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Overview: Drives the transition from business requirements to functional requirements for the development of new software applications or enhancements to existing systems. Represents Product as member of Agile development team. Consults with users to identify current business6/15/2015 Austin, TX Save This Job
Senior Business Systems Analyst Enterprise Applications6/16/2015 San Francisco, CA Save This Job
The Business Analyst is an integral analytics role within Yield, Pricing, and Advanced Analytics at Quantcast. As a Business Analyst, you surface actionable insights from data to drive revenue, market-share, long-term profits, and/or operational efficienc5/7/2015 San Francisco, CA Save This Job
Quantcast is seeking a Campaign Optimization Analyst for our San Francisco office to ensure successful delivery of all display advertising campaign goals in conjunction with the Client Strategy and Sales teams. This is an analysis and client sup6/24/2015 San Francisco, CA Save This Job
Quantcast is seeking a Campaign Optimization Analyst for our San Francisco office to ensure successful delivery of all display advertising campaign goals in conjunction with the Client Strategy and Sales teams. This is an analysis and client sup6/23/2015 San Francisco, CA Save This Job
The Product Analytics team is looking for a Data Analyst to join their team in Brooklyn NY6/4/2015 Brooklyn, NY Save This Job
As a Product Manager, you'll develop and ship successful, meaningful products that help Etsy sellers succeed.5/18/2015 Brooklyn, NY Save This Job
As a member of Product Leadership at Etsy, you'll lead new product initiatives and contribute to Etsy's product strategy and overall roadmap. You'll attract, develop and retain product management talent while building and evolving the organization's5/18/2015 Brooklyn, NY Save This Job
Location: Ridgeland, MS Position Summary: The Quality Assurance Analyst is responsible for planning and implementing the quality assurance procedures for daily, milestone and release candidate testing of the Bomgar product line of screen-sharing and remote control technologies.6/9/2015 Ridgeland, MS Save This Job
Zend is looking for an experienced Senior Technical Support Engineer to join the Americas Global Services team. The Sr. Technical Support Analyst is responsible for daily communication with Zend?s customers, strategic partners and field operation teams. The Sr. Analyst oversees6/2/2015 Cupertino, CA Save This Job
Location:Wayne, PA Exempt/Non-Exempt:Exempt Benefits:Full Comprehensive Benefits Employment Type:Full Time Department:HealthWorks Division Description:Passport Health Communications, Inc. a part of Experian Health, a nationally recognized pioneer developing innovative solutions3/30/2015 Wayne, PA Save This Job
Job Summary The Project Management Principal Analyst, Research Product Operations will coordinate and manage multiple products and projects across DRG?s Research Insights teams to improve content creation, quality, and delivery. This is a key role to ensure seamless execution5/12/2015 Waltham, MA Save This Job
Base CRM is looking for a talented and analytical mind to manage and oversee the daily operations of our customer success and support teams. This individual will work with our product support, success engineering and customer success teams to determine areas of opportunity for4/29/2015 Mountain View, CA Save This Job
JOB DESCRIPTION: Are you interested in joining a fast growing software company delivering enterprise patient care management solutions that truly empower our clients to provide ?member focused? care? We are looking for talented, energetic and exceptional people to join our6/17/2015 Bedford, MA Save This Job
Summary Pentaho is looking for an individual who is a talented and excellent troubleshooter with exceptional communications skills. This individual is the first point of contact for customers and will interact directly with the customer to troubleshoot, document defects or5/25/2015 Orlando, FL Save This Job
Summary Pentaho is looking for an individual who is a talented and excellent troubleshooter with exceptional communications skills. This individual is the first point of contact for customers and will interact directly with the customer to troubleshoot, document defects or5/25/2015 Orlando, FL Save This Job
Location: Bedford, MA Description: As a member of the SaaS Operations Team at FirstBest, the Production Support Engineer will work closely with your team, R&D Engineers, and our Professional Services team to diagnose and resolve technical issues for your customers. You will5/18/2015 Bedford, MA Save This Job
At Pandora, we're a unique collection of engineers, musicians, designers, marketers, and world-class sellers with a common goal: to enrich lives by delivering effortless personalized music enjoyment and discovery. Peopleâthe listeners, the artists, and our employeesâare6/13/2015 Oakland, CA Save This Job
Do you want to work for a Pre-IPO powerhouse? Â Do you want to join the $500 billion integration market? Â MuleSoft is going through a period of explosive growth and we want a user-first Salesforce Developer who will drive our team to maximum performance.As a member of the5/18/2015 San Francisco, CA Save This Job
ABOUT US: GREE, Inc. (âGREEâ) is a global leader in building top-quality, high engagement free-to-play mobile games. GREEâs annual revenue run rate is over $1 billion, and the Company has a market cap of $1.4 billion with over $500 million available in cash andSan Francisco, CA Save This Job


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Senior Assessment Specialist Irene Joseph can't believe her part-time position with Los Alamos County in August 1978 turned into permanent employment spanning three decades.
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Average Rating
User Reviews
Perfect from beginning to end. Would rewatch.This anime as a whole is just, perfect. Each character is unique and many of the songs (especially Beginner) leave you with goosebumps with how perfectly it matches the atmosphere of a scene. The little kirara are adorable, each character that gains major screen time goes through some sort of character development one way or the other, and just everything in this anime screams cute but badass at ...Read more
Creative and Inspiring!This anime has a bit of everything, but it is definitely more of a 'girly' anime I think. (Although kudos to all the guys out there that like it!)Read more
I really really enjoyed this show. There are funny moments, exciting moments where you are just cheering the characters on, and very emotional moments. There is more noticeable character growth that is in this anime, than I have seen in most others. I ...
amazing soundtrack and feelsGreat soundtrack the songs will stay in your head for weeks after you finish it. and there are so many feels with these girls as they change and grow. (also gotta give it points for a unique setting) overall this anime is a must watch for anyone that likes music anime or just a good story about cute girls growing thru hard experiences
This is my all time favorite anime!Okay, I have always been a fan of AKB48 but when my friend showed me the first episode of this series I was hooked. This is first show in general that I was so moved by that every episode made we cry for joy or for sadness. I love this show forever and always <3
Went into this blind with a random scroll on alphabetical and was not disappointed!I picked this completely at random and found a gem. i was at first thinking " great a cutesy series with idols" and then the tone of an oppressed people hits you. so i start thinking "ok its darker than i thought it would be maybe it won't be all happy rainbows." next thing i know i'm enjoying the music and getting into the songs. and i thinking "what the hell!?! i'm a metal head! i don't enjoy ...Read more
1 out of 2 people found this review helpful:Great Mix of Music/Action, Overall a great show.I enjoyed this anime more than I taught I would, I can't believe this isn't more popular. There is a good mix of action, adventure, singing, dancing, drama, etc. I would definitely recommend this show and I hope there will be more episodes in the future as I am definitely still interested in this show. Also don't forget to skip out on the first season, it makes the 2nd season all that much better( ...Read more
AKB0048 is really good!AKB0048 is a good anime. The Music is very catchy and will get stuck in your head and you will love it. the Characters are very developed in the first season and in the second season is just gets better and better with a very nice ending.
It's based on a real group but AKB0048 stands well on its own.I suspect a lot of people are avoiding this show because they think it's just AKB48 animated. They couldn't be more wrong if that's so. While most of the songs, dance moves and idol culture come directly from the popular J-Pop group, the story is totally original.Read more
There's a lot more as this show combines elements from sci-fi and a little political intrigue(entertainment bans aren't that ...
A MUST WATCH! BEST ANIME EVER!I've seen many magical girl and idol animes...heck i've seen alot of animes in general and this is by far my FAVOURITE. I dearly hope theres a third season. It makes you laugh, smile and cry and inspires you. Truely a work of art. Not to mention you get to listen to amazing AKB48 songs. woot!
2 out of 4 people found this review helpful:Average good show to pick up in passingI started watching this show only a month ago when CR finally started to release season 1, its cute and most of the characters are likable. I'm not a AKB fan normally, not like I hate them or like them they are just there to me so I didn't go into this with a fan girl mentality.Read more
Its not "deep" by any means and I wouldn't call it a work of art but it isn't a bad way to spend 20-30minutes. I ...


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Good luck on getting a shut down on the TIDE - it is not going to happen. RTR!
