text:
Business Black Friday Starts Now!
New Customer ? Start Here.
Can't find what you're looking for? Shop all ink and toner cartridges by brand
Business Black Friday Starts Now!
Item: 148422 Model: 9420MO
This organizer has adjustable or removable shelves to customize individual compartment size.
This attractive literature organizer by Safco is the perfect place for everyday items to which you need immediate access. The 16-inch-high unit adjusts to accommodate letter-size folders as well as notepads, stationery supplies, and other small items. The piece's exterior is made of sturdy particleboard and solid fibreboard, while its shelves are made of hardboard. An oak-finished laminate completes the convenient and compact twelve-compartment organizer.
|Color Family
|Literature Organizer Depth (inches)
|Literature Organizer Height (inches)
|Literature Organizer Material
|Literature Organizer Width (inches)
REVIEW SNAPSHOT®by PowerReviews
Safco® 9420 Adjustable Literature Organizer, 16"(H) x 19 1/2"(W) x 12"(D), Medium Oak
Reviewed by 1 customer
Handsome Spacesaver
Comments about Safco® 9420 Adjustable Literature Organizer, 16"(H) x 19 1/2"(W) x 12"(D), Medium Oak:
I did not buy this piece to organize my literature, I bought it to hold my in -progress beadwork trays, easy to place and remove trays, and they are safe from accidental bumping or being pushed off the edge of my work table. (saves a lot of picking up tiny beads from the carpet) It was easy to put together, take care when hammering in the shelf holders). Took out two shelves to make double-high shelves, my tiny bead trays fit in beautifully. All of this stuff is safe, and easy to reach from my chair, and it looks good too! I am seriously considering ordering another one, kinda watching for a sale, if it makes me look organized I need it.
Would you recommend this product? Yes, I would recommend this to a friend
Was this review helpful? Yes / No
- You may also flag this review
Distressed: No Material: Wood Number of Items Included: 1 Overall Height Top to Bottom: 7.5 Overall Width Side to Side: 9.5 ...
Material: Wooden Overall Height Top to Bottom: 23.25 Overall Width Side to Side: 29 Overall Depth Front to Back: 12.5 Overall ...
Safco® Adjustable literature organizer in medium oak color measures 25 1/4" x 39 1/4" x 11 3/4" and keeps your paperwork neat ...
Safco® E Z Stor® Literature organizer in medium oak color measures 32 1/2" x 40" x 11 3/4" and offers easy assembly with locking ...
Overall Height Top to Bottom: 18 Overall Width Side to Side: 58 Overall Depth Front to Back: 12 Overall Product Weight: 68
This Web site is intended for use by US residents only. See International Sites. See our delivery policy for full details. Copyright 1998-2014, Staples, Inc., All Rights Reserved.


text:
Relevant offers
Real estate agents forecast the property trends for 2014.
1. The impact of loan-to-value restrictions
There was no doubt LVRs had made first-home buyers postpone their plans, Marty Scott of Harcourts Wellington City said. But there was also evidence from Auckland that it had cooled price growth, and first homes were still attracting plenty of interest and multiple bidders. John Ross, owner of The Professionals in Lower Hutt, said the recent exemption from the LVR restriction for new build homes would lead to growth in that sector.
2. Apartment body corporate fees and earthquake strengthening
Add the potential cost of quake strengthening to the equation if you are thinking of buying an apartment, Euon Murrell, of Tommys Real Estate in Porirua said. "You've got to be aware of it and bite the bullet." Mr Scott said Wellington's apartment market was still strong, and complexes with high earthquake ratings remained very attractive.
3. Potential hot suburbs
Titahi Bay and Tawa were attractive for first-home buyers as lower prices meant they could afford a deposit with the LVR restrictions, Mr Murrell thought. The same applied for parts of Lower Hutt. Upper Hutt could see a growth in new builds with the LVR exemption as there were plenty of opportunities to build there.
4. The impact of rising interest rates
The Reserve Bank indicated last month the official cash rate would likely rise to 4.75 per cent in the next two years. Mr Ross said the housing market had historically not been overly affected by interest rates. "The market rises and falls on confidence. Job security, employment prospects, a sense of an improving market are what helps or slows the market." Mr Scott felt an improving economy would compensate for interest rates and LVR restrictions.
5. Warrant of fitness for rental properties
Wellington City Council will pilot a warrant of fitness rating for rental properties, ensuring they are warm, dry and in good condition this year. Mr Murrell said some landlords needed to do more to improve their properties, but it would not happen overnight. "Not all landlords have the money to do something."
- The Dominion Post
Sponsored links
Maori studies captivate German student
Crime stats go online for all to see
Banks buoyant, Dotcom disdainful
One man fights to save fish as water dries up
Cartoonist Tom Scott always quick on the draw
Tall totara to tell long story of youth group
Drinking water won't beat new booze limit
Bridges: NZ can take lead on driverless vehicles
Golf phenom Zhuoyi Hu, 9, sets sights on Ko
Wellington cricketers feel safe despite Phillip Hughes' death
NZ's zoo escapes: Tigers, cheetahs and meerkats, oh my
NZ's zoo escapes: Tigers, cheetahs and meerkats, oh my
Wellington cricketers feel safe despite Phillip Hughes' death
Drinking water won't beat new booze limit
Bridges: NZ can take lead on driverless vehicles
Banks buoyant, Dotcom disdainful
Crime stats go online for all to see
Slow down, this road trip's too fast
Ernie Merrick told to 'please explain' referee rant
James Marshall aces dreaded 'yo-yo' test as Hurricanes resume training
Reason: McCaw, Ko legends; Hamilton an ass
SIS actions incompetent and unwise
From a million in a month to broke
Drinking water won't beat new booze limit
Cartoonist Tom Scott always quick on the draw
NZ's zoo escapes: Tigers, cheetahs and meerkats, oh my
Banks buoyant, Dotcom disdainful
Golf phenom Zhuoyi Hu, 9, sets sights on Ko
Man found dead on Kapiti Coast hill
Get checked and stay positive, says survivor
Creeping arrogance and deceit is no way to run the country
Bridges: NZ can take lead on driverless vehicles
Petone burglars tracked down using Facebook
What do you make of the proposed conference centre/hotel for Wellington?Related story: Convention centre to get OK

subset: commoncrawl


text:
- Love the music, now get the T-shirt. Click here for the full range.
Image Unavailable
Image not available for
|£4.37 & FREE Delivery in the UK on orders over £10. Details
Product details
Would you like to update product info or give feedback on images?
This album is worth the price in itself for 'Achilles Last Stand'. It is the quintessential Led Zeppelin track where all the elements of John Bonham's and John Paul Jones'... Read morePublished 21 days ago by strangerbytheminute
I love Zeppelin. Moving with the day on Presence but a must have for the collection.Published 26 days ago by benduh
Of course I knew Achilles Last Stand and Nobody's Fault But Mine (I had them on the Latter Days collection) but had written the rest off as sub-standard later Led Zeppelin... Read morePublished 1 month ago by P. Gardiner
This is Led Zeppelin at its most urgent, powerful and focussed. It's an album which, though not taking in as much of the flowery scenery on its journey as "IV" or... Read morePublished 2 months ago by Mr W Croft
This product's forum
Search Customer Discussions


text:
Holdays.net Home
Adidas originals I Love MOSCOW Russia track top WOMANS
100% authentic UK stock
we are an honest UK seller with many years retail and web experience
We offer a no problem return/replace policy if your not in anyway happy with your item get in touch with our friendly customer care team on 01704 892713 or email us on firstname.lastname@example.com many thanks
We are proud that we also run our business/office and shop in an eco friendly ethical way, from fairtrade biscuits to solar energy and recycable packaging we aim to run every aspect of our business in the most eco friendly way possible! any questions simply contact us!
This item has been shown 0 times.
Vtg Puma Tracksuit Xl Baby Blue W White Womens
New Nike Women's Dri Fit Printed Epic Run Long ¾ Capri Tights
Nike Black And Purple Running Pants, Size Xs, Drawstring Pants, Athletic Wear
C9 By Champion Black Jacket Zipper Puffer Front Venture Loft Workout
Reebok Women's Size 14/16 Black Sports Bra
Chad Pennington New Jersey
Lululemon Orange Scuba Hoodie Thick Sweatshirt Sz 4
Womens Under Armour Sleeveless Shirt Size Large Very Nice
Womens Nike Dri-fit Athletic Dance Tennis Skort Size Med. Very Nice
Women's Clima 365 Adidas Skort Size X-small Very Nice


