dog-- coincidentally named Snowflake-- at the end of the song, the reunion comes with its own specter of bittersweet afterlife. The same sort of disconnect defines "Snowed in at Wheeler Street", an eerie duet with Bush's teenage idol Elton John about a star-crossed pair who have "been in love forever"-- literally. The time-traveling track finds its leads going from ancient Rome to World War II to 9/11, always losing each other along the way. It acts as something of a sequel to Bush's "Running Up that Hill", another tale of pained co-dependence. There's no happy ending. "When we got to the top of the hill/ We saw Rome burning," sings Elton.
While much of 50 Words for Snow conjures a whited-out, dream-like state of disbelief, it's important to note that Bush does everything in her power to make all the shadowy phantoms here feel real. Her best music, this album included, has the effect of putting one in the kind of treasured, child-like space-- not so much innocent as open to imagination-- that never gets old. "I have a theory that there are parts of our mental worlds that are still based around the age between five and eight, and we just kind of pretend to be grown-up," she recently told The Independent. "Our essence is there in a much more powerful way when we're children, and if you're lucky enough to... hang onto who you are, you do have that at your core for the rest of your life." Snow isn't a blissful retreat to simpler times, though. It's fraught with endings, loss, quiet-- adult things. This is more than pure fantasy. When faced with her unlikely guest on "Misty", Bush pinches herself: "Should be a dream, but I'm not sleepy."
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Is this restaurant good for couples?
Is this restaurant good for dinner?
Does this restaurant serve Mexican food?
Does this restaurant serve burritos?
Does this restaurant serve tortillas?
Is this restaurant good for breakfast?
Is this restaurant good for brunch?
Is this restaurant family-friendly?
Does this restaurant offer takeout or food to go?
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Thanks for helping!
I had the beef and queso burrito. What impressed me most was that they made the tortilla fresh and I front of me versus the sub par tortillas at most San Antonio places. Make sure and ask for the habanero sauce, that's if you like it hot!
3 days in San Antonio
San Antonio for young kids
San Antonio for free
Seriously! One of the best meals ever! We tried three different tacos - chicken, beef, and pork. All tender, all tasty (my personal favourite was the fork tendered beef). We shared the nachos - piled mile-high and topped with a scoop of guacamole . We ordered burritos too...but we're too full to try them. We enjoyed their huge margaritas although...
Fast food from fresh ingredients. locally owned. Our go to spot for a quick bit when at the Rim or after church.
I used to live in San An and frequented HG often. I loved it. Back through on a road trip and had to hit it up, but the former quality I was used to from about 5 years ago was sadly lacking. I hope I hit them on an off day. It wasn't bad, but it certainly wasn't the burrito...
My husband and I visited this place for the first time late last night. John, the counter guy, took the time to explain the menu items and how the food was prepared. The tortilla soup and queso were almost gone but we were there late at night so we knew that might be a possibility. Some more queso was being...
I have been to chipotle and Freebirds, this place is neither! It was was different and you should be looking for different when you go there, the foods seemed fresh and the tortillas are fresh made, the service was terribly slow(don't know if that's the rule or not) it wasn't bad, was better than Taco Bell. The staff was friendly,helpful...
I have tried Chipotle and I have tried Freebirds. I can tell you right off the bat that I do not like Chipotle at all. I believe that it's the many years of eating real Mexican food that I can't stand a place like that claims it is Mexican. But this review is not about Chipotle or Freebirds (which is...
I've known about this place on West Ave for years but never had the opportunity to eat there. Had some time this evening after dropping off my son for church youth meeting and decided to give it a try. The place had a good mix of some families, couples, and high school kids eating there. Friendly counter person asked if...
Good little burrito place if you're looking for an alternative to Chipotle. They press and cook the tortillas when you order and have a variety of options including build-your-own. All the ingredients tasted fresh and burrito is HUGE. Definitely recommend.
I went for the first time yesterday, at the recommendation of a person that used to live in San Antonio. The food is fresh, large portions, and very reasonably priced. The queso was great! I would recommend this place to everyone.
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A Clear View of Cash
Volatility in the forex market, the prospect of higher rates and the effects of Basel III are all encouraging companies to get a better handle on their cash flows.
By Simone Meier, Bloomberg |
August 14, 2012
The currency bloc's GDP declined 0.2% from Q1 levels, with at least six nations in recessions.
By Jeff Black, Bloomberg |
July 5, 2012
Central bank also lowers its rate on overnight deposits to zero.
By Emma Ross-Thomas and Simone Meier, Bloomberg |
April 30, 2012
GDP contraction in Q1 signals country's second recession since 2009.
By Maria Petrakis and Fabio Benedetti-Valentini, Bloomberg |
March 8, 2012
Private investors with about 60% of the debt have agreed to participate.
By Maria Petrakis, Bloomberg |
March 7, 2012
Investors holding $106 bln of Greek bonds have agreed to swap.
By Fabio Benedetti-Valentini and Natalie Weeks, Bloomberg |
March 6, 2012
Finance minister says nation willing to force investors to sign on.