Originally written on Gamedayr | Last updated 11/19/13
Lynch Toyota of Auburn is offering free cars if the Auburn Tigers shut out the Alabama Crimson Tide in the Iron Bowl on November 30.
8 Comments:
Um I think that's pretty much gambling lol on a sportsbetting level at least!
Of course its a pretty dangerous bet due to the potential for manipulation. Not to say anyone on Alabama would throw the game. But for the price of a car, id highly consider sending a few of my family members over to pickup a few new vehicles, if I did want to, maybe drop a few balls......
I would put my money (if I were a bettin man) on BAMA shutting down Auburn instead. Just sayin . . . ROLL TIDE!!!
Stranger things have happened. WDE!!
I'm with you. I believe Alabama is destine to win. Who won last year? Hummmm Alabama. Do it again and my vote is for McCarron for the Heisman. Should've gotten it last year.
I'm giving away cars (you dont even have to buy it first)if the sun doesn't come up on Nov 30th! It's about the same odds!
Never say never...just ask any Michigan fan about Appalachian State...
Guy on Finebaum just said McCarron wasn't really showing up in the polling for Heisman nation-wide. Says it'll be Winston Jameison, Manziel, or Bryce Petty. I thought McCarron was doing better in the polls. http://espn.go.com/college-football/heisman13/
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Alice LeJeune
Kimmerly "Kim" McBride
James Clavier
Thomas Fruge
Ramona Daigle Pole
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Elvin Richard
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Through compassionate care, it is the goal of Guidry Funeral Home to provide every family we serve with the highest standard in professional funeral service. We will give comfort in a time of need, show commitment and dedication, demonstrate respect and courtesy, be honest and ethical and welcome others into our family. We will work with each family to create lasting memorials and support the growth of our community. We will provide assistance every day in every way possible. At a time of great sadness, our family is here to help your family reflect and remember the life of your loved one.


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Col. Vernon H. Jarrell, U.S. Air Force (Ret.), 87, of Fort Walton Beach, Fla., passed away on Thursday, Jan. 23, 2014. He was born July 3, 1926, in Shawnee, Okla., to Hazel Golden McIntire and Lawrence Eugene Jarrell. He retired in 1980 after 33 years in the military (first in the Navy and then in the Air Force), serving in
World War II
, Korea and Vietnam. Vernon graduated from high school in Stillwater, Okla., earned his bachelor's degree at Oklahoma A&M and his MBA from the University of Missouri.
While serving his country, he received the Distinguished Flying Cross, Legion of Merit, Meritorious Service Medal with one Oak Leaf cluster, among many others. He was an Electronic Warfare Officer, Navigator, Radar Navigator/Bombardier/B-52, Missile Launch Offi-cer/Instructor Minute Man II, B-66 Navigator during the
Vietnam War
, Missile Squadron Commander and Wing Director of Operations – Minute Man. His final assignment before retirement was with the 15AF, Director of Missile Operations for one Titan and five Minute-Men wings.
Since retirement, Vernon was active with the
Elks Lodge
#1795 (BPOE) in Fort Walton Beach. He served in all chairs, was 2002-03 Dis-trict Vice-President and 2003-04 District Deputy Grand Exalted Ruler. He was a Christian, who loved his country, his family and Elkdom. He was also a 32nd Degree Mason.
Vern was predeceased by his parents; brother, Lawrence; sister, Vivian; and niece Donna.
He is survived by his wife and soul mate, Ina Jarrell; son, J. Phillip Jarrell (Marcia) of Novato, Calif.; stepdaughter, Darlene Dean (Tom) of Fort Walton Beach; and grandchildren, Carmen, Nathan and Olivia of Novato; niece, Louise Anderson (Ellis) of Cibolo, Texas, and Phil-lip's mother, Etta Jean, of Birmingham, Ala.
The family wishes to thank Babs and Amanda from Medi Home Health Agency, and Mary and Kathy from Home Instead, for their kindness and caring these past months.
Due to inclement weather, the visitation and memorial service will be held on Friday, Jan. 31, from 10 to 11 a.m., at Emerald Coast Funeral Home, 113 Racetrack Rd. NE, Fort Walton Beach, Fla., with a memorial service at 11 a.m. Interment will be Monday, Feb. 3, 2014, at 2 p.m., at Barrancas National Cemetery, Pensacola, Fla.
Arrangements and services are under direction of the Emerald Coast Funeral Home, 113 Racetrack Rd, NW, Fort Walton Beach, Fla. In lieu of flowers, donations may be made in his memory to Harry-Anna Trust, c/o Elks Lodge #1795, PO Box 535, Fort Walton Beach, FL, 32549, or to
Expressions of love and sympathy may be shared online at
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Emerald Coast Funeral Home
113 Racetrack Rd NE
Fort Walton Beach
(850) 864-3361
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Published Online in Northwest Florida Daily News on Jan. 30, 2014
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Key things you need to know aboutDr. Tornos:
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- Anatomic & Clinical Pathology
- View all 2 specialties and 1 board certification
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Hospital Quality
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- Stony Brook University Hospital
- 101 Nicolls Road
- Stony Brook, NY 11794
9 Facts About Hospital Quality
Patients' risk of dying during a hospital stay for heart bypass surgery could be 85.2% lower, on average, at a hospital rated 5 stars compared to a hospital rated 1 star for that procedure. Choosing the right hospital is critical to your health. View Slideshow
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Likelihood of recommending Dr. Tornos to family and friends is 5 out of 5 5 1 1
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Patient satisfaction surveys provide a standardized way of reporting about healthcare experiences. But there can be more than meets the eye when reviewing scores. Here's what you should know
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25 year old woman | Davenport, FL, USA | Seeking men 25-29 within 50 miles
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Hey name is Michelle. I was born and raised in Wisconsin. I love the doing anything outdoors and going to the beach as much as I can when I'm not working. I like to have fun and laugh and not have to worry about everything. I am a very outgoing person and will let nothing stop me. I try and stay active as much as i can. I played soccer since i was 4 and miss the game. I'm looking for a guy that will make me laugh and smile, someone that will do something just spur of the moment. I'm not looking for much in a guy just someone to make me happy and feel loved.
Camping , Cooking , Dining out , Fishing/Hunting , Movies/Videos , Music and concerts , Nightclubs/Dancing , Playing cards , Playing sports , Travel/Sightseeing , Volunteering , Watching sports
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I exercise 3-4 times per week.
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I love to travle back to wisconsin to see the season change. I dont miss snow tho. I am always looking for new place to go and see the world.
Im a country girl so i love country music, but i listen to pretty much everything. I watch a little tv but not much. I did get hooked into glee, i didnt think i was going to like it but i watched one and got hooked.
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|5'4" (162cms)
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OECD Unit Labour Costs up 0.4% in the first quarter of 2014 as labour productivity falls
This report provides an initial evaluation of the comprehensive reform of the Spanish labour market undertaken in 2012. It describes the key components of the 2012 reform and places them in the context of the evolution of labour market institutions in other OECD member countries, with a particular focus on collective bargaining and employment protection legislation. The report also assesses the impact of the reform on the ability
This report delivers evidence-based and practical recommendations on how to better support employment and economic development in Canada. It builds on sub-national data analysis and consultations with local stakeholders in four case study areas across Ontario and Quebec. It provides a comparative framework to understand the role of the local level in contributing to more and better quality jobs. The report can help federal,
Modest decline in OECD unemployment rate in April 2014
Canada has experienced solid economic growth since the global crisis, allowing it to reverse recession-induced job losses and put federal public finances on a sound footing, says the OECD. Growth is expected to accelerate from 2.5% this year to 2.7% in 2015.
This project assesses the contribution of labour market policy to boosting quality employment and enhancing productivity by better matching skills supply to demand, improving training provision and addressing skills gaps but also improving skills utilisation by firms. It involves a series of country reviews.
Business dynamics – entry and expansion of successful businesses, and the contraction and exit of the least productive ones – are at the core of the creative destruction process, resource reallocation and productivity growth. To address these issues, the OECD has embarked on the Dynamics of Employment ("DynEmp") project.
This review looks at a range of institutions and bodies involved in employment and skills policies in the Czech Republic, focusing on local strategies on the Ústí nad Labem and South Moravian regions.