text:
Randy Moss Doc Draws Strong Audience MLB Fires Back Against MASN In Court Battle Bama Again Draws CBS' Top CFB Audience Rogers Defends NHL GamePlus Exclusivity Back9Network Will Need To Fight For Traction NHL Calls For Dismissal Of Concussion Suit Media Notes Browns Ink TV Deal With Local ABC Affiliate Fox Sports Promotes NBA In-Market Streaming Players' Tribune Has Mixed Reviews To Date
Upcoming Conferences and Events
Dec 2-3
Dec 10-11
Apr 8-9
Apr 9
May 20
SBD/25/Sports Media
Published April 25, 1995
CBS is changing the name of "Eye on Sports" to "The CBS Sports Show" (N.Y. TIMES, 4/25)....HBO Sports President Seth Abraham said despite George Foreman's controversial decision over Axel Schulz, they have experienced "no drop-off in our interest in George." In fact, expect Foreman to fight again July 22 from Germany with Schulz featured in a separate bout (Richard Sandomir, N.Y. TIMES, 4/25). Tonight's USA Network boxing coverage will feature a 900 number for opinions on Foreman-Schulz (USA TODAY, 4/25)....In Philadelphia, Mike Bruton notes that the "NHL on Fox" is getting a "tremendous response" in St. Louis, Detroit and Philadelphia (PHILADELPHIA INQUIRER, 4/25)....Wayne Huizenga and Liberty Sports have invested in the Classic Sports Network, the cable service debuts on May 6 (N.Y. TIMES, 4/25).


text:
The top 20 of The Stage newspaper's recently published "power list" of the 100 most influential people in British theatre made for fascinating reading. Most of the usual suspects were there, but many of them found themselves paired with another name for their entry. For it's not only the artistic directors, the Nick Hytners and Gregory Dorans, who are celebrated but their all-important executive directors, the men and women who oversee every aspect of an organisation except what goes on its stages. Without executive directors, no contracts would be written, no money raised and no ambitious building projects undertaken.
Like this page on Facebook for updates
Health chiefs ponder moving 70st man
Tuesday 20 October 2009
Doctors and health officials were on a mission today to find a way to safely move a 70-stone man more than 150 miles.
Separate Tables, Festival Theatre, Chichester
Tuesday 22 September 2009
Ben Hur, O2 Arena, London
Judgement Day, Almeida, London
Separate Tables, Festival Theatre, Chichester
Sunday 20 September 2009
Behind the scenes at Glorious Goodwood
Saturday 01 August 2009
The newcomer to Goodwood should leave the main road and instead approach from the hamlet of Charlton, huddled in the valley below. Your car creeps up the steep, narrow lane until, rounding a turn, you catch your breath. The grandstands are suddenly disclosed upon the horizon, like an elegant galleon riding some swollen, green sea.
Enron, Minerva Theatre, Chichester
Monday 27 July 2009
After what's happened in the past few years, no-one should be surprised if our theatre comes up with a compelling tragedy of modern capitalism: the collapse of Enron, America's seventh largest corporation, going from $70bn (£42.5bn) of building plants and gas and electricity supplies to bankruptcy in just 24 days, is the signature story of the age.
The House of Special Purpose, Minerva Theatre, Chichester
Thursday 02 July 2009
As the television scriptwriter of Cranford, Heidi Thomas has anatomised damped-down friendships, budding romance and marital "getting along" with some finesse. And her sharp-eyed writing made more than was there, perhaps, of cultural collisions and imminent tragedy.
Oklahoma! Festival Theatre, Chichester
Monday 29 June 2009
Apologia, Bush, London
Everything Must Go, Soho, London
Oklahoma! Festival Theatre, Chichester
Sunday 28 June 2009
'Rockefeller' guilty of kidnapping daughter
Saturday 13 June 2009
A German-born man who emigrated to the US more than 30 years ago only to take on a series of increasingly unlikely aliases, including that of Clark Rockefeller, was convicted yesterday of trying to kidnap his seven-year-old daughter. He was jailed for four to five years.
Wallenstein, Minerva Theatre, Chichester
Tuesday 09 June 2009
Schiller's verse drama of a fallen idol, rarely seen here, deserves to be much better known, especially in such a thrilling production as this one by Angus Jackson – this season's associate director – who gets better all the time.
Cyrano de Bergerac, Chichester Festival Theatre, Chichester
Wednesday 20 May 2009
Alice Eve: Blonde ambition
Tuesday 05 May 2009
Alice Eve is flitting from table to table at the Electric, a private members' club in Notting Hill Gate. A social butterfly in flight, the British actress is waving at everybody in sight with a dreamlike, old-fashioned and polite air about her. She greets the waiter as if he is the kindest person on the planet, rocking her head slightly from side to side as she talks to him.
First Night: Hay Fever, Chichester Festival Theatre
Friday 17 April 2009
Patrick Caulfield: Serenely secular
Tuesday 14 April 2009
Madame de Sade, Wyndhams, London
Kafka's Monkey, Young Vic, London
The Last Cigarette, Minerva, Chichester
Sunday 22 March 2009
Rochester by-election: Ukip gains second MP as Tory defector Mark Reckless holds seat
'Beast of Bolsover' Dennis Skinner takes Ukip MP Mark Reckless to task moments after he is sworn in
Rochester by-election: Labour MP Emily Thornberry resigns after posting white van and England flags tweet
France 'blocks' Russian sailors from boarding a warship
The young are the new poor: Sharp increase in number of under-25s living in poverty, while over-65s are better off than ever
Green Party Caroline Lucas interview: 'We could be on the edge of something very big'
- 1 Lego letter from the 1970s still offers a powerful message to parents 40 years later
- 2 To help fuel their propaganda machine against the poor, our government has now decided to redefine the word 'welfare'
- 3 Naked free runner captured in breathtaking photographs above London's streets
- 4 Woman opens professional cuddling shop – gets 10,000 customers in first week
- 5 Grayson Perry: London needs affordable housing because 'rich people don't create culture'
WIN a trip for two to Cuba
Follow Simon Calder's journey in Cuba, and enter our competition to win a trip for two to Cuba
Rainbow list 2014: The LBGT people who make a real difference
Introducing our annual celebration of the lesbian, bisexual, gay, and transgender people who make a real difference
2014 WISE Summit
For the past four years, Qatar Foundation has been awarding an international prize for education each year, the first award of its kind in the world. Find out more...
Build yourself a brighter future
Chartered surveyors will be critical to shaping our new world
Why HD audio will lead to smarter calling
Telecom giant Vodafone is looking to improve voice quality, becoming the latest company to introduce new HD technology.
i100: A single mother on benefits who became one of the world's most successful authors
11 rags-to-riches underdog success stories
Made of London Series
Sir Ranulph Fiennes maintains that a lack of qualifications drove him on to climb Everest , circumnavigate the globe and walk to the South and North Poles.
From medieval to ultramodern
Mons is embracing the future as it prepares for its role as next year's European Capital of Culture, but it's also steeped in intriguing history. Philip Sweeney explores its two sides
Expertly tailored
From sharp cuts to discerning details, an expertly tailored look requires careful curation. Along with a few well-chosen accessories...
Enter the latest Independent competitions
Win anything from gadgets to five-star holidays on our competitions and offers page.
Business videos from commercial thought leaders
Watch the best in the business world give their insights into the world of business.