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Female out of NFC/FC Rawhide's Clown top and bottom - German Shorthaired Pointers in California - HUNTING DOG Kennels
Pleasure to hunt with. Dixie is a 5 year old Female, you can hunt and actually kill birds with her tomorrow. She knows her job hardly needs any commands in the field. Points till you flush and retrieves to hand every time she has been force broke to retrieve. She is just outstanding bird dog close working perfect for the Hunter on foot. Please check out her pedigree and picture below. She is Priced at $2,800 Only Serious Buyers Please.
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Edmonton mayor calls for voters to support their city
Edmonton mayor calls for voters to support their city.
Edmonton mayor calls for voters to support their city.
Madonna shone a ray of light on an unsuspecting couple in the front row at her Sunday concert in Edmonton.
After an Edmonton man was ordered to clean up his months-long yard sale, neighbours say they are relieved they no longer have to stare at what quickly turned into an eyesore.
Edmonton's Millbourne Laundromat Thanksgiving Dinner has become a tradition in itself.
St. Albert will get freaky on Halloween weekend with plant-people, goth-punks and an 800-square-foot haunted house.
A week after Spider-Mable saved the city the six-year-old has won another fight, this time finishing her last round of chemotherapy on Friday.
Two Edmonton doctors are going to space.
Standing on the corner where her son was last seen seven years ago, Melanie Alix made an emotional plea asking anyone who knows what happened to Dylan Koshman to come forward.
JASPER — Looking west out of our hotel room, there's a mighty mountain and the sun fades in out, shining between the intermittent cloud.
Around 850,000 Canadians cast their ballots on just the first day of advance polls on Friday, according to Elections Canada.
NAIT students cooked up a Thanksgiving meal for hundreds of less fortunate Edmontonians Sunday.
A man is dead and another was flown to hospital by STARS after a crash near Stony Plain.
While Edmonton's police chief pointed to low oil prices for a recent spike in crime, the root causes of crime in the city are far more complex.
A couple got a wedding day scare in Saturday when a family of guests went missing, but the family was found safe on Sunday.
A councillor who sat on the Northlands board for six years only heard about the $1 million parking theft through the news.
Connor and the Oilers won out over the Eskimos at local watering holes Saturday.
A north-side community has its fire station back after a year of renovations.
Edmonton students are dishing out a few courses of their own Sunday to help those in need celebrate Thanksgiving.
After a three-month battle, a yard sale in Edmonton's McKernan neighbourhood has been cleaned up.


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Page 1
Activation of the Unfolded Protein
Response Contributes toward the
Antitumor Activity of Vorinostat1
Soumen Kahali*,†, Bhaswati Sarcar*,†, Bin Fang‡,
Eli S. Williams§, John M. Koomen‡,¶, Philip J. Tofilon§
and Prakash Chinnaiyan*,†
*Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa,
FL, USA;†Experimental Therapeutics, H. Lee Moffitt Cancer
Center, Tampa, FL, USA;‡Proteomics, H. Lee Moffitt Cancer
Center, Tampa, FL, USA;§Drug Discovery, H. Lee Moffitt
Cancer Center, Tampa, FL, USA;¶Molecular Oncology,
H. Lee Moffitt Cancer Center, Tampa, FL, USA
Histone deacetylase (HDAC) inhibitors represent an emerging class of anticancer agents progressing through clinical
trials. Although their primary target is thought to involve acetylation of core histones, several nonhistone substrates
have been identified, including heat shock protein (HSP) 90, which may contribute towards their antitumor activity.
Glucose-regulated protein 78 (GRP78) is a member of the HSP family of molecular chaperones and plays a central role
in regulating the unfolded protein response (UPR). Emerging data suggest that GRP78 is critical in cellular adaptation
and survival associated with oncogenesis and may serve as a cancer-specific therapeutic target. On the basis of
sharedhomology withHSP family proteins,wesoughttodetermine whether GRP78could serve asa moleculartarget
of the HDAC inhibitor vorinostat. Vorinostat treatment led to GRP78 acetylation, dissociation, and subsequent activa-
tion of its client protein double-stranded RNA-activated protein-like endoplasmic reticulum kinase (PERK). Investiga-
tions in a panel of cancer cell lines identified that UPR activation after vorinostat exposure is specific to certain lines.
Mass spectrometry performed on immunoprecipitated GRP78 identified lysine-585 as a specific vorinostat-
induced acetylation site of GRP78. Downstream activation of the UPR was confirmed, including eukaryotic initiat-
ing factor 2α phosphorylation and increase in ATF4 and C/EBP homologous protein expression. To determine the
biologic relevance of UPR activation after vorinostat, RNA interference of PERK was performed, demonstrating
significantly decreased sensitivity to vorinostat-induced cytotoxicity. Collectively, these findings indicate that
GRP78 isabiologictargetofvorinostat,andactivationoftheUPRthroughPERKphosphorylationcontributestoward
its antitumor activity.
Neoplasia (2010) 12, 80–86
Although cancer has traditionally been considered a disease originating
from genetic alterationsresultingin functional loss of tumor-suppressor
genes or gain of oncogenes, epigenetic modifications, or modulating
gene expression through mechanisms other than changes in the under-
lying DNA sequence have emerged as a contributing factor toward
inanopen configuration,allowing accessibility forspecifictranscription
factors and/or the general transcription machinery [2]. The opposing
Abbreviations: ATF, activated transcription factor; CHOP, C/EBP homologous protein;
eIF, eukaryotic initiation factor; GRP78, glucose-regulated protein 78; HSP, heat shock
endoplasmic reticulum kinase; UPR, unfolded protein response
Address all correspondence to: Prakash Chinnaiyan, MD, H. Lee Moffitt Cancer Center
and Research Institute, SRB3, 12902 Magnolia Dr, Tampa, FL 33612.