OECD unemployment rate stable at 7.5% in March 2014
After six long years of pain and fear, the major advanced economies are finally building momentum. While two of the four cylinders of the global economy's growth engine – credit growth and emerging market activity – are still running below full speed, there are encouraging signs that the other two, trade and investment, are finally warming up.


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Men's Tennis Advances to Big Ten Semifinals
April 26, 2013
The Minnesota men's tennis team made a lot of noise as they began their journey at the 2013 Big Ten Tournament today at the Varsity Tennis Courts in Columbus, Ohio. The Golden Gophers delivered a dominating performance over the Spartans of Michigan State, winning by a score of 4-0 to advance to the semifinal round.
Despite the outcome, Michigan State was the first team to notch a point in the match after winning the No. 2 doubles game. However, Minnesota would rally back to take the next two for the team point. Leandro Toledo and Eric Frueh defeated Aaron Pfister and Denis Bogatov, 8-4, at No. 3, while Jack Hamburg and Mathieu Froment combined for an 8-5 finish over Harry Jadun and Gijs Linders at ones.
Hamburg and Toledo, along with Juan Pablo Ramirez, would go on to win their singles matches in straight sets to clinch the shutout and earn the advancement in the tournament. Hamburg finished first, topping Bogatov by scores of 6-2, 6-2 from the third singles position. Ramirez followed closely behind with a 6-1, 6-1 trouncing of Jadun at sixth. At No. 2, Toledo, the No. 79-ranked competitor in the nation, clinched the team victory with the defeat of MSU's Drew Lied (6-1, 6-4)
As the last step before the championship match, the Maroon and Gold will face the winner of this afternoon's match between No. 3 Michigan and No. 6 Indiana. The semifinal battle will begin at 12:30 p.m. CT tomorrow, April 27.
Big Ten Tournament - Quarterfinals
#2 Minnesota 4, #7 Michigan State 0
Order of Finish
More Headlines
6/29/2015Summer Update: Jeremy Lynn
6/10/2015Season in Review: 2014-15
5/19/2015Toledo Begins NCAA Singles Wednesday
5/9/2015Gophers Fall in NCAA Round of 32
05/08/2015Gophers Rally for Win Over Princeton
05/07/2015Gophers Trek to Virginia for NCAAs
04/28/2015Minnesota Receives NCAA Tournament Bid
04/24/2015Gophers Oust Michigan With 4-0 Victory


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Dipped in Gold
The glitter and glamour of gold is catching the eye as a 2015 home decor trend.
By Guatemala's Jose Arriola, this charming nativity scene depicts the Holy Family, angels and the Three Kinds. The nativity scene is crafted of ceramic and painted by hand.
ITEM#: 13963686This handmade creation is offered in partnership with NOVICA, in association with National Geographic.
|Nativity Scene
|Worldstock Country
|Accent Type
|Ornaments Other Accent Pieces
|Christmas Seasonal
|Season or Holiday
|Largest piece: 4.7 inches high x 2.6 inches long x 2 inches wide; Smallest piece: 0.6 inches high x 1.6 inches long x 1.8 inches wide
|Model Number
The glitter and glamour of gold is catching the eye as a 2015 home decor trend.
If you want to refresh your home this spring, new pendants and lamps help create a chic, brightening effect.
How to Start Your Holiday Shopping in July from Overstock.com. Start planning for the holiday season early and you'll feel less stress come December.
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Dream big, beautiful. From creative spaces to the kitchen, every room could use a little encouragement. That's why we've found artwork, throw pillows, and jewelry that will leave you feeling inspired.
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[Thanks for visiting. Our website is undergoing renovation. Please feel free to browse around while we are in progress and check back 6.30 for the finished site! Meanwhile, plants are still available by clicking here. ]
Welcome to Marshall Strawberry, a relational work of art by Leah Gauthier working to help revive this very special berry.
The Marshall strawberry — once deemed by James Beard, the father of American gastronomy, as the tastiest berry ever grown — was on Slow Foods most endangered foods list just 8 short years ago. Since 2007, artist Leah Gauthier has been lovingly working to help revive this American treasure. Please join us!
During this first phase of the project, Leah has released an edition of plants so berry lovers everywhere can grow and enjoy Marshall strawberries in their very own farms or backyards. To date, over 500 plants have been adopted!
Next steps are to set up hubs across the country with successful new growers so more plants will be available locally, and realize Leah's dream of a rare herb and berry farm to serve as a permanent home to Marshall where she lives in Mid Coast Maine.
2015 spring plants are SOLD OUT. Baby marshalls for fall planting will be ready to travel starting in August and can be ordered here.
Read more about Leah + Marshall here.


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The Global FlyFisher - The Largest and Best Place to go for Online Fly Fishing and Fly Tying
Guide and Angler talking tactics on this beautiful spring creek.
Central Sth Island New Zealand
Submitted by: Dave Cook
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The Dirty WhiteWe continue our series of tube flies tied in the Scandinavian style. This fly is another subdued yellow, white and gray fly, well suited for bright light and clear water. It uses a mallard hackle to create a nice, closed shape.
November 14th 2008


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Awards Calendar
Comic-Con Starts
July 10, 2015
ATAS, Primetime Emmys Awards: Nominations are announced live (8:30 PM PDT)
July 16, 2015
Teen Choice Awards
August 9, 2015
ATAS, Primetime Emmys Awards: Final round voting begins
August 17, 2015
ATAS, Primetime Emmys Awards: Final round voting ends
August 28, 2015
MTV: Video Music Awards
August 30, 2015
Venice International Film Festival Begins
September 2, 2015
ATAS, Primetime Emmys Awards: Creative Arts Awards and Ball
September 12, 2015
ATAS, 67th Primetime Emmy Awards (5:00 PM PDT)
September 20, 2015
New York Film Festival Begins
September 25, 2015
Oscars: Darlene Love Gets Standing Ovation After '20 Feet From Stardom' Win
The prolific singer-actress showed off her pipes while accepting the award for best documentary.
Darlene Love stole the show at Sunday's Academy Awards.
The prolific singer and actress received a standing ovation after showing off her pipes moments after Radius-TWC's 20 Feet From Stardom won the best documentary feature Oscar.
PHOTOS: Oscar Red Carpet Arrivals 2014
Love was one of several backup singers featured on the crowd-pleaser 20 Feet From Stardom and has backed up legendary musicians including Elvis Presley, Tom Jones, Frank Sinatra, Aretha Franklin and Bruce Springsteen.
An iconic voice of the 1960s on The Crystals hits "He's a Rebel" and "He's Sure the Boy I Love" and tracks such as "Today I Met the Boy I'm Gonna Marry" and "Christmas (Baby Please Come Home)," Love has been riding a wave of fame for the past year since the documentary exposed the famous backup singer's rich career.
Best Documentary winners told THR at the Indie Spirit Awards on how their lives have changed from their first screening at Sundance until now. Watch below for the conversation.
In February, OWN acquired the television rights to Love's memoir, My Name Is Love: The Darlene Love Story, which will be adapted into a scripted television movie.
Since its June release, 20 Feet From Stardom has made more than $5.2 million at the box office.
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Hollywood Insiders Descend on Havana
CBS Entertainment Chief and "Loudmouthed Feminist" Nina Tassler Reveals the Strategy Behind 'Supergirl' Gamble
Paul Rudd and Marvel's Kevin Feige Reveal 'Ant-Man's' Saga, from Director Shuffle to Screenplay Surgery to Studio's "Phase Three" Plans
Comic-Con 2015: THR's Full Guide to Parties in San Diego
HBO's Real-Life Game of Thrones: The Fight to Stay Rich, on Top and Score Bill Simmons
Taraji P. Henson, Viola Davis and Drama Actress A-List Tackle Race, Sexism, Aging in Hollywood
Lena Dunham, Amy Schumer and Comedy Actress A-List in Raunchy, R-Rated Roundtable
Bob Odenkirk, David Oyelowo and Drama Actor A-List on Oscar Snubs, Bad Scripts and Getting Ignored by Robert Redford


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Two La Crosse murder suspects in court again
Published 05/22/2012, Pierce County Herald
Western Wisconsin News
-- Two men are due back in court July 24th, after they pleaded innocent to the murder of a young La Crosse woman for her purse – and a random drive-by shooting at an elderly woman's house.