text: Wife and I hit Applebees's last Sunday to try some place different. We use to eat here all the time when it was the only sit down restaurant in Lawrenceville. Service was really good based on what I remembered, my water glass never got empty a single time, this might have been because it was a Sunday night and the... More


text:
Accounts Payable Clerk Jobs in Andover, Massachusetts
7 Andover, MA Accounts Payable Clerk jobs found on Monster.Jobs 1 to 7 of 7
East Coast Seafood, Inc. an International seafood company is seeking to hire an Accounts Payable Clerk. Responsibilities Include but are not limited to: -Act as primary contact for all vendors associated with all domestic companies -Receive incoming invoices from vendors and gather supporting documentation to prepare for processing -Enter data from invoices into the computer system using estab...
MES, a respected pioneer of the independent medical examination and review services industry, is setting the standard for IME services nationwide. We are convinced that the high growth environment, the longevity of our client relationships and our leading-edge security network protocol enable us to offer generous programs to our customers. MES professionals have provided the leadership and energy ...
ExamWorks Mishawum, MA, 01801
MES, a respected pioneer of the independent medical examination and review services industry, is setting the standard for IME services nationwide. We are convinced that the high growth environment, the longevity of our client relationships and our leading-edge security network protocol enable us to offer generous programs to our customers. MES professionals have provided the leadership and energy ...
For over 40 years Analogic has created markets by anticipating and solving some of the world's most complex medical and engineering challenges. Today, our specific areas of expertise include developing enabling technologies used in computed tomography (CT), ultrasound, digital mammography (DM), and magnetic resonance imaging (MRI). We also develop state-of-the-art threat detection systems for airp...
Flagship Motorcars of Lynnfield IMMEDIATE OPENINGS FOR: Automotive: Accounting – CVR Clerk This is an opportunity to grow with New England's most exciting and progressive automotive retailer. We have a state of the art facility! Previous Automotive experience Necessary. We offer a complete benefits package, paid holidays, vacation and a 401K plan. If you take your career seriously and want ...
Company Confidential Billerica, MA, 01821
Accounting Clerk We are currently seeking an experienced Accounting Clerk to join our team in our Billerica, MA location. This is a full-time salaried position in a fast paced business. Job Summary: This position is primarily responsible for computing, classifying, recording, and verifying numerical data for use in maintaining accounting records by performing the following duties. Job Duties a...
Veritiv Wilmington, MA, 01887
Overall scope and purpose of job is to perform warehousing tasks of receiving product, putting away product, picking product (filling orders), preparing product for shipment, general housekeeping, completing appropriate paperwork, operating equipment safely, and in some locations, loading trucks with product. Job Responsibilities Inspects, fills and stages orders in accurate, thorough and effici...
Get new jobs by email for this search
We'll keep looking and send you new jobs that match this search.
Upload your resume and let employers find you!
It's that simple!
Accounting Career Tools
Accounts Payable Clerk
$27,040.00 - $49,920.00
Typical Salary for Accounts Payable Clerk in Andover
(15 Respondents)
Source: Monster.com Careerbenchmarking Tool
Education / Training
Some College Coursework Completed
(10 Respondents)
Source: Monster.com Careerbenchmarking Tool
Accounts Payable Clerk
Completes payments and controls expenses by receiving, processing, verifying, and reconciling invoices.
Rate of Growth
11.40 %
Size of Industry in 2006:
Source: Bureau of Labor Statistics, May 2006
Related Skills
Analyzing Information
Attention to Detail
Data Entry Skills
Related Duties
Disburses petty cash by recording entry; verifying documentation.
Pays employees by receiving and verifying expense reports and requests for advances; preparing checks.
Popular Accounts Payable Clerk Articles
Finance Jobs
Whether your beat is auditing, tax, financial analysis, lending or another specialty, explore careers in finance and search for finance jobs now.
Sample Resume for a Mid-Career Accounts Payable Specialist
Wondering if your finance resume adds up? Compare it to our sample document for a mid-career accounts payable specialist and get inspired.
Sample Resumes by Industry
Writing a resume specific to your industry is a great way to be a star candidate. If you need help customizing your resume to your field, check out these resume examples for various careers.
Resume Tips for Finance Professionals
Tune up your resume to highlight the financial expertise and accomplishments employers are looking for.
Admin/Support Resume Tips
In the space of a one-page document, you've got to demonstrate you're organized, reliable, skilled and motivated. Does your resume do that?...


text:
TE Connectivity
"TE Corporate is a cohesive and intelligent group of people "
- Comp & Benefits
- Work/Life Balance
- Senior Management
- Culture & Values
- Career Opportunities
I have been working at TE Connectivity full-time (more than 3 years)
$15B dollar company with diversified products and technologies, extensive reach into a variety of markets ranging from automotive to military. Career opportunities abound as well as locations to work.
Big company can also mean being "reduced" if deemed necessary. HR is slow to respond to applications and has no followup mechanism acknowledging receipt of interest.
Create incentive programs for EVERY employee to succeed. Make sure that people feel valued as contributors to TE's success, by offering bonuses for going above and beyond. Finally, make sure that people are treated with care, not as a number.
348 Other Employee Reviews for TE Connectivity (View Most Recent)Sort: Rating Date
2 people found this helpful
"TE is definately not Raychem "
- Comp & Benefits
- Work/Life Balance
- Senior Management
- Culture & Values
- Career Opportunities
I have been working at TE Connectivity full-time (more than 3 years)Pros
Lots of good people to work withCons
E-Team is trying to shift as many jobs to low cost countries as possible without regard to the customer or products. I have had several heated discussions to prove that the implied savings is not there when you move to either china or mexico.
TE has been transfering jobs and production to china at an alarming rate but still have a tremendous problem with quality control and maintaining the equipment.Advice to ManagementAdvice
Respect your current personnel and their skill set- You can not just teach somebody in a few days what it took decades to learn.RecommendsNegative OutlookApproves of CEO
3 people found this helpful
"Deutsch Oceanside "
- Comp & Benefits
- Work/Life Balance
- Senior Management
- Culture & Values
- Career Opportunities
I have been working at TE Connectivity full-timePros
Hope is that TE can do no worse than what current Deutsch management has done with Oceanside. Hard to say what TE is really like since management withholds all information and participation with TE for regular employees.Cons
Two words: people issues. Deutsch has long suffered due to poor morale and low pay across the board. There are even supervisors and managers who work multiple jobs to make ends meet. Failure to attract and retain good employees and high turnover even in recent years. Future is bleak when good young talent come and leave once they get better job offers. Only those who can't find jobs elsewhere are left running the place.
Most of the management are very underqualified and don't show any traits of being a leader. Current management is living off the reputation and legacy of the old Deutsch company. Management just does enough to get by with their new TE masters and are waiting to hit retirement age. This gives no opportunity for anybody to move up at Oceanside. All these people issues lead to zero motivation, poor product quality, angry customers, no new products, and a poisonous work environment.Advice to ManagementAdvice
For TE mgmt: There is room for growth but opportunities are hampered by the crippling people issues at Deutsch. Send your brightest leadership to run Deutsch to straighten things out or send somebody to see beyond the Deutsch management shell game.


text:
Madden 13's wrong photo leaves NFL star incensed
Madden NFL 13 endured league star Marcus Thomas' ire yesterday, Kotaku discovered, after the New York Giants player discovered the game had a photo of a completely different Marcus Thomas in his profile. The Marcus Thomas it did feature (below right, after the break) last played in the league three years ago. To make things worse, he didn't even play at the same team (Denver Broncos), and he looks nothing at all like the first Marcus Thomas (below left). All of that incensed the first Marcus Thomas.
In a furious flurry of tweets – well, maybe not that furious – Thomas branded the football game "unprofessional" and "disrespectful." The defensive tackle's temper apparently cooled down once content producer Donny Moore tweeted he'd make the fix in Madden 13's next update. As yet, we've yet to hear what the other Marcus Thomas thinks about that. Or Belgian actor Marcus Thomas. Or Marcus Thomas, LLC.
Featured Stories
WWE 2K15 review: Disqualification match
Posted on Nov 26th 2014 2:00PM
Tales from the Borderlands Episode One review: Busy earnin'
Posted on Nov 26th 2014 9:00AM
Assassin's Creed Rogue review: Avast ye, clone!
Posted on Nov 25th 2014 9:01AM