E-mail: firstname.lastname@example.com
1This work was supported in part by the Miles for Moffitt Research Award (P.C.). The
Moffitt Proteomics Facility is supported by the US Army Medical Research and Material
Command under Award No. DAMD17-02-2-0051 for a National Functional Genomics
Center, the National Cancer Institute under Award No. P30-CA076292 as a Cancer
Center Support Grant, and the Moffitt Foundation.
Received 18 August 2009; Revised 8 October 2009; Accepted 8 October 2009
Copyright © 2010 Neoplasia Press, Inc. All rights reserved 1522-8002/10/$25.00
DOI 10.1593/neo.91422
Volume 12 Number 1 January 2010pp. 80–86
Page 2
result in histone acetylation and deacetylation, respectively, leading to
chromatin remodeling and transcriptional regulation.
Currently, it is widely recognized that HDACs represent promising
therapeutic targets, with an underlying rationale of reversing aberrant
epigenetic states associated with cancer. For example, both aberrant re-
cruitment of HDACs to promoter regions and altered expression of
there has been considerable effort in the development of HDAC in-
hibitors as a form of targeted anticancer therapy. A large number of
structurally diverse HDAC inhibitors have been identified demonstrat-
ing preclinical activity in various cancer cell lines [4–6]. Several are cur-
rently in clinical evaluation, including valproic acid and vorinostat
(suberoylanilide hydroxamic acid; Zolinza), which is an HDAC in-
hibitor that has recently been granted Food and Drug Administration
approval for use in cutaneous T-cell lymphoma and is currently being
tested in solid tumors.
Although reversalofaberrant epigeneticchangeshas beenconsidered
the primary mechanism underlying HDAC inhibitor antitumor ac-
tivity, recent investigations suggest their effects may be considerably
broader, largely based on the expanding number of recently identified
nonhistone substrates of HDACs. At least 50 nonhistone proteins
of known biologic function have been identified, suggesting a more
appropriate term for these enzymes may be protein rather than histone
deacetylases [3,4]. These nonhistone protein targets include transcrip-
tion factors, chaperone proteins, DNA repair proteins, and structural
proteins, and acetylation can either increase or decrease their function
or stability. As these identified HDAC substrates are involved in a di-
verse array of biologic processes, multiple mechanisms may influence
the activity of HDAC inhibitors.
A specific nonhistone target of HDAC inhibitors that has gained re-
cent attention isthechaperone protein heatshock protein 90(HSP90).
HSP90 is required for the stability and function of numerous client
proteins, including mutated and overexpressed proteins that promote
cancer cell growth and survival, suggesting its potential to serve as a
therapeutic target [7]. Recent investigations demonstrated the potential
of HDAC inhibitors to acetylate HSP90, leading to dissociation of its
clientoncoproteins,including ErbB1,ErbB2,bcr-abl,andAkt.Further
investigations identified HDAC6 as the putative target [8,9] and acety-
lation to play a functional roleinregulating theHSP90chaperonecycle
[7]. Although HDAC inhibitors have demonstrated the capacity to in-
fluence HSP90 acetylation, it remains unclear the degree to which this
influences their antitumor activity.
In this report, we identified the endoplasmic reticulum (ER) chap-
eroneproteinglucose-regulatedprotein 78(GRP78) to serveasanother
nonhistone target of HDAC inhibitors. GRP78, which shares close
homology with the heat shock family of proteins, serves as the critical
sensor for ER stressand asanactivator ofthe unfoldedproteinresponse
(UPR), a highly specific signaling pathway to cope with the accumula-
tion of unfolded or misfolded proteins [10,11]. Recent investigations
suggest that GRP78 may be an important mediator in maintaining
survival in"stressed" cells, suchascancer, and thereforemay have thera-
peutic implications[12].We have shownthatGRP78isacetylatedafter
HDAC inhibition, leading to dissociation of its client protein double-
stranded RNA-activated protein-like ER kinase (PERK), activation of
the UPR, and abrogating this pathway leads to decreased sensitivity to
vorinostat-induced cytotoxicity. Collectively, these findings indicate
that GRP78 is a biologic target of HDAC inhibitors, and activation
tumor activity.
Materials and Methods
Cell Lines and Treatment
Tumor Repository. Cells were maintained in RPMI medium sup-
plemented with either 5% (U251, DU145, or SF539) or 10% (U87
or PC3) fetal bovine serum and glutamate (5 mM). Cell cultures
were maintained at 37°C and 5% CO2. Vorinostat was provided by
Merck Research Laboratories (Whitehouse Station, NJ) through the
NCI-CTEP and was dissolved in DMSO at 1 mM. Valproic acid was
purchased from Sigma-Aldrich (St. Louis, MO) and dissolved in PBS
at 100 mM.