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|Home Software category Just in softwares Submit a program Contact us Link to us
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Facebook Spy Monitor 2.53
Facebook profile monitoring and parental control software.
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Icecream Ebook Reader 1.64
Icecream Ebook Reader works with EPUB, MOBI, FB2, PDF, CBR, CBZ ebooks.
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Facebook Auto Poster and Scheduler 5.5
The Ultimate Facebook Auto Poster - Automatic Group Joining and Posting
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eBook Publishing Software - Make Beautiful eBooks For Any Platform & Device
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Facebook Deluxe 2015 is a better way to surf Facebook
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Facebook Chat Instant Messenger!Chat with your Facebook friends right from your!
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Online eBook Creator Paves the Way for Sharing Your Digital Content
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Notebook Wars is an interesting action game for free.
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Flip Html5 - Free Free PDF to Page Flip eBook based on HTML5 and jQuery
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Software to help you advertise on Facebook social network.
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Master Ebook Editor 1.0
Converts Ebooks to sound files to sell, adds page numbers
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Directors NoteBook 4.5 SA (Stand Alone) 4.5u
shotlist software work on your Mac, and your iPhone/iPad
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shotlist software work on your Mac, and your iPhone/iPad
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PDF eBook security remover enables and disables PDF security & page permissions
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Ebook protection crack personal security and password edit modify Adobe contents
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Chit Chat for Facebook allows you to use Facebook Chat without your browser
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Very strong utility to speed up performance of slow note book on all Windows OS
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Live Seminar Information
This is a 2-day course being taught by Tom Tam.
The two day class will focus on the theory of Tong Ren, the different techniques and methodology of Tong Ren including ultrasound theory and healing modality, case studies and Tong Ren application to cases, and lots of Q+A for those who have questions about different cases.
Saturday July 11, 2014 (10:00am to 4:00pm)
Sunday July 12, 2014 (10:00am to 4:00pm)
For those planning to attend the class, please arrive at 9:30am on July 11 for registration.
15 Cottage Ave 5th Floor
Quincy MA 02169
Class registration: $300.00 and will require a non-refundable $50.00 deposit
Class recordings: $50.00 (Optional)
(Tong Ren supplies and books will be available for purchase and are not included with the cost of the seminar.)
===> Seminar sign up form
Sign up sheets available in our Quincy office, Haverhill office and Chinatown office


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Sometimes you just can't help but feel sorry for Malfunction Junction, aka, the city of Atlanta. Admittedly, it is hard to do because it is such a blowhard town and not half as hip as it thinks it is.
Anthropogenic (man-made) global warming skeptics have an unusual ally from the land Down Under. Recently, by a vote of 42 to 30, the Australian Senate rejected their version of cap-and-trade.
Most Americans want reform in health care that will reduce cost without sacrificing quality of care. This is long overdue and just about everyone agrees that the status quo is unsustainable.
The push to revise America's health care system is one of those rare events that can dramatically change how our society works. The approval of Social Security in the 1930s was one such turning point, as was the passage of civil rights legislation in the 1960s.
U.S. democracy may be imploding, eating itself up from within. Constitutionally guaranteed free speech has become the right to say absolutely anything, no matter how untrue or inflammatory. The right of assembly approaches mob rule, and hostility toward a legally elected president drifts toward insurrection. How did this happen?
I believe that family structures are the building blocks for all societies, here and in other countries as well. We live in a fast-changing world with so many things in our lives that seem to be just happening beyond our ability to control or avoid. Families give us an anchor that can tie the present with our personal history in the past.
I was discussing with my son, Ken, the free-for-alls taking place in town hall meetings around the country as angry people confront members of Congress over the Obama Administration's current health care reform proposals. It isn't all that surprising, he said, and it's not just about health care.
Lately there's been a lot of talk about H.R. 3200, America's Affordable Health Choices Act of 2009.
Georgia's labor commissioner, Michael Thurmond, has seen the effects of the recession up close and personal.
As predicted in the last column, new developments for the 2010 elections continue to change the political landscape on a near daily basis. This column is written early because I will have been hospitalized during its deadline period.
I have just attended the Sweet Tea Summit. It was like President Barack Obama's recent Beer Summit except we didn't have to endure Joe Biden and his motor mouth.
Forget Obamacare. Forget stimulus plans, government bailouts, cap-and-tax or any other recent or imminent spending legislation. The current level of government involvement in pensions (Social Security) and health care (Medicare, Medicaid) alone could soon bankrupt this country. General Motors and Chrysler provide the lesson here.
If you are trying to figure out what your congressmen really believe in, don't focus on what they say - look closely at what they do when it comes time to vote.
Who owns America? Not you and me, that's for sure, and that's why Americans don't have universal health coverage.
During congressional hearings concerning Sonia Sotomayor's nomination to be a justice on the Supreme Court, we had an interesting exchange of ideas over lunch. Two of my friends were very concerned that Sotomayor might rule in future cases based upon her personal values and not the law itself. That is a valid concern. After all, justice is supposed to be blind.
Page 80 of 114
You won't often see so many history-making events crammed into such a small period of time, but that was the case last week with three huge stories breaking in a little less than 30 hours - a bonanza for those of us who work in the news industry.
Five young men, ages 18 to 23. Two college graduates. Two currently attending college. The youngest headed that way this fall. All good students. All excellent athletes. All standing resolutely before a large assemblage to pay tribute to their grandfather, Rob Neely, who passed away recently after a courageous battle with cancer. And what a tribute it was.
It's as if we stepped into a time machine and went 15 years back into the past.
It has been 31 years since he passed away and not a day goes by that I don't miss him, especially on Father's Day.
Speaking ill of the dead and their grieving relatives is something that those of us with any social graces tend to avoid. We take the higher road out of respect for those who have passed, no matter how much we may have disliked them or how vile they may have been, primarily because they no longer are able to defend themselves, at least in public.
Page 1 of 1
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ohsas 18001 certification Companies in Norway
Certification Europe
based in Dublin, IRELAND
Certification Europe is an accredited certification body which provides International Organization for Standardization (ISO) management system certification and inspection services to organisations globally. ISO Standards provide a recognised framework to achieve best practice management. Certification Europe can certify your organisation to Quality (ISO 9001), ...
SQFE MEXICO S.A. de C.V.
based in Metepec, MEXICO
SQFE Mexico is certification company who certificied qms and ems under iso 9001, iso 14001, ohsas 18001, haccp. The company have a wide expertise in several branch of activities and several countries.SQFE zertifiezierung nach iso 9001, iso 14001, ohsas 18001, haccp, dienststelle.
Filter Concept Pvt. Ltd.
based in Ahmedabad, INDIA
Filter Concept Pvt. Ltd. Is an ISO 9001:2008, ISO 14001:2004, OHSAS 18001:2007, ASME `U` & `UM`, The National Board Of Boiler & Vessel Inspectors `R` & `NB` & CE/PED certified Company involved in business of Manufacturing & Export of Industrial Filter Systems & Consumables for Air, Gas & Liquid.Fresh Concept - Complete relief to the customers from all filtration related ...
P4C Global Inc
based in CALIFORNIA (USA)
P4C Global Inc., located in Los Angeles California has proudly been an industry leader in wireless technology recycling since 2003. P4C Global is the preferred asset recovery management and reverse logistics vendor to some of the largest entities in the wireless industry. In addition to handset and cellular battery recycling, we also have extensive experience in the ...
Harry Staniforth Associates (HSA) Consulting Ltd.
based in Leicester, UNITED KINGDOM
Harry Staniforth Associates Ltd is an elite UK management consultancy specialising in helping our clients to continually improve their levels of performance through the implementation of ISO Quality Management Systems and other business management disciplines. We have become one of the most respected UK management consultancies, assisting a range of clients from start-ups ...
RSK Group plc
based in Helsby, UNITED KINGDOM
RSK is a fully integrated, environmental, health, safety and engineering services company employing over 920 technical staff in offices across the UK and worldwide. The company has a turnover in excess of £50m and was recently voted one of the top six environmental consultancies by the ENDS Market Consultancy Guide 2007. RSK has a diverse client base but mainly services ...