text:
Fourth time lucky for Namibia?
ESPNscrum Staff
September 20, 2011
A young Neil Jenkins kicked 13 points aganist Namibia in June 1993 © Getty Images
Wales face Namibia for the fourth time at international level in New Plymouth on Monday - with the Welwitschias boasting a surprisingly competitive record against the Welsh. Although Wales have won all three of the previous encounters between the two nations, their margins of victory have been relatively tight.
When the two sides met for the first time in June 1990 in Windhoek Wales struggled to a 18-9 victory over Namibia, who finished the game with 14 men after the sending off of Andre Stoop. Fullback Paul Thorburn scored 15 points in the game to save Wales from defeat.
The two sides played again seven days later at the same location. And Namibia pushed Wales even closer as they came within five points of a famous upset. Wales scored four tries with two from Arthur Jones as well as one from Owain Williams and a penalty try. But the accurate kicking of Jaco Coetzee and Shaun McCulley - along with two tries from Ben Swartz and one from Gerhard Mans - ensured a nervy day for the Welsh who eventually won 34-30.
Wales' biggest winning margin over the Southern Africa side came in June 1993 when they ran in five tries to record a 38-23 victory.
Namibia v Wales
All-time record: Played: 3, Namibia won 0, Wales won 3,
Biggest winning margin:: Wal: 15, 38-23 at Windhoek, 1993
Highest score: Nam: 30 (30-34) at Windhoek, 1990; Wal: 38 (38-23) at Windhoek, 1993
Most tries: Nam: 3 (30-34) at Windhoek, 1990; Wal: 5 (38-23) at Windhoek,1993
Most points (individual): Nam: Jaco Coetzee, 28 Wal: Paul Thorburn 29
Most tries (individual): ; Nam: 2 Gerhard Mans and Ben Swartz; Wal: 2 Arthur Jones and Emyr Lewis
Most points in a Test: Nam: 18 Jaco Coetzee at Windhoek, 1993; Wal: 15 Paul Thorburn at Windhoek, 1990
Previous Rugby World Cup meetings:: 0
Click Here for Namibia's full Test record courtesy of Statsguru
Click Here for Wales's full Test record courtesy of Statsguru.
Click Here for a full record of all Namibia v Samoa matches courtesy of Stasguru
© ESPN Sports Media Ltd.
|Live Scores
The time for tinkering is over - England must nail their colours to the mast in key positions, writes Phil Vickery
Gatland should learn from Joe Schmidt
"New Zealand-born Joe Schmidt has forged the Irish into a street-smart, well- prepared side," John Mitchell on the Irish renaissance
"I am bored of hearing 'I can't fault the effort'. Let us take that for granted and look for some quality." John Taylor writes
Damned if they do, damned if they don't
Reports comparing the 2014 Wallabies with their rabble-like predecessors of 2005 are unfair and self-serving, Greg Growden reports


text:
Move over Danica! Former soccer player set to make history as first woman in the NFL
- Lauren Silberman, 28, will kick at an NFL regional scouting combine
- It follows success of Wisconsin-born Nascar driver Danica Patrick
A 28-year-old woman from New York is set to become the first female to be given a try out for the NFL.
Lauren Silberman had never kicked anything more than a soccer ball in an organised game before she started practicing long-range field goals.
Now she has been given a chance at an NFL regional scouting combine on Sunday at the New York Jets' training facility in Florham Park, New Jersey.
Scroll down for video
Lauren Silberman's NFL.com bio listed her as a former club soccer player at Wisconsin
Lauren Silberman, who has been handed a chance to make it into the NFL with a try out
Scouts are likely to want to Silberman her connect on extra points and chip-shot field goals with some consistency before moving on to the heavy kicking
It follows the success of Wisconsin-born Nascar driver Danica Patrick, 30, who became the first woman to start the Daytona 500 on pole position.
Patrick's achievement sparked predictions she could become the first woman to win the 'Great American Race' in Florida, but she eventually finished eighth.
Speaking about her chances of getting the NFL call, Silberman said: 'I am working hard to prepare but I am also realistic about my chances.
'I hope my willingness to put myself out there inspires others to seize opportunities and challenges. The support from around the world has been so heartening.'
Her goal for the weekend is to kick perfect 60-yard field goals.
However, the odds are against her - scouts are likely to want to see her connect on extra points and chip-shot field goals with some consistency before moving on to the heavy kicking.
Silberman wrote her Master's thesis on how college and pro athletes can use video games to improve their athletic performance
Silberman (pictured with a friend) had never kicked anything more than a soccer ball in an organised game and she just started practicing long-range field goals
The 30-year-old Lauren Silberman, from New York, taking aim for a kick at an indoor session
Danica Patrick waves to fans as she walks down pit road before the start of the Nascar Daytona 500
Silberman will compete against more accomplished or polished college kickers, all hoping to prove they have the leg strength and accuracy worthy of earning an invite to an NFL training camp.
St Louis Rams kicker Greg Zuerlein participated in a regional combine last year before he was drafted and morphed into 'Legatron'.
Cincinnati Bengals special teams coach Darrin Simmons said teams look for several things specifically when judging kickers in these situations.
The most important is leg strength, followed by accuracy on field goals over 40 yards, and how they did on clutch kicks in college.
Patrick won the pole at the Daytona 500, becoming the first woman to secure the top spot for any Sprint Cup race
'When rating field goals, the deepest we test at the combine is a 50-yard field goal. There's not many attempts over 55 yards.
'We don't practice kicks much deeper than that - rarely do we do them,' Simmons said. 'You can tell after watching a 50-yard field goal how far the ball goes over the crossbar if they can hit from 55.
'They've got to be able to hit from 55. On kickoffs, they've got to be able to get the ball out of the back of the end zone.'
The regional combines debuted in 2011, and feature players who weren't among the 333 invited to the main combine in Indianapolis.
The league is holding these sessions in 10 cities this offseason, with the most impressive players advancing to a super-regional in April in Dallas.
It's sort of the sports version of a TV reality show, where each hit and tackle can wow a scout and move a player on to the next round. Only instead of a recording contract, it's an NFL one.
'It's all up to those guys. If you're talented enough, you're going to get recognised. And if you put up good numbers, the numbers don't lie,' said Doug Whaley, assistant general manager/director of
player personnel for the Buffalo Bills.
'That's one of the things about the combine part of this business. It's the least subjective part of the business. And it's really objective, because you're looking at numbers.'
Steve Rosner, a partner with 16W Marketing in New Jersey, said: 'The real upside is if she reaches the next level.
'Kickers, in general, aren't brands. Very rare. Even someone like Adam Vinatieri, who (has won) Super Bowls, would have to do a little more than kick to capitalise and endorse at the national level.
'The one thing she has that they don't have is that she's a woman. The uniqueness of her and the possible success she has will differentiate what she has at that position.'
While a female has never played in the NFL, if the gender breakthrough did happen, it most likely would be at kicker.
As a grad student at MIT, Silberman wrote her Master's thesis on how college and pro athletes can use video games to improve their athletic performance.
She built upon the results of the study to start her own consulting firm, Double Play Media
- Meet Asuna, the 14-year-old android girl who looks human
- Whoopi's emotional announcement of Mike Nichols death
- Shocking moment Sheriff's Deputy knocks out female student
- Bill Cosby refuses to comment on rape allegations during AP...
- Man's PRICELESS reaction upon being told his wife is...
- Scariest voice in the world? Woman roars support at match
- INTENSE moment owner saves dog from python's clutches
- Students erupt in outrage after Sheriff's Deputy knocks out...
- Haifa Wehbe sparks outrage due to her provocative dress
- Jay Leno surprises wounded soldier with brand new muscle car
- Kim Kardashian meets Pink at an orphanage in Thailand
- Terrifying moment students in FSU Library alerted of...
- Michael Phelps' self-proclaimed 'girlfriend', 41, reveals...
- GOP factions tear into each other over strategy to block...
- The hyper-real robots that will replace receptionists, pop...
- Duchess of Alba, who died today aged 88, leaves nothing to...
- Oscar-winning director Mike Nichols dies suddenly of a heart...
- The library book that saved my life: Student shows off pages...
- EXCLUSIVE: Life with the Kardashians? I'd rather stay in...
- Keep on digging! Buffalo braces for three MORE feet of snow...
- Jacksonville Jaguars quarterback splits from gorgeous high...
- Rockin' in the FROZEN world: Snowed-in rock band trapped on...
- Jordan's Queen Rania in powerful attack on ISIS for...
- Wal-Mart tricked into selling $400 PlayStation 4 consoles...