Cellular extracts were prepared with lysis buffer (50 mM Tris-HCl
[pH 7.4], 150 mM NaCl, 1 mM EDTA, 0.5% Na-deoxycholate,
0.7 μg/ml pepstatin, 1% NP-40, and protease inhibitor cocktail).
Five hundred micrograms of whole-cell lysates was precleared with
a 50-μl mixture of protein A-agarose and protein G-agarose (Roche
Diagnostic Corp., Indianapolis, IN) in a rotator at 4°C overnight.
Fifteen micrograms of rabbit GRP78 polyclonal primary antibody
(Santa Cruz Biotechnology, Santa Cruz, CA) was added to the lysate
and incubated for 3 hours at 4°C. Then, 50 μl of protein A-agarose
beads was added to the lysate and incubated overnight at 4°C. Beads
were then pelleted by centrifugation and washed three times with 1)
ice-cold washing buffer, 2) high salt buffer (50 mM Tris-HCl [pH 7.4],
500 mM NaCl, 1 mM EDTA, 0.05% sodium deoxycholate, 0.1%
NP-40, and protease inhibitor cocktail [Roche Diagnostic Corp.]),
and (3) low salt buffer (50 mM Tris-HCl [pH 7.4], 1 mM EDTA,
0.05% sodiumdeoxycholate,0.1%NP40,andproteaseinhibitorcock-
tail [Roche Diagnostic Corp.]). Pellet was then resuspended in sample
buffer, heated at 90°C for 10 minutes, and centrifuged.
Immunoblot Analysis
For the extraction of the whole-cell lysates, cells were harvested by
centrifugation at 1000 rpm for 5 minutes. Cell pellets were washed
once with PBS, gently resuspended in 200 μl of lysis buffer (1% Triton
X-100, 1 mM phenylmethylsulfonyl fluoride, 10 μg/ml leupeptin,
1 μg/ml pepstatin-A, 2 μg/ml aprotinin, 20 mM p-nitrophenyl phos-
phate, 0.5 mM sodium orthovanadate, 1 mM 4-(2-aminoethyl)
benzenesulfonylfluoride hydrochloride) with protease inhibitor cocktail
(Roche Diagnostic Corp.) and phosphatase inhibitor (Sigma-Aldrich),
and incubated on ice with occasional vortexing for 30 minutes. Cell
lysates were centrifuged at 12,000 rpm in a tabletop centrifuge for
15 minutes to remove the nuclear and cellular debris. Proteins were
resolved by sodium dodecyl sulfate–polyacrylamide gel electrophoresis
(SDS-PAGE), transferred to polyvinylidene difluoride (PVDF) mem-
with primary antibody. Primary antibodies used include anti–acetyl
Ser51 phosphospecific antibody (Cell Signaling Technology, Beverly,
MA), anti–phosphospecific PERK, anti-PERK, anti-ATF4, anti–C/EBP
homologous protein (CHOP), and anti-GRP78 (Santa Cruz Biotech-
nology), and antiactin (Sigma-Aldrich). Secondary antibodies conju-
gated to horseradish peroxidase (Santa Cruz Biotechnology) were
used, and chemiluminescence (Thermo Fisher Scientific, Rockford,
IL) or enhanced chemiluminescence (GE Healthcare, Piscataway, NJ)
was used for detection.
Neoplasia Vol. 12, No. 1, 2010 Vorinostat-induced Activation of the Unfolded Protein ResponseKahali et al.
Page 3
Liquid Chromatography Coupled with Tandem
Mass Spectrometry
For the detection of discrete acetylation sites of GRP78, liquid chro-
matography coupled with tandem mass spectrometry (LC–MS/MS)
was used. Immunoprecipitated GRP78 was resolved on 4% to 15%
gradient gel (Bio-Rad, Hercules, CA) using SDS-PAGE. Gel bands
corresponding to GRP78 were excised and washed once with water
and twice with 50-mM ammonium bicarbonate in 50% aqueous
methanol. After reduction with triscarboxyethyl phosphine and alkyl-
sequencing grade trypsin (Promega, Madison, WI). Peptides were ex-
tracted from the gel slices and concentrated under vacuum centrifuga-
tion. A nanoflow liquid chromatograph (U3000; Dionex, Sunnyvale,
CA) coupled to an electrospray ion trap mass spectrometer (LTQ
peptide sequencing experiments. Peptides were separated with a C18
reverse phase column (75-μm inner diameter × 15 cm, C18Pepmap;
Dionex) using a 90-minute gradient from 5% to 50% B (A: 2%
acetonitrile/0.1% formic acid; B: 90% acetonitrile/0.1% formic acid).
Five tandem mass spectra were acquired for each MS scan (spray
voltage, 2.5 kV; 30% normalized collision energy; scanning m/z,
450-1600). Sequences were assigned using SEQUEST (Thermo)
and Mascot (www.matrixscience.com) database searches against
SwissProt human protein entries. In addition to acetylysine, oxidized
Figure 2. GRP78acetylationassessedinU251cellstreatedwithvorinostat(1μM,24hours)andvehiclecontrolusingLC–MS/MS.Thepeptide
was detected at 16.20 minutes in the total ion chromatogram (A) with a mass-to-charge ratio of 855.4332 (B). The tandem mass spectrum
and y12is consistent with this localization (C). Theassignment was made with MASCOT with an ion score 35.8; SEQUEST XCorr 2.30 ΔCn0.15.