RVSL Aachen GmbH
based in Cologne, GERMANY
Founded in 1994 with Offices and customers in: Germany, Malta, Spain, Mexico. Certification bodies for ISO´s MS and Consulting for Risk Management, Business Continuity, Energy Management.Management systems that we assess: Quality ISO 9001, Environment ISO 14001, Safety and Health OHSAS 18001,Management systems that we advice: RISK Management ISO 31000, Corporate social ...
Shandong Buoy&pipe Industry Co., Ltd.
based in Liaocheng, CHINA
Shandong Buoy&Pipe Industry Co.,Ltd(SDBEP)specifilizes in research and manufacture of UHMWPE(ultra high molecular weight polyethelene)products ranging from navigation buoy,light house, pipe and sheet.Further,SDBEP is the sole member of IALA(International Associations of Lighthouse Authorities)in China.SDBEP patented UHMWPE products hold significant advantages over other ...
EUSEBI IMPIANTI S.r.l.
based in Ancona, ITALY
Eusebi Impianti s.r.l., the parent company of the Eusebi Group, with more than 30 years of experience in the field of fire fighting, has become one of the leading European companies in the design and manufacture of automatic fire fighting systems. Technological innovation, quality and internationalisation are the strong points that have made Eusebi Impianti one of the ...
Donusen Adam Health, Safety Environmental Training and Consultancy LLP
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Donusen Adam is the leading provider of occupational health, safety and environmental training & consultancy services in Turkey. For this services, we rely on our expert staff of experienced, certified and qualified professionals. Our team consists of : Safety Professionals - Medical Advisors - OHSAS 18001 and ISO 14001 Lead Auditors - Law Consultants
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Ken Rozen, a longtime policy advisor and legislative liaison to the state Land Department and Corporation Commission, died July 23. He was 56.Read More »
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Group initiates lawsuit against feds over jaguar permit
Macho B is gone, but his spirit may live on in a lawsuit against the U.S. Fish and Wildlife Service. The Silver City, N.M.-based Center for Biological Diversity on July 26 took its first steps toward a lawsuit against the federal agency for issuing a permit to the Arizona Game & Fish Department that it said could lead to the incidental capture and death of other wild jaguars.Read More »
Judge: First Things First ballot language is impartial
A Maricopa County Superior Court judge decided Monday against changing the description of a ballot measure that aims to eliminate a voter-approved program for early childhood development and sweep its money.Read More »
Horne, Thomas bring clash to the airwaves
Tom Horne and Andrew Thomas' campaigns against each other didn't get any more brutal, but they did become a bit more visible as the Republican attorney general candidates unleashed their first television ads of the campaign season.Read More »
Mills spends nearly $3.2M in governor's race
Yavapai County businessman Buz Mills reports spending nearly $3.2 million in his campaign for the Republican nomination for governor.Read More »
Brewer creates AZ Commerce Authority – but no authority yet
The Arizona Commerce Authority is officially on the job, though it currently exists in name only.Read More »
524 soldiers headed to Arizona-Mexico border
The White House will deploy 524 National Guard troops to Arizona to bolster security along the Mexican border, federal officials said.Read More »
Martin survives challenge, gets Clean Elections cash
State Treasurer Dean Martin received Clean Elections money for his gubernatorial campaign after the Secretary of State's Office determined that his $5 qualifying contributions did not contain enough duplicates to prompt a full review.Read More »
Rabago, Rotellini spar as Dem AG hopefuls outline experience
Outside of a late sparring match between Vince Rabago and Felecia Rotellini, the first televised debate among the three Democrats vying for the attorney general's seat lacked the fireworks and animosity of their Republican counterparts.Read More »
Horne, Thomas go on the attack in debate
Andrew Thomas accused Tom Horne of being a con artist in his opening statement, and the debate never got more civil than that. The first televised debate between the two Republican candidates for attorney general was replete with the now-familiar accusations and denunciations that have characterized their campaigns thus far.Read More »


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If you are a mom that live in California and will like to meet mom close to you, this is the right place to be.Visit this Group
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A group for moms and moms 2 b all around the inland empire. All cities welcome here no discrimination.Visit this Group
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This group if for moms that live in Northern California around the San Francisco Bay Area. Please join us to chat!Visit this Group
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Planning a mommies night out, stuck doing the same old thing? Get the girls together for a wild women only "girlie party"!Visit this Group
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A place to talk Pinterest ideas and share your results with others.Visit this Group
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Live in Humboldt County,Ca? come on in!!!Visit this Group
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Just moms who want to talk with other moms while the kiddos have fun!Visit this Group
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To share tips and advice on everything: good sales, good/bad childcare, good doctors, relationship questions, used items & moVisit this Group


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Learn how to use SharePoint Designer 2013 to alter the default appearance of SharePoint websites and brand them for your business.
Be your organization's SharePoint site champion. Learn how to create and export libraries, override checkouts, manage permissions, work with webpages, and create views in SharePoint 2010.
Design workflows that boost your team's productivity with SharePoint Designer.
Edit and customize web sites created with the SharePoint 2010 platform.
Use SharePoint Designer to create rich, highly visual web pages in SharePoint that connect, read, and even update information stored externally.
Highlights the new tools and user interface enhancements Microsoft includes in the 2010 version of SharePoint Server.
Explores using SharePoint Designer 2007 to alter the default appearance of SharePoint web sites.
"I really get a lot of value from my monthly subscription. You make me feel like my subscription is the best $25-a-month I spend in my budget." —Don M.
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Livers of infants with biliary atresia and of neonatal mice infected with rotavirus (RRV) have increased expression of interferon-gamma (IFNγ) and interleukin (IL)-12. While the expression of IFNγ regulates the obstruction of extrahepatic bile ducts by lymphocytes, the role of IL-12 in the pathogenesis of biliary obstruction is unknown. Based on the role of IL-12 as a key proinflammatory cytokine, we hypothesized that loss of IL-12 prevents the obstruction of extrahepatic bile ducts.
IL12-knockout (IL-12KO) and wild type mice were injected with RRV or saline at day 1 of age and monitored for the development of symptoms. The cellular and molecular phenotypes were determined at days 3, 7, and 14 by real-time PCR and flow cytometry.
RRV infection of IL-12KO mice resulted in growth failure, jaundice/acholic stools, and decreased survival similar to wild-type mice. IL-12KO mice had a remarkable neutrophil-rich portal inflammation and epithelial sloughing of extrahepatic bile ducts. Loss of IL-12 decreased but did not abolish the hepatic expression of IFNγ, displayed a remarkable increase in expression of TNFα, IFNα, IFNβ and decreased expression of IL-4 and IL-5.
Loss of IL-12 did not modify the progression of bile duct obstruction in experimental biliary atresia. However, the inflammatory response was predominantly neutrophil-based and displayed a Th1 response in the absence of IL-12.
Elucidation of the molecular mechanisms regulating injury and obstruction of extrahepatic bile ducts is critical to understand the pathogenesis of biliary atresia, the most common cause of pathological jaundice in infants. In biliary atresia, the extrahepatic bile ducts undergo progressive inflammatory and fibrosing obstruction, which disrupts the lumenal continuity between the biliary tree and the duodenum [1-3]. Although the etiology of the disease is undefined, the pathogenesis involves the interaction of environmental and genetic factors that produce an injury targeting the biliary tree. While the identification of environmental agents in affected patients has varied among different populations, analyses of liver samples obtained from patients at different phases of disease support an important role for inflammatory cells in tissue injury [3]. For example, CD4+ and CD8+ lymphocytes, NK cells and activated macrophages infiltrate the hepatic environment, populating primarily the portal system in diseased tissues, in contrast to the lobular staining found in liver samples from patients with other forms of neonatal cholestasis [4-8]. We recently investigated the transcriptional program in livers of patients with biliary atresia and found a unique footprint containing a significant number of genes related to a proinflammatory activation of lymphocytes at the time of diagnosis, with an increased expression of interferon-gamma (IFNγ) [9].