text:
Digital Home & Smartphones Help
It's free to register, to post a question or to start / join a discussion
Investing in mobile apps
Likes # 0
Posted January 23, 2012 at 9:52AM
I am interested in investing to
Likes # 0
Posted January 23, 2012 at 9:58AM
... investing in the smartphone apps market. Specifically, I am interested if app developers are interested in finding funding for their ideas?
Reply to this topic
This thread has been locked.
Check out PC Advisor's other tech forums
Top 5 Most Popular
Black Friday 2014 tech deals UK Live: Best Black Friday deals from Apple, Amazon, Argos, eBay, John Lewis, Tesco, Sainsbury's, Asda, Google and more
Tesco Hudl 2 vs Nexus 7 tablet comparison: the best cheap tablet you can buy
2014 MacBook Pro vs MacBook Air comparison review: Apple laptop buying advice UK
Nexus 7 review: why the Nexus 7 is still the best tablet you can buy in 2014
Asus Memo Pad 7 (ME176CX) review: A competitive new entry into the budget tablet market


text:
Pikeville Forum
Forums and message boards for Pikeville, KY
Tell us your thoughts, ask questions, add a photo or create a poll!Start Discussion
Topix Talk
Let's hear your thoughts on trending Topix wide conversations.
Who do you side with in Ferguson?
ferguson 8,736
Fed Judge Strikes Down California's 10-Day Gun Waiting ...
guns 7,602
What role do you think humans play in global warming?
Environment 2,204
1,001 - 1,100 of 33,836
Keep Me Updated!
Sign up to receive new Topix forum notifications.
Updated: Sun Jul 27, 2014 01:07 am
Copyright © 2014 Topix LLC


text:
Portable Document Format (PDF) is a file format used to represent documents in a manner independent of application software, hardware, and operating systems
Bolero jacket sewing pattern.
Lightweight jacket fabrics with some body.
Fine gabardine, width: 150 cm (59 ins) length: 1.30 m (1 1/2 yds).
Lining, width: 140 cm (55 ins) length: Size 17 – 19: 0.90 ( 1yd) Size 20, 21: 1.10 m (1 1/4 yds).
Vilene/Pellon G 785. Vilene Bias Tape/stay tape.
This pattern doesn't include seam allowance
Produced by burda style magazine
As an early special Black Friday promotion you can now enroll in the course ($80 value) for $49.99!
Register for Meg's new course, space is limited!
Sewing & Techniques
Learn how to use your bodice sloper to draft this popular collar style
Get the Piped Trench Coat pattern
What Burda Academy Course is Right for Your Sewing Style?
Pattern of the Week
This is a quintessential ladylike coat with turned down shawl collar and fit and flare silhouette.
We're taking a sneak peak at the upcoming fashion design course.
You must allow our "request for permission" request to login to Burdastyle with Facebook.


text:
Atchison, 36, spent last season with Boston, appearing in 42 games out of the bullpen and compiling a 2-1 record with a career-best 1.58 ERA (nine earned runs/51.1 innings). The 6-2, 200-pound native of Denton, TX ranked second in the American League, and fourth in the majors, in ERA among relievers with at least 50.0 innings pitched.
Originally selected in the 49th round of the 1998 First-Year Player Draft, Atchison made his debut in 2004 with Seattle. Over six major league seasons with the Mariners, San Francisco and the Red Sox, Atchison owns a 7-7 record and a 3.48 ERA (81 earned runs/209.2 innings) in 155 games, one start.
Today on MiLB.com
Top Stories on MiLB.com
- Notable prospects added to 40-man rosters
- Moya, Ziomek claw their way up Tigers system
- With affiliation change, Fresno returns to roots
- San Antonio Missions get new look for 2015
- Padres send Fuentes to Royals for lefty Bartsch
- Valentine named 2014 King of Baseball
- Lindor, Urshela among Indians' standouts in '14
- Report: Red Sox's Kukuk arrested for robbery


text:
42,531 results
SORT BY Relevancy
Simon the Magician and the Quran
in Religion
A discussion of how Simon the MAGIician of the book of Acts was instrumental in some of hte teachings of hte Quran
The School of Greatness: Simon Sinek
in Entrepreneur
#BGERadio Presents: Special Broadcast
"The School of Greatness with Lewis Howes"
Lewis Howes is an author, Lifestyle Entrepreneur, former pro athlete and world record holder in football. The goal of the School of Greatness is to share inspiring stories from the most brilliant business minds, world class athletes and influential celebrities on the planet; to help you find out what makes great people great.
Featured Episode:
Simon Sinek: Why Leaders Eat Last
Simon Sinek is the mastermind behind Start with Why. His latest work, Leaders Eat Last, is another masterpiece on the topic of leadership. On this episode of the School of Greatness podcast, Lewis Howes and Simon go in-depth on the most pressing concerns for those seeking to create amazing, un-paralleled results with their lives and teams.
in News
TwinSpires Horse Racing Podcast w/Derek Simon
in Sports
In the News & Notes segment, host Derek Simon speculates on California Chrome's turf debut, analyzing both his pedigree and previous pace figures. He also opines on jockey injuries — can we prevent them and how?
In the U. Of Bet segment, Derek discusses money management and bankroll optimization and explains why ROI isn't the only thing that matters for players seeking consistent racetrack earnings.
TwinSpires Horse Racing Podcast w/Derek Simon
in Sports
In the News & Notes segment, host Derek Simon opines that "ruining" the Breeders' Cup may have been good for racing and he also reports on a Crazy News story from Britain.
In the U. of Bet segment, Derek unveils a "revolutionary" approach to handicapping and, because he's old and senile and forgot to mention it, the upcoming race he was alluding to is pictured above.
TwinSpires Horse Racing Podcast w/Derek Simon
in Sports
Host Derek Simon recaps the 2014 Breeders' Cup and uses his pace figures to answer the burning question: "Was there a speed bias at Santa Anita over BC weekend?"
Derek also weighs in on the non-disqualification of Bayern and a bunch of other racing-related stuff.
TwinSpires Horse Racing Podcast w/Derek Simon
in Sports
Derek Simon of TwinSpires.com and Ed DeRosa of Brisnet.com preview the 2014 Breeders' Cup races and Ed gives out his weekend "singles."
In the Handicapping segment, Derek takes a further, more in-depth look at selected BC races, including the Classic. He also drops more stats than Eminem drops rhymes.
TwinSpires Horse Racing Podcast w/Derek Simon
in Sports
In the News & Notes segment, host Derek Simon discusses the top stories in the Sport of Kings, including a new claiming rule in New York and a tragic confrontation between Steve Coburn, part-owner of California Chrome, and some members of the Breeders' Cup media.
In the U. of Bet / History segment, Derek discusses a great piece by Patrick Cummings regarding the way races are timed in the U.S.
Lastly, in the Handicapping segment, the Breeders' Cup Classic is analyzed.
The David Nozar Radio Show
in Business
The David Nozar Show introducing David Nozar and talking about Big Ticket DPS.
TwinSpires Horse Racing Podcast w/Derek Simon
in Sports
TwinSpires' Derek Simon discusses all the latest happenings in the Sport of Kings, including the untimely passing of jockey Juan Saez. Was the racing media irresponsible in reporting his death prematurely? Are racing fans and bettors partly responsible for Saez' untimely demise?
Then, in the Crazy News segment, Derek explains why he now cries everytime "The Notebook" comes on.
Lastly, in the I Need to Know segment, some juicy Breeders' Cup statistics are shared and dissected.
TRUNEWS 10/31/14: Sovereign Man Simon Black & Rodney Thompson
in News
Sovereign Man Simon Black talks with Rick about the rising number of Americans renouncing their citizenship because of Washington's heavy hand of tyranny. He also discusses how relocating can dramatically improve your lifestyle with less stress, lower cost of living, non-GMO food, and more friends. In Part 2, Trunews listener Rodney Johnson shares with Rick his thoughts about the meaning of Pastor T.D. Hale's dream involving Barack Obama on the Truman Balcony.
David Fore Interview
in Music
David Fore will be my guest talking about his drumming career with Bubble Puppy , Demian, D-Day , and The Eggmen.
- ...
Today's Best Podcasts
Join Host Live Chats
- Hagmann and Hagmann Report (491 chatters)
- thisisit4321 (93 chatters)
- Mindzmatter (87 chatters)
- Phoenix3333 (49 chatters)
- Tha Boxing Voice Radio Show (32 chatters)
- in5d (31 chatters)
- BacktoBasicsRadio (24 chatters)
- BerniceBennett (23 chatters)
- JohnMcTernan (20 chatters)
- thelordshour (19 chatters)
- Black Author Network (18 chatters)
- ALLFACTS CONCEPT CRUSHER (17 chatters)
- Radio Jihad Network (14 chatters)
- Supernatural Radio (14 chatters)
- Rifleman (13 chatters)
- African History Ntwk (13 chatters)
- Namaste Farms (12 chatters)
- SpeakEasy Cafe (12 chatters)
- the LMC Radio Network (11 chatters)
- Wake Up To The Truth (10 chatters)
- Talk Real Solutions (10 chatters)
- New Beginnings Radio (10 chatters)
- Dead Air Paranormal Radio (10 chatters)
- A Just Cause Coast 2 Coast (9 chatters)
- Bill Murray (9 chatters)
- WGAG Radio (9 chatters)
- Andrea Shea King (8 chatters)
- The Advise Show (8 chatters)
- Renegade Radio Network (7 chatters)
- MHHS Eyes Wide Open (7 chatters)
- ParanormalPsychicRadio (7 chatters)
- Cross Talk Radio brother Lawrence (7 chatters)
- Journey Into Light (7 chatters)
- Body of Christ (5 chatters)
- Cage Side Submissions (5 chatters)
- WE RESISTERS RADIO (5 chatters)
- The Forbidden Fruit (4 chatters)
- Psychics Gone Wild (4 chatters)
- Apostle Antonia (4 chatters)
- Living a Richer Life (4 chatters)
- Loren and Arjeana Due (4 chatters)
- Healing Light Radio (4 chatters)
- Get Real LOL uncensored reality tv (4 chatters)
- CommunityRadio (3 chatters)
- redmaryland (3 chatters)
- The Seika Network (3 chatters)
- Tha Real McCoy (3 chatters)
- The Axiom Radio Program (2 chatters)
- RichKid Radio (2 chatters)
- Politics and A Beer (2 chatters)
- SISTERS IN HARMONY (2 chatters)
- Talking Terror Presents (2 chatters)
- Sport City Chefs (2 chatters)
- Brain Injury Radio (2 chatters)
- David Coney (2 chatters)
- Dollhouse Radio by India Morel (2 chatters)
- Fellowship of Deliverance (2 chatters)
- Higher Truth Radio (2 chatters)
- dtm radio (2 chatters)
- Ed Boston Podcast (2 chatters)
- Ernest Radio Network (2 chatters)
- Matty Ps Radio Happy Hour (2 chatters)
- OUR Talk Radio Show (2 chatters)
- URN Radio Network (2 chatters)
- WHTP Radio Network (1 chatters)
- Witch School (1 chatters)
- minister sophie (1 chatters)
- Enterpraisement Media Group (1 chatters)
- Drunken Radio (1 chatters)
- Cowboy Wisdom Radio (1 chatters)
- American Preppers Radio (1 chatters)
- SavingSouls (1 chatters)
- Shifting Times Radio (1 chatters)
- The Captain0 (1 chatters)
- The Crystal Show (1 chatters)
- The New World Order Revolution (1 chatters)
- The Voice of Leadership (1 chatters)
- Throne Seekers Bible Study (1 chatters)
- Universal Christian Ministries (1 chatters)
- The American Republic (0 chatters)