Figure 1. HDAC inhibitionwithvorinostatleads to GRP78 acetylation
and dissociation with its client protein PERK. The glioblastoma cell
line U251 was exposed to vorinostat (1 μM) for 6 and 24 hours. Cell
lysateswereimmunoprecipitated(IP)forGRP78 andimmunoblot (IB)
as loading control.
Vorinostat-induced Activation of the Unfolded Protein ResponseKahali et al.Neoplasia Vol. 12, No. 1, 2010
Page 4
methionine, deamidation, and carbamidomethyl cysteine were se-
lected as variable modifications, and as many as three missed cleavages
were allowed. Assignments were manually verified by inspection of
the tandem mass spectra and coalesced into Scaffold reports (www.
proteomesoftware.com). The integrated peak areas for peptide quan-
tification were calculated from extracted ion chromatograms using
QuanBrowser from Xcalibur 2.0. These values were restricted by m/z
(±0.02) and retention time (120 seconds). The masses and isotopic
peak patterns of the target peptides were manually inspected to ensure
proper sequence assignment and to verify peak quality. The signal in-
tensities from unmodified GRP78 peptides were used to normalize the
amount of protein introduced into mass spectrometer.
Protein Synthesis
U251 cells were seeded in six-well plates and allowed to adhere
overnight. Cells were then treated with vorinostat or vehicle control
(DMSO) for the described periods. Before collection, cells were starved
in methionine- and cysteine-free medium for 1 hour and radiolabeled
with 50 μCi/ml [35S]-methionine (specific activity, 1175.0 Ci/mmol)
Easytag Express Protein labeling mix [35S] (PerkinElmer, Waltham,
MA) for 40 minutes. As a positive control, an untreated culture was ex-
posed to cycloheximide (50 μg/ml) atthetime of methionine/cysteine–
free medium addition. Medium was aspirated, and cells were lysed by
adding 1% Triton X-100 in 50 mM Tris (pH 7.5), 2 mM EDTA, and
molecules and scintillation counting were performed as follows: 20 μl
of cell lysate was added to 60 μl of 20% TCA in water (vol./vol.).
The samples were kept on ice for 1 hour and then filtered through
glass filters (GF/C filters; Whatman, Piscataway, NJ) under vacuum.
The filter was washed three times with ice-cold TCA (10%, vol./vol.)
followed by one wash in 95% ethanol and then immersed in 5 ml of
EcoLume Liquid Scintillation Fluid (MP Biomedicals, Solon, OH).
Disintegrations per minute were measured on a Beckman LS6500
ration compared with that of untreated control cells.
Small Interfering RNA
U251 cells were seeded at 1 × 105cells per well in six-well plates
and allowed to reach 70% confluence on the day of transfection. The
small interfering RNA (siRNA) constructs (siGENOME SMARTpool
PERK [M-004883-03-0010], siControl nontargeting siRNA pool
[D-001206-13-20], and siGENOME SMARTpool reagents) were
purchased from Dharmacon (Lafayette, CO). Cells were transfected
with 50 nM siRNA in Opti-Mem medium (Invitrogen Life Technol-
ogies, Carlsbad, CA) with 5% FCS according to manufacturer's pro-
tocol. Forty-eight hours after transfection, cells were trypsinized and
plated for clonogenic survival, and the remaining cells were used for
Western blot.
Clonogenic Survival
Cells were seeded as single cells in six-well plates and allowed to
adhere for 6 hours, treated with vorinostat (1 mM) or vehicle control
(DMSO) for 48 hours, then medium was replaced with drug-free
medium, and cells were allowed to incubate for 10 to 14 days. Plates
were then stained with crystal violet, and colonies consisting of 50 or
more cells were manually counted. Results were normalized to the
colony-forming efficiency of the vehicle control.
Statistical Analysis
Thestatisticalanalysiswas done using a Student's t test. Aprobability
SD from three independent experiments.
GRP78 Is a Molecular Target of the HDAC
Inhibitor Vorinostat
Because the ER chaperone protein GRP78 is a member and shares
close homology with the heat shock family of proteins, a previously de-
scribed target of HDAC inhibitors [3,8,13], we sought to determine
whether GRP78 could also be modulated by HDAC inhibition. Initial
studies focused on U251, a glioblastoma cell line that has been previ-
ously described to both aberrantly express and be reliant on GRP78 for
Figure 3. HDAC inhibitors activate the UPR. Western blot was performed on U251 cells in a time course manner to determine whether
HDAC inhibitorsfrom disparate molecular classes can activate PERK (P-PERK), a key signaling pathway associated with theUPR.The HDAC
inhibitors used include (A) the hydroxamic acid vorinostat (1 μM) and (B) the short-chain fatty acid valproic acid (2.5 mM). (C) Glioblastoma
(U251, U87, SF539) and prostate cancer (DU145, PC3) cell lines were treated with vorinostat (1 μM) or vehicle control for 24 hours. Western
blot was performed on cell lysates to evaluate for activated PERK (P-PERK).
Neoplasia Vol. 12, No. 1, 2010Vorinostat-induced Activation of the Unfolded Protein Response Kahali et al.