To directly investigate whether IFNγ played a key role in pathogenesis of biliary injury, we first determined the functional commitment of lymphocytes in the hepatobiliary system in a mouse model of rotavirus-induced biliary atresia [9]. In these mice, inoculation of rhesus rotavirus type A (RRV) soon after birth triggered a hepatobiliary inflammation by CD4+ and CD8+ lymphocytes and an overproduction of IFNγ. Then, we applied the same model of rotavirus infection to mice deficient in IFNγ due to a mutation in the IFNγ gene. We found that loss of IFNγ in mice prevented the obstruction of the extrahepatic bile ducts by inflammatory cells and maintained biliary continuity between the liver and duodenum [9]. Notably, loss of IFNγ attenuated but did not abolish the hepatic infiltration of CD4+ and CD8+ lymphocytes and allowed for an increase in interleukin (IL)-12 after RRV challenge. Based on these data, on the synergistic role of IL-12 in the regulation of the proinflammatory commitment of lymphocytes, and on the increase in IL-12 expression in livers of children with biliary atresia [7], we hypothesized that loss of IL-12 prevents duct obstruction in experimental biliary atresia.
Mouse model of biliary atresia
Wild-type (WT) Balb/c mice were procured from Charles River Laboratories Inc (Wilmington, MA, USA) and Balb/c mice deficient in IL-12 due to the targeted disruption of the IL-12p40 gene (IL-12KO) were procured from the NIH-Taconic consortium. They were maintained in a specific pathogen-free vivarium and housed in a room with a 12-hour dark-light cycle. Within 24 hours of birth, mice were injected with 0.9% saline solution (controls) or 1.5 × 106 fluorescence forming units (ffu) of RRV intraperitoneally, as described previously [9-11]. Infected mice that died within the first 2 days were excluded from further analysis because early death is associated with complications of injection, such as intra-abdominal bleeding. All mice were weighed daily, examined for the development of icterus of the skin not covered with fur and for the appearance of acholic stools, and sacrificed at 3, 7, and 14 days after saline or RRV challenge. The number of mice used in each experiment and each time point is presented in the Results section or in the tables/figure legends. The Institutional Animal Care and Use Committee (IACUC) of the Cincinnati Children's Hospital Research Foundation (Ohio, USA) approved all animal protocols.
Histopathology and gene expression
Livers and extrahepatic bile ducts were harvested from neonatal mice at 3, 7 and 14 days following saline or RRV using a dissecting microscope. Liver samples and the extrahepatic bile ducts were fixed with formalin, paraffin-embedded, sectioned with microtome (5-μm thickness), and stained with H&E for microscopic analysis. Neighboring samples from the same livers were snap-frozen in liquid nitrogen, and later used for RNA isolation with Trizol (Invitrogen Life Technologies, Carlsbad, California, USA), as described previously [9]. Quantification of RNA was performed with a spectrophotometer, with purity and integrity of RNA verified by 260/280 ratios and by agarose gel electrophoresis.
Total RNA samples were treated with RNAse-free DNAse I (Invitrogen Life Technologies, U.S.A.) to remove any contaminating genomic DNA. Reverse transcription was performed with Superscript II reverse transcriptase and oligo (dT)12–18 (Invitrogen) according to the manufacturer's instructions. cDNA pools were subjected to real-time kinetic PCR on a Mx-4000 Multiplex Quantitative PCR (Stratagene, La Jolla, California, USA) using SYBR Green I as a double-strand DNA-specific binding dye to quantify mRNA expression for IL-12, IFN-γ, IFN-α, IFN-β, TNFα, IL-4, IL-5, IL-18, IL-23, IL-27, RRV structural protein VP6, and the nonstructural protein NSP3. PCR amplifications were performed with specific primers outlined in Table 1 in a total volume of 20 μl containing 0.1 pmol of each primer, 10 μl of 2× Brilliant SYBR QPCR master mix (Stratagene), 3 nM of 1:500 diluted reference dye (ROX), 1 μl of 1:5 diluted cDNA and nuclease free water, after initial denaturation at 95°C and 40–45 cycles (95°C for 30 seconds, 55°C for 1 minute and 72°C for 30 seconds). The levels of gene expression were calculated as a ratio to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), as described previously [9].
Table 1. Primers used in real-time PCR to quantify levels of mRNA expression.
Isolation and fluorometric analysis of liver cells
Single cell suspensions of freshly harvested livers were obtained from mice 14 days after RRV or saline injection by mincing the livers, followed by passing through a nylon mesh. Mononuclear cells were suspended in RPMI Medium 1640 (Invitrogen, USA) and then centrifuged at 270 g for 10 minutes at 4°C. After lysis of the erythrocytes with RBC lysis buffer (0.15 M NH4Cl, 10 mM KHCO3, and 0.1 mM Na2EDTA, pH 7.2), cells were washed with PBS supplemented with 3% fetal calf serum and counted using a Neubauer chamber. Cells were stained by incubation with the following antibodies: anti-mouse CD3-FITC, anti-mouse CD4-PE, anti-mouse CD8a-PE, and anti-mouse neutrophil (CD11b-FITC and GR1-PE) (BD Biosciences, San Jose, California, USA). Then, two-color fluorometric analyses were performed in FACS buffer (PBS containing 0.01% sodium azide and 2% {v/v} FCS) as described previously [9]. Cells were then analyzed using a FACSCalibur dual-laser flow cytometer (BD Biosciences), with excitation at 488 and 633 nm. At least 150,000 events were acquired on the FACSCalibur for each sample, with non-viable cells and cellular debris excluded by forward and side scatter gating. Data were analyzed using CellQuest software (BD Biosciences), as described previously [9].
Statistical analysis
Values are expressed as mean ± SD, and statistical significance was determined by unpaired t test between IL-12KO mice injected with RRV or saline (controls) unless noted otherwise, assuming normal distribution, with a significance level of P < 0.05.
Outcome of IL-12KO mice after RRV infection
Administration of 1.5 × 106 ffu of RRV intraperitoneally into WT mice in the first 24 hours of life resulted in the onset of jaundice and acholic stools within 1 week, with impaired growth, and <10% survival beyond 3 weeks, as described previously [9]. IL-12KO mice did not display overt abnormalities after saline administration, grew well during the suckling period and survived into adulthood. In contrast, IL-12KO mice injected with RRV developed jaundice and acholic stools within 1 week, had poor growth, and only 10% survived beyond 3 weeks of life in a fashion similar to the outcome of WT mice challenged with RRV (Figure 1A–C). Collectively, these data demonstrated that loss of IL-12 did not protect neonatal mice from the development of progressive jaundice after RRV infection.
Figure 1. Outcome of IL-12KO mice infected with RRV. (A) Injection of RRV into newborn Balb/c mice leads to growth failure, as demonstrated by a significantly lower body weight when compared to non-infected mice (P < 0.05). RRV injection also leads to symptoms of cholestasis in mice between 4–8 days (B), and to decreased survival (C). The poor growth, onset of cholestasis, and decreased survival are similar to wild-type (WT) mice infected with RRV. Total number of animals at the time of injection of RRV or saline: IL-12KO-saline = 8, IL-12KO-RRV = 21, WT-RRV = 19. During the course of the study, all mice injected with normal saline remained healthy. In RRV injected IL-12KO mice, 20 out of 21 animal had died by day 17; similarly, 17 out of 19 RRV infected WT mice had died by day 21.
Neutrophilic cholangiopathy in IL-12KO mice
To determine the cellular basis of progressive jaundice in IL-12KO mice, we examined histological sections of livers at 3, 7, and 14 days after saline or RRV administration. Livers of IL-12KO mice injected with saline had normal lobular architecture and residual extramedullary hematopoiesis that is typically seen in the first few days of life (Figure 2). Following RRV, however, IL-12KO mice displayed a mild periductal inflammation at 3 days, which progressed to portal expansion by inflammatory cells and duct profiles at 7 and 14 days. The inflammatory pattern at 3 days was similar to that observed in livers of WT mice injected with RRV (Figure 2). However, the cellular components differed at days 7 and 14, with a mixed inflammatory infiltrate containing predominantly neutrophils in IL-12KO mice, while lymphocytes were the predominant cell types in WT mice (Figure 2). To precisely determine the extent to which neutrophils infiltrate the portal space of IL-12KO mice, we quantified T lymphocytes and neutrophils by flow cytometry at 14 days after RRV challenge. We found that the total number of hepatic lymphocytes and neutrophils increased in IL-12KO mice infected with RRV 2–4-fold above saline controls (Table 2). Interestingly, while the increase of CD3/CD4+ and CD3/CD8+ cells was similar to WT mice infected with RRV, the number of neutrophils (dual staining by CD11b-FITC and GR1-PE) in IL-12KO livers was greater than in WT mice after RRV. The changes in the nature of the inflammatory response induced by the loss of IL-12 did not impair the ability of the mice to effectively clear RRV, as demonstrated by the inability to detect the mRNA for structural (VP6) and nonstructural (NSP3) proteins by PCR 14 days after RRV challenge (Figure 3).