text:
- Age / Gender:
- 21, Male
- Location:
- Somewhere
- Joined:
- 2/22/13
- All Stats >
Forgotten Dawn is not just a user's caprice, but a whole new universe of sounds, visuals and feelings. // VG Composer - Graphic designer - Game designer
User Statshot
- Community Stats
Level 15 Blank Slate
Normal Whistle
Ranked as Civilian
Contact Info / Websites
- Skype
- kkslider60
Latest News
Hello folks, I've got some news for you.
Coupled with the recent partnership with Freedom!, a Youtube network I applied to not too long ago, in these days I've been thinking of revamping the visual identity of Forgotten Dawn, not just the channel, but the entire network of related pages.
I believe it's important to give people a better idea of what this project's about, since I think the current imagery doesn't exactly fit the overall direction this channel as a whole has been taking. It's more than just an update, as I'm also planning to better organize the structure of my Youtube channel and pave the ground for multiple projects that will likely see the light at some point in the future.
Speaking of Youtube, in order to preserve intellectual rights pertaining to those people whose music I've shared through my "Inspiring Music" playlist, I will temporarily be taking the playlist down in order to avoid unwanted monetization (yes, it can happen) and therefore legally screw everything up. I think it's probably safer to create a side non-profit channel promoting such music when hopefully this project will welcome a wider audience, so my hopes are as good as yours right now.
Long story short, expect some changes in the graphics in these days and some general revamp on my own Youtube. Songs shared on Newgrounds and Soundcloud will remain untouched by the redesign.
Stay tuned and thanks for your support
[forgottendawn@Unity3D // Music for your Unity 3D games and projects]
Latest Audio Submissions
|FD - Club Wario Inc.
|Video Game Song
|FD - Sad Underground
|Cinematic Song
|FD - Nu Dead Cell
|Cinematic Song
|FD - K.K. Dirge
|Video Game Song
Favorite Audio
|~SW~ Float
|Ambient Song
|The Nightingale Order
|Cinematic Song
|The Wishing Tree
|Cinematic Song
|Fox-trot Fletcher
|Miscellaneous Song
Favorite Art
Favorite Games
Favorite Movies
Latest Shared Creations
Recent Game Medals
Total Medals Earned: 151 (From 49 different games.)


text:
Available in Grey/Black, Ivory/Silver
Love 21 - This slouchy knit cap-sleeve tee features alternating solid and metallic stripes for the perfect amount of shimmer. It has everything we look for in an off-duty piece: comfort with just a hint of glam. Lightweight59% rayon, 30% polyester, 6% nylon, 5% metallic yarn25.75" full length, 42" chest, 44" waist, 2.5" sleeve lengthMeasured from SmallHand wash coldImported
Available in Heather Grey
Redefined basics are completely of the moment, as they can elevate any outfit into something that's a bit more special. Take this classic crewneck tee: it has the straightforward silhouette that we all love but it's taken to the next level with the addition of beautifully embroidered lace sleeves. Pair it with everything from skinny jeans to pencil skirts. Knit Shell 1: 100% cotton, Shell 2: 100% nylon; Trim: 100% polyester21.5" full length, 18" chest, ...
Available in Black, Cream, Navy
A lightweight tee featuring a lace back yoke and short sleeves. Round neckline. Semi-sheer. Knit. Unlined. Lightweight. DETAILS:26" approx. length from high point shoulder to hem, 38" chest, 36" waist, 6" sleeve length from high point shoulderMeasured from SmallShell 1: 100% rayon; Shell 2: 94% nylon, 6% spandexHand wash cold, dry flatImported
Available in Black, Dusty Pink, Ivory, Red
Forever 21+ - Your favorite basic gets a femme update! This classic knit tee features a floral lace back and short sleeves. LightweightShell: 96% rayon, 4% spandex; Lining: 82% nylon, 18% spandex26" full length, 46" chest, 46" waist, 7" sleeve lengthMeasured from 1XHand wash coldImported
Use Code: SAVE20
November 21, 2014, 12:00 am PST – 11:59 pm PST
Valid on your purchase of $100 or more at forever21.com, or valid on your purchase of $60 or more at participating Forever 21, XXI Forever, or For Love 21 locations in the U.S. and U.S. territories. To redeem online, use the promo code at checkout. This promo code is unique to your email address. To use this code online, you must be logged in to the Forever 21 account associated with this email address. Promo code is one-time use only. To redeem in-store, show offer at register and discount will be applied to eligible purchases. Minimum purchase requirement must be met in a single transaction. Gift cards, E-Gift certificates, and previous purchases do not qualify toward the minimum purchase requirement. Discount not valid in the Branded Shop™, or on the purchase of gift cards or e-gift certificates, applicable taxes, or shipping and handling charges. Cannot be applied to previous purchases. Cannot be combined with any other offer, promo code, or discount. Items are final sale and non-returnable or exchangeable. Forever 21 reserves the right to modify or cancel this promotion at any time without notice.