Page 5
its continued proliferation [12]. U251 cells were exposed to a clinically
relevant concentration of vorinostat (1 μM) [14] or vehicle control in
a time course manner. Cell lysates were then immunoprecipitated for
GRP78 followed by immunoblot analysis with an antibody that recog-
nizes anti–acetylated lysine residues. As shown in Figure 1A, GRP78 is
acetylated after 6 and 24 hours of exposure to vorinostat. We next
sought to determine whether vorinostat-induced GRP78 acetylation
could have a functional consequence of dissociation with its client pro-
teins, the central process involved in UPR activation. Of the known
on the PERK. As demonstrated in Figure 1B, GRP78 dissociates with
its clientproteinPERKinatimecoursemannerconsistentwithprotein
acetylation after vorinostat exposure. In addition to GRP78 acetylation
and PERK dissociation, both studies demonstrate a modest increase in
GRP78 expression after vorinostat exposure, which represents a recog-
nized downstream signaling consequence of UPR activation [10].
As acetylation of GRP78 has not been previously described, we went
on to define the specific acetylation sites using LC–MS/MS. Immuno-
precipitated GRP78 from U251 cells exposed to vorinostat (1 μM) for
24 hours or vehicle control was separated on SDS-PAGE, and the band
identified by molecular weight as GRP78 was excised. In-gel tryptic
digestion was performed, and the extracted peptides were analyzed by
LC–MS/MS. A nanoflow liquid chromatograph (U3000; Dionex)
coupled to an electrospray ion trap mass spectrometer (LTQ Orbitrap;
Thermo) was used for tandem mass spectrometry peptide sequencing
by LC–MS/MS from tryptic digests. To further evaluate our ability to
localize acetylation sites, 35 (57%) of 61 lysine residues were contained
in peptides sequenced in these experiments. As demonstrated in
Figure 2, we identified lysine-585 of GRP78 to be a specific site of
acetylation after 24 hours of exposure to vorinostat. Using extracted
ion chromatograms for eight peptides, the expression of GRP78 was
sistent with immunoblot experiments (Figure 1), suggesting down-
stream activation of the UPR. Overall, the signal for the acetylated
peptide containing lysine-585 was increased by a factor of 4 after treat-
ment. After normalization for GRP78 expression, which was increased
after vorinostat exposure (consistent with our previous studies), acetyla-
tion on lysine-585 increased an average of 1.5-fold in two biologic re-
plicates after 24 hours of exposure to vorinostat.
HDAC Inhibition Leads to Activation of the UPR
As dissociation of PERK from its chaperone protein GRP78 leads
to PERK dimerization and autophosphorylation, a hallmark of the
UPR, Western blot was performed to determine whether HDAC in-
hibitors have the capacity to activate the UPR signaling cascade. Fig-
ure 3A demonstrates PERK phosphorylation in a time course manner
after exposure to vorinostat (1 μM), with maximal activation between
16 and 24 hours, consistent with the above-described GRP78 acetyla-
tion and PERK dissociation. Similar findings were observed with the
HDAC inhibitor valproic acid using an equitoxic drug concentration
(Figure 3B), suggesting UPR activation after HDAC inhibition is not
agent-specific. To determine whether UPR activation after HDAC in-
hibition is specific to U251, experiments were expanded to a panel of
glioblastoma and prostate cancer cell lines. Although UPR activation
cell lines DU145 and, to a lesser extent, PC3, confirming this biologic
process was not specific to U251 (Figure 3C). Mechanisms underlying
disparate UPR activation between cell lines remain unclear.
A primary goal of PERK activation involves reducing the workload
on the ER by inhibiting protein biosynthesis, which is accomplished
principally through phosphorylation of the alpha subunit of eIF2α
and selective expression of activated transcription factor 4 (ATF4).
initiation complex eIF2/GTP/Met-tRNAiMetis prevented, leading to a
generalized attenuation of translation and protein synthesis.In addition
to a generalized decrease in protein synthesis, phosphorylated eIF2α
selectively promotes translation of ATF4, which subsequently activates
transcription of genes involved in amino acid metabolism and trans-
port, oxidation-reduction reactions, and ER stress–induced apoptosis
[10,15]. As shown in Figure 4A, eIF2α is phosphorylated after HDAC
inhibition in a time course manner consistent with PERK activation.
The functional consequence of eIF2α phosphorylation after HDAC
inhibition was also confirmed, with increased ATF4 expression (Fig-
ure 4A) and decrease in overall protein synthesis determined by
S-methionine incorporation (Figure 4B).
Figure 4. Vorinostat activates downstream signaling of the UPR. (A)
Western blot was performed to evaluate activated eIF2α (P-eIF2α),
translational up-regulation of ATF4, and CHOP expression in U251
cells after vorinostat exposure. (B) Cells were treated with vorinostat
(SAHA) for indicated times or thapsigargin (THG, positive control)
were then radiolabeled with [35S]-methionine, and protein lysates
were collectedafter 40 minutes. Countsper minute were measured,
adjusted for protein concentration, and normalized to the DMSO
control. Columns, mean; bars, SD. *P < .001 versus control by Stu-
dent's t test.