Table 2. Number (× 106 cells) of hepatic mononuclear cells 14 days after RRV challenge
Figure 2. RRV infection induces biliary inflammation in livers of IL-12KO mice. Infection of IL-12KO mice with RRV leads to minimal portal changes when compared to saline-injected mice and RRV-infected wild-type (WT) within 3 days (panels A, B, C). In contrast, RRV induces a remarkable portal expansion at 7 and 14 days in both IL-12KO and WT mice (panels E, F, H, I). Although the portal expansion has the same extent in both genotypes, IL12-KO livers have a mixed cellular infiltration with a predominance of neutrophils, while the portal spaces of WT livers contain primarily lymphocytes (insets in panels E, F, H, I). Arrows point to extramedullary hematopoiesis at day 3; N = 15–20 mice in each group; scale bar (left upper portion of each panel): 100 μ.
Figure 3. Clearance of mRNA expression for viral proteins. The hepatic expression of mRNA encoding RRV nonstructural (panel A: NSP3) and structural (panel B: VP6) proteins in IL-12KO mice was undetectable at days 3, high at day 7, and undetectable at day 14 after infection. P < 0.05; N = 4–6 mice per group at each time point.
To directly determine whether RRV induced cholangiopathy of the extrahepatic biliary tree in IL-12KO mice, we analyzed serial sections of extrahepatic bile ducts 7 and 14 days after RRV challenge. These time points were chosen because they have been reported to display a typical inflammatory obstruction following RRV infection (at 7 days), followed by matrix components and minimal inflammatory cells in atretic segments of bile ducts (at 14 days). We found obstruction of extrahepatic bile ducts in IL-12KO mice (Figure 4). The segments of obstruction, however, displayed ongoing epithelial injury and loss of epithelial integrity, with areas of exfoliation and invasion of the layer of cholangiocytes by neutrophils (Figure 5). Altogether, these data suggest that the in vivo loss of IL-12 did not impair viral clearance nor modify the long-term outcome of RRV-induced biliary atresia. However, the predominant neutrophilic infiltration suggested that neutrophils, rather than lymphocytes, may be the cellular effectors of bile duct obstruction in IL-12KO mice.
Figure 4. Representative cross sections of extrahepatic bile ducts in IL-12KO mice. Panels A and B show the normal epithelium and unobstructed lumen at 7 and 14 days after the injection of saline in the first 24 hours of life. In contrast, the injection of RRV leads to an obstruction of the lumen by inflammatory cells at day 7, and by sloughed epithelial cells of cellular debris at 14 days (panels C, D). Scale bar: 100 μ.
Figure 5. Neutrophil-rich biliary infiltration in IL-12KO mice. Representative cross sections of extrahepatic bile ducts in IL-12KO mice 14 days after infection with RRV soon after birth show exfoliation and sloughing of the epithelium (short arrows), associated with an epithelial infiltration by neutrophils (arrows). Scale bar: 100 μ.
Predominant expression of interferons and TNFα in IL-12KO mice
To explore the potential mechanisms regulating the neutrophil-rich cholangiopathy and duct obstruction in IL-12KO mice, we determined the hepatic mRNA expression of the proinflammatory cytokines IFNγ and TNFα. Levels of mRNA expression for both cytokines increased in RRV-injected IL-12KO mice above controls (Figure 6A, B). Interestingly, a comparison of the mRNA levels for IFNγ following RRV challenge between IL-12KO and WT mice demonstrated that the rise of IFNγ was higher in WT mice. These findings suggest that the loss of IL-12 reduced but did not abolish the development of a Th1-like phenotype in the hepatic environment. Based on a previous report showing the role of type 1 interferons in generating a Th1 response in IL-12KO mice [12], we determined the expression of IFNα and IFNβ. We found that the hepatic levels of mRNA expression for both cytokines in RRV-injected IL-12KO mice increased significantly above levels of saline-injected controls, with a peak expression at 7 days that was similar to levels observed in RRV-infected WT mice (Figure 6C, D). In contrast, the levels of mRNA expression for the Th1 inducer cytokines IL-18 and the IL-12 related cytokines IL-23 and IL-27 were either decreased (for IL-18; Figure 7) or undetectable (for IL-23 and IL27; data not shown) after RRV infection. The low levels of expression for IL-18 support a lack of potential involvement of IL-18 in the development of the Th1-like phenotype in IL-12KO mice. Interestingly, the hepatic expression of prototype Th2 cytokines either decreased (IL-4; P < 0.05) or did not change (IL-5) in IL-12KO mice after RRV infection (Figure 7). This is consistent with a dominant activation of proinflammatory cytokines in the hepatic environment during the course of biliary injury and obstruction.
Figure 6. Expression of proinflammatory cytokines in IL-12KO mice. RRV infection in the first day of life leads to an increased hepatic mRNA expression of IFNγ (A), TNFα (B), IFNα (C) and IFNβ (D) in IL-12KO mice above levels of saline-injected IL-12KO mice and WT mice injected with RRV. Also shown are the levels of expression. Levels of expression are shown as a ratio to GAPDH; *P < 0.05 for IL-12KO mice injected with RRV vs saline; #P < 0.05 for IL-12KO mice are compared to WT, both after RRV infection; N = 4–6 mice per group at each time point.
Figure 7. Expression of IL-18 and Th2 cytokines in IL-12KO mice. RRV infection in the first day of life leads to a decrease in the hepatic mRNA expression of IL-18 (A) and IL-4 (B), with no changes in IL-5 mRNA (C). Levels of expression are shown as a ratio to GAPDH; *P < 0.05; N = 4–6 mice per group at each time point.
Despite the pivotal role of IL-12 as an innate cytokine and a promoter of the Th1 response, the genetic loss of functional IL-12 did not protect young mice from the development of biliary obstruction after RRV challenge. Following neonatal viral infection, IL-12-deficient mice developed jaundice and acholic stools by 7 days of life, a time when the liver underwent a remarkable expansion of inflammatory infiltrate in the portal space. Although high levels of structural and non-structural viral elements were detected at this phase of injury, loss of IL-12 did not impair viral clearance at later phases. The portal inflammation was of mixed cellularity, with a remarkable presence of neutrophils at 7 and 14 days, which is in contrast to the predominantly lymphocytic infiltrate typically observed in livers of wild-type mice at the same time points after RRV infection. Notably, neutrophils also infiltrated the extrahepatic bile ducts, where they formed subepithelial clusters or invaded the epithelium. These changes were clearly associated with lumenal obstruction and interruption of bile flow. While the loss of IL-12 did not modify the final outcome of the inflammatory target and obstruction of extrahepatic bile ducts, analysis of IL-12-deficient livers identified two biological components with potential roles in the regulation of neonatal cholangiopathy: 1) neutrophils as cellular effectors of duct injury, and 2) type-1 interferons as an alternate molecular circuit to induce a proinflammatory microenvironment.
Neutrophils are key components of the initial inflammatory response to tissue injury. In previous studies of experimental biliary atresia, neutrophils accumulated near intrahepatic bile ducts in early phases of liver injury after RRV challenge, but became inconspicuous as the portal inflammation expanded by the accumulation of lymphocytes, and bile ducts underwent obstruction by 7 days [9]. In the current study, we found that this temporal switch to a lymphocyte-rich population in the portal spaces is controlled, at least in part, by IL-12, as demonstrated by the contribution of neutrophils to the expansion of the portal inflammation at 7 and 14 days (time of bile duct obstruction), as well as by their presence near and within injured epithelium of extrahepatic bile ducts. These findings are of particular interest in view of the previous report of an increase in the number of neutrophils when mice lacking IFNγ were subjected to the same model of RRV-induced biliary atresia. Without IFNγ, the number of hepatic neutrophils increased by 62% above non-transgenic littermates 7 days after RRV challenge [9]. However, this increase was only transient and was not sufficient to promote obstruction of bile ducts owing to a generalized attenuation of the lymphocytic infiltration of extrahepatic bile ducts in mice lacking IFNγ.