text:
iSP200 2.1 Channel Speakers For Laptops And Desktops Is Also A USB Hub
Much like Philips, iLuv is getting ahead of the CES curve (yesterday they released the i9500). Today they unveiled the iSP200 2.1 Channel Speakers for laptops and desktops. If you're still looking for the other 'speakers' don't, they're all jammed into one box, although they're apparently removable. Inside are 2 smaller satellite like speakers and a powered sub putting out a max 32 watts of sound. The iSP200 is magnetically shielded for up close placement to a CRT and includes a 3x port USB 2.0 hub, USB or 3.5mm speaker input, 3.5mm aux input and volume/bass/treble controls.
The iLuv iSP200 will hit the open market June 2009 for $100.
Christen Costa
Grew up back East, got sick of the cold and headed West. Since I was small I have been pushing buttons - both electronic and human. With an insatiable need for tech I thought "why not start a blog focusing on technology, and use my dislikes and likes to post on gadgets."
Related Posts
iTunes Gift Card 15% Off, Roku 3 lowest price ever, 60% off men's shirts and pants
Skybar's Wine Preservation System Is A Wine Enthusiast's Dream
Sex With Glass Sounds Pretty Much Completely Awful
Panasonic's New "Hybrid" Vacuum Can Suck Up A Bowling Ball
Now You and Your Friends Can Borrow a Google Street View Camera
JIBO Is A Robot The Whole Family Will Enjoy (video)