Vorinostat-induced Activation of the Unfolded Protein Response Kahali et al. Neoplasia Vol. 12, No. 1, 2010


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Travel Blogs from Vieste
Day 5 Leaving Croatia
... got up to 24 knots and the seas got much bigger, I kept thinking that you could surf these waves ! So we wedged ourselves in and felt like we were on a roller coaster ride at times. After 3 hrs of this we were glad to see the Italian coast. We arrived in Vieste at around 18.00 moored up and went straight to the bar and had a long cold beer or two ! Supper tonight was out in the town, plenty of pasta and pizza. 58 miles travelled ...
Vieste Day 2
... served in a different way. Pasta with broccoli rob, white beans with pasta soup, and spaghetti with sardines and red pepper for flavor (part of a group lunch). S walked old town, church, fort, huge white rock, and trabucco for fishing. Great vistas and photos. J pizza, S tuna, both GELATO
Matera to Vieste
... br>
We drove up to the start of the walk and parked at a small snack bar / caf�. The visitors centre was � km away so we headed there to see if we could get a clearer map than the badly photocopied one the man in the Tourist Information had given us. The same map in its original form cost us a couple of euros but at least we could now plan a route. The paths are all well marked and we followed number 3. It was very peaceful walking ...
Rome to Vieste
... still unknown to American travelers. At our cliff-side hotel, we had dinner tonight, and slept in Vieste, Puglia.
Group dinner - Pea soup, cod, pasta w/shrimp, cake. Ate dinner with Tram who worked on Air Force One. Both her and Rocky (104 trips to China) work for Boeing.
Ferry to Athens
... trip. AND... We can't flush our toilet paper down the toilet eww. From now until Tirana it has to go in the bucket next to the bin. It's not as bad as I expected but it still takes a bit of getting use to. It was scorching hot again today so fingers crossed it stays this way for the rest of the ...


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Ford Gives Insight Into Development Of New GT... Motorsports
26 minutes ago
26 minutes ago
First Drives
Auto Shows
Spy Shots
Car Tech
If you're an automaker selling cars in China, doing so from outside the country is made much more difficult due to high import tariffs imposed at the border. But do so from within--as Tesla Motors is considering with its Model S electric sedan--and you skip those tariffs, allowing customers to buy... read more
While some see a recent string of three battery fires involving Tesla Motors' [NSDQ:TSLA] Model S electric sedan as nothing more than unfortunate happenstance, the National... read more December 3, 2013 by Nelson Ireson
After three recorded Model S electric car fires, The National Highway Traffic Safety Administration (NHTSA) is opening an investigation. Last month, the NHTSA said it would... read more November 19, 2013 by Stephen Edelstein
A third Tesla Model S has caught fire, and while many pundits speculate as to the impact the news will have on Tesla Motors' [NSDQ:TSLA] stock, the future of electric cars... read more November 7, 2013 by Nelson Ireson
The city manager of tony Atherton, California, thinks he'd like some new police cruisers. In fact, George Rodericks suggested to the San Jose Mercury News, "I'd love to see... read more November 6, 2013 by John Voelcker
There are very few places you can safely test the top speed of modern vehicles, and even fewer where it's legal to do so--but some sections of Germany's autobahn network tick... read more November 5, 2013 by Antony Ingram
Here in the U.S., Tesla Model S owners are likely to rarely reach the car's 130 mph top speed, but in Germany, where the electric sedan has just been launched, this... read more October 22, 2013 by Viknesh Vijayenthiran
The Tesla Model S fire that we asked everyone not to get all worked up about because it's just like any other car fire is still not a big deal (in fact, it may be less of a... read more October 4, 2013 by Nelson Ireson
Toyota's well-known issues with unintended acceleration (whatever the actual root cause) gave the company headaches and cost it millions of dollars for years--in fact, it's... read more September 25, 2013 by Nelson Ireson
The Tesla Model S battery-electric luxury sedan is a remarkable car, and it's elevated the public perception of electric cars to a new level. It's won awards, thrilled... read more September 20, 2013 by John Voelcker
Tesla's effort to build an autonomous car could reach fruition by 2016 according to a new Reuters report today. The question isn't so much whether the technology is feasible... read more September 18, 2013 by Nelson Ireson
The Tesla Model S is an undeniably quick car, especially considering its considerable weight. But just how much power does the world's only real electric car produce? A lot... read more September 17, 2013 by Nelson Ireson
We love it, and we love to hate its marketing almost as much as we despise the overzealous, often ignorant coverage in the press. First, Tesla insists on listing prices with... read more August 23, 2013 by Nelson Ireson
The Tesla Model S electric sedan isn't just receiving awards from all quarters--it's also incredibly safe should the worst occur. Just how safe has come to light in extra... read more August 20, 2013 by Antony Ingram
Tesla CEO Elon Musk has said in the past that more Model S variants were in the pipeline, which led us to speculate that one would likely be an all-wheel-drive version built... read more August 9, 2013 by Viknesh Vijayenthiran
Anyone who initially wrote off Tesla as not lasting should start officially eating their words. I mean that literally... go write down what you said on a piece of paper... read more August 8, 2013 by Jeff Glucker


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4625 Penkwe Way
Eagan, Minnesota, 55122
Commute to Downtown Eagan
Most errands require a car.