The differences in the outcome of biliary obstruction between mice lacking IFNγ and IL-12 are probably due, at least in part, to the combined effects of the neutrophilic infiltration in IL-12 deficient mice through day 14 after RRV challenge and the mild-moderate increase in the expression of IFNγ. Although lower than the expression in WT mice, the rise in IFNγ in IL-12-deficient mice was sufficient to produce a Th1 pro-inflammatory response. Collectively, these findings suggest that young mice activate accessory molecular networks that trigger an increase in IFNγ and maintain a neutrophil-rich mixed inflammatory infiltration in the hepatobiliary system in the absence of IL-12.
The production of IL-12 by phagocytic mononuclear cells and dendritic cells is a key component of the molecular networks that induce functional commitment of naïve CD4 T lymphocytes to a Th1 proinflammatory phenotype [13-15]. In keeping with this physiologic role, mRNA expression of IL-12 increases remarkably after RRV infection [9]. Here, we show that such an increase is not essential for the expression of the proinflammatory response in experimental biliary atresia, as demonstrated by the increases in mRNA levels for IFNγ, and TNFα at the onset of jaundice and acholic stools in mice lacking IL-12. The increase in IFNγ mRNA, however, was of lower magnitude when compared to the levels observed in wild-type mice challenged with RRV. Although of lower magnitude, this increase may have been sufficient to promote the obstruction of bile ducts in IL-12KO mice. Although IL-18, -23, and -27 are candidate cytokines able to trigger the expression of IFNγ [16-19], we found no increase in their levels of mRNA expression in livers of IL-12 deficient mice. Interestingly, the lack of expression of IL-23 and -27 are in accordance with the requirement of p40 as a critical subunit to form functional heterodimers with p19 (to generate IL-23) and p28 (for IL-27; p40 shares high homology to the EB12 subunit). Thus, the loss of IL-23 and -27 induced by the deficiency of p40 disrupts the network among these related cytokines. Despite this disruption, the injury and obstruction of extrahepatic bile ducts proceeded in a timely fashion, albeit with different cellular components. This may have been facilitated by type I interferons, as supported by the increase in the mRNA levels for IFNα and IFNβ in IL-12-deficient mice. Collectively, these data are consistent with a biological setting in which type-1 interferons work independently of IL-12 to induce the expression of IFNγ and other Th1 proinflammatory cytokines after RRV challenge. A similar biological setting was previously demonstrated in IL-12-deficient mice subjected to lymphocytic choriomeningitis virus infection [20]. Direct proof that an IFNα/β-dependent circuit regulates induction of IFNγ and duct obstruction in IL-12KO mice will require the analysis of the biliary phenotype following the in vivo inactivation of type-1 interferons in the same experimental model.
The genetic loss of functional IL-12 in vivo does not protect neonatal mice from an inflammatory-driven injury and obstruction of extrahepatic bile ducts after a viral insult. However, the inflammatory response displayed a persistent neutrophilic response and a gradual rise in the expression of type-1 interferons at the time of duct obstruction. Exogenous administration of IFNα before or at the time of RRV challenge was previously reported to significantly alleviate the progression of jaundice and cholestasis in this mouse model of bile duct obstruction [21]. In these experiments, however, the authors did not examine the impact of RRV challenge or administration of IFNα on the native production of type-1 or -2 interferons, or on other molecules that may regulate biliary injury and obstruction. In this context, the findings in IL-12KO mice presented herein further underscore the importance of future studies to address the independent or synergistic roles of type-1 interferons and neutrophils in the development of experimental biliary atresia in mice.
RRV: Rhesus rotavirus
IL: Interleukin
IL-12KO: Interleukin-12 knockout
WT: Wild type
IFNγ : Interferon gamma
IFNα : Interferon alpha
IFNβ : Interferon beta
mRNA: Messenger RNA
TNFα : Tumor necrosis factor alpha
Competing interests
The author(s) declare that they have no competing interests.
Authors' contributions
SKM: Study design, carried out the majority of experiments, analyzed data, drafting of the manuscript.
PKS: Animal phenotyping, flow cytometric analysis, data analysis.
GS: Animal phenotyping, histopathology, data analysis.
JAB: Design and supervision of the study, data analysis, drafting of the manuscript.
We thank Drs. William Balistreri and Mitchell Cohen for insightful review of the manuscript, David Witte for morphological analysis of bile duct histology, and Elizabeth Majane and the NIAID/Taconic Repository for providing IL-12KO Balb/c mice.
The study was supported by the NIH grant DK-64008 (to J.A.B.) and by the Integrative Morphology Core of the NIDDK-Digestive Disease Research Development Center of Cincinnati (DK-064403).
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Sorry for Rough Landing
JetBlue Attendant Who Left Flight Via Escape Chute Pleads Guilty, Apologizes
JetBlue flight attendant Steven Slater had his moment of fame last summer when he ditched his job by launching into a profanity-laced tirade over the P.A. before taking a joyride down the jetliner's emergency chute, a beer in each hand.
Mr. Slater was more contrite in court Tuesday, entering a guilty plea to two counts of attempted criminal mischief in a deal that spared him jail.
"It's fair to say I was not amused by that which occurred," said Queens District Attorney Richard Brown after the proceeding. Mr. Brown added that the escape chute opened with a force of 3,000 pounds per square inch—deadly, had someone been below, on the tarmac.
Under the plea deal, Mr. Slater agreed to undergo counseling and drug and alcohol rehabilitation.
"At the end of the day, I'm a grown adult and I must take responsibility for my actions," Mr. Slater said outside of Queens Supreme Court. He was flanked by three people: his boyfriend, lawyer and publicist, from the aptly-named firm, Fifteen Minutes. "I'm very grateful to the court for making these arrangements that will allow me to do so."
Mr. Slater's emergency-chute exit at New York's JFK Airport became an Internet sensation. Dozens of Facebook pages were set up in his honor, branding him a folk hero for doing what many working stiffs wished they could.
After he was suspended by JetBlue, he resigned as rumors of a reality show contract spread and were only coyly denied by his publicist. Mr. Slater appeared to bask in the adoration, offering light-hearted comments on the incident and constantly thanking his supporters.
"The public interest in this case surprised me," Mr. Slater said Tuesday, when he also thanked supporters, his legal team and his mother, who is suffering from cancer. But his tone was far more chastened.
The narrative on Mr. Slater's 15 minutes of fame changed as law enforcement officials interviewed every passenger on the jet and found they couldn't corroborate his tale. Detectives never found the rude female passenger at whom he had allegedly directed his P.A. tirade, and who he said gashed his head with a piece of luggage.
Interviews by the Wall Street Journal with passengers on the flight from Pittsburgh to New York revealed Mr. Slater appeared unhinged and possibly drunk.
Howard Bragman, Mr. Slater's publicist, answered "no" Tuesday when asked if Mr. Slater lied about the confrontation on the flight.
Mr. Slater was found to be eligible for the "alternative sentencing program," an option offered to defendants with mental health issues, in exchange for pleading guilty to attempted second-degree criminal mischief, a felony, and attempted fourth-degree criminal mischief, a misdemeanor.
He also has to pay $10,000 to JetBlue towards the cost of repairing or replacing the emergency slide. A JetBlue spokesman declined to comment, saying Mr. Slater is no longer an employee.
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Others besides Steven Slater have had professional lapses:
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- February 2009. An online video showed actor Christian Bale in profane rant against a crew member who had walked into a shot on a film set. Mr. Bale later apologized.
- February 1985. Indiana University basketball coach Bobby Knight, after getting a second technical foul for protesting officials' calls, hurled a folding chair across the court. He was ejected and later apologized.
If Mr. Slater completes the program, he will get no jail time and receive one year probation. If he fails, he will face one to three years in jail, Mr. Brown said.
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Daniel Horwitz, Mr. Slater's attorney, has said his client snapped under the pressure of his work, the death of his father, his mother's illness and his own health problem (Mr. Slater is HIV positive).
Asked about Mr. Slater's future, offers of reality TV stardom and new sources of income, Mr. Bragman bristled.
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—Sean Gardiner contributed to this article.