Score Details
4625 Penkwe Way has a Walk Score of 27 out of 100. This location is a Car-Dependent neighborhood so most errands require a car.
This location is in Eagan. Nearby parks include Lebanon Hills Park and Lebanon Hills Park.
Explore how far you can travel by car, bus, bike and foot from 4625 Penkwe Way.
Bus lines:
472 Eagan Blackhawk-Minneapolis
0.1 mi
438 Cliff Lake Flex
0.1 mi
This location is in the city of Eagan, MN. Eagan has an average Walk Score of 18 and has 64,206 residents.Learn More About Eagan


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As this Island lies in the fifty-seventh degree, the air cannot be supposed to have much warmth.
At fifty-seventh Street I paused, before turning, to look about me and to listen.
He was passing fifty-seventh Street; he recognized the neighborhood he traversed so often in visiting Ruby.
He had written from an address on East fifty-seventh Street.
fifty-seventh week, he hitches along on hands and knees; can not walk without support.
The fifty-seventh vessel I boarded was the Melampus frigate.
The driver turned into fifty-seventh Street, and the sun jumped above the housetops.
Paula lingered to her fifty-seventh year, worn out with cares and vigils.
Then proceed as M. Lalanne directs in his fifty-seventh paragraph.
This also was lost with the adjournment of the fifty-seventh Congress.


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From 'charismatic Indie Jesus' to 'SuperKlopp' and 'the Messiah', the national papers are swooning over Jurgen Klopp.
Plus, the transfer committee that didn't seem to stop Jurgen taking the job, and an attack from 2008...
It's a Mailbox of two halves. Liverpool fans are incredibly excited; everyone else is jealous and fearful.
Jurgen Klopp believes Liverpool were "not free" under the management of Brendan Rodgers.
Manchester City pair Sergio Aguero and David Silva could both miss the Manchester derby later this month.
Jack Butland, Phil Jones, Phil Jagielka and Jonjo Shelvey are all in line to start for England against Lithuania on Monday.
Theo Walcott started out wide but took centre stage with a goal in England's 2-0 win over Estonia.
Spain and Switzerland became the latest countries to book their tickets to Euro 2016.
Jurgen Klopp discussed the transfer committee, title hopes and existing squad in his first press conference.
Kenny Dalglish has advised Liverpool supporters to "fasten their seat belts" for life under new boss Jurgen Klopp.
Being sacked is never nice, but a whacking great pay-off helps. Is football incentivising failure?
Arsenal boss Arsene Wenger says Liverpool's decision to sack Brendan Rodgers is "hard to understand".
Jurgen Klopp has praised the standard of the existing squad at Liverpool.
Man United back in for Sadio Mane, Spurs want Laurent Depoitre, and are Barca being offered Jermain Defoe?
Sunderland have stunned the football world with the appointment of Sam Allardyce as manager.
Pedro says he is "happier" and more confident after leaving Barcelona to join Chelsea in the summer.
Arsenal attempted to sign Dynamo Moscow striker Aleksandr Kokorin on a season-long loan in the summer.
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- 76Promote
Phone Cases
creamby Vin Zzep
Protect your iPhone with a one-piece, impact resistant, flexible plastic hard case featuring an extremely slim profile. Simply snap the case onto your iPhone for solid protection and direct access to all device features.
a sketch of an elderly man with glasses, pen on newsprint. cream being his apparent self importance.
newspaper a common item is his failings.
Nice One Vince, I like it.
cheers Cassius, glad you like it :)
Me gusta!!
thank you Maria, pleased you like it. :)
Thanks GT :)
wonderful :)
love the concept and the outcome!
great stuff! good art!
Thanks Carina, Catherine, TaLins , Marko and Lisa. I'm so glad you like it :)
Great work - really grabs ones attention!
Cheers J. :)
Very cool!
cheers Mo, thanks :)
Really like this sketch, Vin! Straight forward, honest and telling of the artist! ;-)
Thanks for the great description Wayne, Cheers :)
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Let's face it, a rookie quarterback is going to have a few good and bad days, but today I think Johnny Football Manziel wishes he could have back.
Running with the first-team offense in the first 11-on-11 drill of Tuesday's practice, Manziel threw his first pass over the middle. No one was around but safety Donte Whitner, who intercepted the pass and ran for what probably would have been an easy defensive touchdown.
After shaking off a little of the rust, Manziel started to get comfortable.
A few plays after he stared down his receiver and had his out route intercepted along the sideline by Joe Haden, Manziel threw a long floater along the other sideline that Haden couldn't reach and veteran Anthony Armstrong caught for what would have been a long touchdown.
Probably the play of the day came late in practice when Manziel rolled right and threw back to his left on what looked like a designed rollout/throwback to Jordan Cameron. Two defenders were on Cameron all the way — one, strangely, was nose tackle Ishmaa'ily Kitchen — but the throw went over the heads of both defenders and fell into Cameron's outstretched arms.
I think Johnny Football will be fine, but his first time in 11-on-11's did not go the way he wanted them too. Expect tomorrow to be better.Do you follow the NFL Draft? If so follow NFL Draft Diamonds on Twitter and Facebook for up to date NFL Draft News, NFL Draft Projections, and NFL Draft Rankings. Jesus is the only way to Salvation