text:
A critical role for OX40 in T cell-mediated immunopathology during lung viral infection.
ABSTRACT Respiratory infections are the third leading cause of death worldwide. Illness is caused by pathogen replication and disruption of airway homeostasis by excessive expansion of cell numbers. One strategy to prevent lung immune-mediated damage involves reducing the cellular burden. To date, antiinflammatory strategies have affected both antigen-specific and naive immune repertoires. Here we report a novel form of immune intervention that specifically targets recently activated T cells alone. OX40 (CD134) is absent on naive T cells but up-regulated 1-2 d after antigen activation. OX40-immunoglobulin fusion proteins block the interaction of OX40 with its ligand on antigen-presenting cells and eliminate weight loss and cachexia without preventing virus clearance. Reduced proliferation and enhanced apoptosis of lung cells accompanied the improved clinical phenotype. Manipulation of this late costimulatory pathway has clear therapeutic potential for the treatment of dysregulated lung immune responses.
- [Show abstract] [Hide abstract]
ABSTRACT: Immunity to viruses must be tightly controlled to avoid pathology. Receptors and ligands of the tumor necrosis factor (TNF) family play important roles in controlling lymphocyte activation and survival during an immune response. The role of specific TNF receptor (TNFR) family members in antiviral immunity depends on the stage of the immune response and can vary with the virus type and its virulence. Here, we focus on five members of the TNFR family that are prominently expressed on CD8(+) T cells during viral infections, namely, 4-1BB (CD137), CD27, OX40 (CD134), GITR, and TNFR2. 4-1BB, CD27, OX40, and GITR have primarily prosurvival roles for CD8(+) T cells during viral infection, although under some circumstances 4-1BB, GITR, or CD27 signals can limit immunity. Although TNFR2 can be costimulatory under some circumstances, its main role in CD8(+) T-cell responses during viral infection appears to be in contraction of the response. Several TNF family ligands are being explored as adjuvants for viral vaccines, and agonistic antibodies to TNFR family members are being investigated for immunotherapy of chronic viral infection alone and in combination with checkpoint blockade. Such therapies will require thorough and specific optimization to avoid pathology induced by hyperstimulation of these pathways.Immunological Reviews 09/2013; 255(1):125-48. · 12.16 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Viral infections are a common cause of acute respiratory disease. The clinical course of infection and symptoms depend on the viral strain, the health status of the host, and the immunological status of the host. Dendritic cells (DCs) play a crucial role in recognizing and presenting viral antigens and in inducing adaptive immune responses that clear the virus. Because the lung is continuously exposed to the air, the lung is equipped with an elaborate network of DCs to sense incoming foreign pathogens. Increasing knowledge on DC biology has informed us that DCs are not a single cell type. In the steady state lung, three DC subsets can be defined: CD11b(+) or CD103(+) conventional DCs and plasmacytoid DCs. Upon inflammation, inflammatory monocyte-derived DCs are recruited to the lung. It is only recently that tools became available to allow DC subsets to be clearly studied. This review focuses on the activation of DCs and the function of lung DCs in the context of respiratory virus infection and highlights some cautionary points for interpreting older experiments.Immunological Reviews 09/2013; 255(1):57-67. · 12.16 Impact Factor
Article: Report of the 'mechanisms of lung injury and immunomodulator interventions in influenza' workshop, 21 March 2010, Ventura, California, USA.[Show abstract] [Hide abstract]
ABSTRACT: The clinical course of influenza and the extent of lung injury are determined by both viral and host factors, as well as sometimes secondary bacterial infections and exacerbations of underlying conditions. The balance between viral replication and the host immune responses is central to disease pathogenesis, and the extent of lung injury in severe influenza infections may be due in part to overly exuberant or dysregulated innate inflammatory responses or sometimes deficient responses. Acute respiratory distress syndrome (ARDS) is the principal cause of respiratory failure associated with severe influenza. ARDS can be triggered by both direct lung insults (e.g. respiratory pathogens) and systemic insults (e.g. sepsis), and the lung damage is exacerbated by the inflammatory response associated with either infectious or non-infectious insults. This workshop aimed to review the current understanding of lung injury in acute influenza and describe cellular and molecular mechanisms of lung injury that are common to influenza and infections by other respiratory pathogens. In addition, therapeutic agents that target host response proteins and pathways were identified and investigational agents in development reviewed. A logical strategy would be to combine antiviral treatment with drugs that modify excessive host responses or supplement deficient ones. However, a better understanding of common cell signalling pathways associated with acute lung injury caused by influenza and other pathogens is necessary to understand immunopathologic causes of lung injury. This will help determine which immunomodulatory interventions might be useful, and to predict the appropriate timing and consequences of their use.Influenza and Other Respiratory Viruses 08/2011; 5(6):453-4, e458-75. · 1.47 Impact Factor
Page 1
The Journal of Experimental Medicine
J. Exp. Med.
Volume 198, Number 8, October 20, 2003 1237–1242
The Rockefeller University Press • 0022-1007/2003/10/1237/6 $8.00
A Critical Role for OX40 in T Cell–mediated
Immunopathology during Lung Viral Infection
Ian R. Humphreys,
and Tracy Hussell
Gerhard Walzl,
Lorna Edwards,
Aaron Rae,
Centre for Molecular Microbiology and Infection (CMMI), Biological Sciences, Imperial College of Science,
Technology and Medicine, London SW7 2AZ, United Kingdom
Xenova Research Ltd., Cambridge CB4 0WG, United Kingdom
Respiratory infections are the third leading cause of death worldwide. Illness is caused by
pathogen replication and disruption of airway homeostasis by excessive expansion of cell numbers.
One strategy to prevent lung immune–mediated damage involves reducing the cellular burden.
To date, antiinflammatory strategies have affected both antigen-specific and naive immune
repertoires. Here we report a novel form of immune intervention that specifically targets recently
activated T cells alone. OX40 (CD134) is absent on naive T cells but up-regulated 1–2 d after
antigen activation. OX40–immunoglobulin fusion proteins block the interaction of OX40
with its ligand on antigen-presenting cells and eliminate weight loss and cachexia without pre-
venting virus clearance. Reduced proliferation and enhanced apoptosis of lung cells accompanied
the improved clinical phenotype. Manipulation of this late costimulatory pathway has clear
therapeutic potential for the treatment of dysregulated lung immune responses.
Key words:costimulation • influenza • weight loss • inflammation
According to the World Health Organization lower respi-
ratory tract infections are the third most common cause of
death (1). Influenza virus is a causative agent of both epidemic
and pandemic respiratory viral illness with over 26,000
deaths attributed to the last outbreak in Britain alone (2).
Though pivotal for viral clearance, over exuberant T cell
responses result in airway occlusion (3, 4) and contribute
significantly to pathology (5). Therefore, in the absence of
universal vaccine candidates, inhibition of inflammatory T
cells presents a novel strategy for therapeutic intervention
in the treatment of influenza virus infection.
Several processes could be inhibited to thwart T cell
proliferation including a reduction of antigen presentation
by MHC, inhibition of costimulatory B7 molecules, or
depletion of T cells themselves. Such strategies, however,
affect both bystander and antigen-activated T cell reper-
toires. A more definitive approach would selectively inhibit
only those T cells recently activated by antigen. OX40
(CD134) is an ideal candidate because unlike CD28, it is
absent on naive T cells but up-regulated 1–2 d after antigen
encounter (6). OX40 imparts a survival signal to the T cell
preventing activation-induced cell death (7) but up-regulating
anti-apoptosis gene expression (8) and cytokine production
(9). Similarly, OX40 ligand (OX40L) is expressed only at
low levels on resting APCs and is up-regulated after
CD40–CD40L interactions (6, 10).
The critical role for OX40 is revealed in OX40-deficient
mice where CD4
T cell responses are abrogated during
both Th1-driven responses to viral infection (11) and
Th2-dominated allergic inflammation (12). Furthermore,
inhibition of OX40 using soluble OX40 fusion proteins
or antibody abrogates the detrimental effects of colitis in
SCID mice (13), inflammatory bowel disease (14), and aller-
gic encephalomyelitis (15).
Manipulation of this late costimulatory pathway has not
been tested during virus-induced inflammation. We show
that interruption of OX40/OX40L with an OX40–Ig fusion
protein ameliorates influenza-driven T cell immunopathology
and associated illness without preventing viral clearance. This
beneficial outcome is directly linked to a reduced inflam-
matory infiltrate caused by an inhibition of proliferation
Address correspondence to Tracy Hussell, CMMI, Biological Sciences,
Imperial College of Science, Technology and Medicine, Exhibition
Road, London SW7 2AZ, United Kingdom. Phone: 44-207-5943091;
Fax: 44-207-5943095; email: firstname.lastname@example.com
Abbreviations used in this paper:
-deoxyuridine; HA, hemagglutinin; MLN, mediastinal LN;
OX40L, OX40 ligand; RT, room temperature.
BAL, bronchoalveolar lavage fluid; BrdU,
on March 18, 2013
Downloaded from
Published October 20, 2003
Page 2
The Journal of Experimental Medicine
Reduced Costimulation Prevents Lung Immunopathology
and enhanced apoptosis. These findings show that OX40
costimulation plays a pivotal role in immunopathology to
respiratory viral infection and highlights a novel therapeutic
approach for the treatment of influenza-induced disease.
Materials and Methods
Mice and Virus.
Ltd.) were kept in pathogen-free conditions according to Home
Office guidelines. Influenza A strain X31 (hemagglutinin [HA] ti-
tre 1024) was provided by A. Douglas (National Institute for
Medical Research, London, United Kingdom).
Production of OX40 Fusion Proteins.
OX40–mIgG1 fusion protein (OX40–Ig) and the OX40–IgG4
fusion protein containing a mutation of Leu (235) to Glu in the
Fc region of IgG4 has been previously described (15, 16). Con-
structs were deemed LPS-free by gas chromatography-mass spec-
trometry of fatty acid methyl esters. In brief, samples were deriva-
tized using methanolic HCl and resulting fatty acid methyl esters
dissolved in hexanes before column injection on a Stabilwax col-
umn (30 m
0.25 mm internal diameter; Restek Corp.). Sam-
ples were analyzed using a temperature gradient of 150–250
a rate of 3
C/min. Characteristic retention times and spectra of
known standards were used to identify any fatty acid methyl esters
present in the samples.
Mouse Infections and Treatment.
tized and intranasally infected with 50 HA units influenza virus.
Mice were injected i.p. with 100
ova Pharmaceuticals) or mouse IgG (Caltag) on alternate days. The
weight of mice was monitored daily and illness severity was scored
as follows: 0, healthy; 1, barely ruffled fur; 2, ruffled fur but active;
3, ruffled fur and inactive; 4, ruffled fur, inactive, and hunched; 5,
dead. Mice were killed on various days after infection by injection
of 3 mg pentobarbitone and exsanguinated via the femoral vessels.
Some mice were challenged with 50 HA units influenza virus 3 wk
later and killed on various days as indicated in the text.
Cell Recovery and Flow Cytometry.
from bronchoalveolar lavage fluid (BAL), lung tissue, and medias-
tinal LNs (MLNs) were stained for surface markers and intracellu-
8–12-wk-old female BALB/c (Harlan Olac
The generation of murine
C at
On day 0 mice were anesthe-
g OX40–Ig fusion protein (Xen-
Single cell suspensions
lar cytokines and analyzed by flow cytometry as previously de-
scribed (17). All antibodies were purchased from BD Biosciences
except anti–OX40-FITC (Serotec). Influenza-specific CD8
cells were identified using an APC-labeled MHC class I tetramer
) loaded with the immunodominant peptide TYQR-
TRALV from the influenza nucleoprotein (National Institute of
Allergy and Infectious Diseases Tetramer Facility). For apoptosis
analysis, binding of PE-labeled annexin V was detected according
to the manufacturer's instructions. All data were acquired on a
FACSCalibur™ and 30,000 lymphocyte events were analyzed
with CELLQuest™ Pro software (BD Biosciences).
-deoxyuridine (BrdU) Labeling and Detection.
were treated with 0.8 mg/ml BrdU (Sigma-Aldrich) in their
drinking water for 4 d. MLNs were taken and cells were stained
with CyChrome anti-CD4 and anti–CD8-PE as previously de-
scribed (17). After washing, cells were resuspended in 500
cold 0.15 M NaCl. While mixing gently, 1,200
ethanol was added drop-wise. Cells were incubated at 4
dark for 30 min before washing with cold PBS and fixing for 30
min at room temperature (RT) with 1% paraformaldehyde and
0.01% Tween-20. Cells were then centrifuged and incubated
with 50 U DNase I (Sigma-Aldrich) in 4.2 mM MgCl
NaCl, pH 5.0, for 10 min at RT. After centrifugation, cells were
incubated in the dark at RT for 30 min with FITC anti-BrdU
(BD Biosciences), washed in PBS/3%BSA/0.01% sodium azide,
and analyzed on a FACSCalibur™. Lymphocytes positive for
FITC anti-BrdU were detected with CELLQuest™ Software
(BD Biosciences) and were identified to have undergone postthy-
mic proliferation (18).
Lung Influenza Titer.
Clearance of influenza was assessed in
lung homogenates 2, 4, 7, and 11 d after virus challenge. Homog-
enized cells were freeze thawed three times, centrifuged at 4,000
and supernatants were titrated in doubling dilutions on Madin
Darby canine kidney cell monolayers in flat-bottomed 96-well
plates. After incubation at RT for 3 h, samples were overlaid with
methylcellulose and incubated for 72 h at 37
were washed and incubated with anti-influenza antibody (Sero-
tec), followed by anti–mouse–horseradish peroxidase (Dako-
Cytomation) and infected cells were detected using 3-amino-9-
ethylcarbazole (AEC; Sigma-Aldrich). Infectious units were
l ice-
l ice-cold 95%
C in the
C. Cell monolayers
Figure 1.
loss, pulmonary inflammation, and OX40 ex-
pression by T cells. (A) Mice were infected
with influenza, BAL removed 2, 4, 7, 11, and
15 d after infection, and total viable cells were
enumerated (right axis). Weight loss was moni-
tored daily and expressed as percent of original
body weight (left axis). Results represent mean
values ? SEM from four mice per group. BAL
(B and C) and MLNs (D and E) were removed
from influenza-infected mice and cells were
stained with OX40-FITC and APC-CD4 (B
and D) or PercP-CD8 (C and E). Results repre-
sent the mean percent (left) and total number
(right) of OX40? T cells ? SEM from five indi-
vidual mice and is representative of three separate
Influenza infection induces weight
on March 18, 2013
Downloaded from
Published October 20, 2003
Page 3
The Journal of Experimental Medicine
Humphreys et al.
enumerated by light microscopy and total plaque-forming units
per lung were quantified (number of plaques
total volume of lung homogenate).
Statistical significance was evaluated using a two-
tailed Student's
test assuming unequal variance with the Minitab
software program. Where more than one comparison was made
within an experiment, the Bonferroni correction was applied.
dilution factor
Results and Discussion
OX40–Ig Treatment Reduces Influenza-induced Weight Loss
and Exuberant T Cell Inflammation During Infection.
nasal influenza virus infection results in rapid accumulation
of lymphocytes within the lung and airways (4). Maximal T
cell expansion at 7 d coincides with peak weight loss (Fig. 1
A). The association between cellular infiltration and weight
loss is characteristic of many lung viral infections (19, 20).
The kinetics of OX40 expression by BAL CD4
and CD8
(Fig. 1 C) T cells followed a similar pattern in
that the highest proportion was present 4 d after influenza
infection. This profile was also evident in the lung (unpub-
lished data). By calculating the total number of CD4
OX40 and CD8OX40 T cells the highest numbers co-
incided with maximum weight loss at day 7. OX40 expres-
sion was also present in the lung-draining MLN. The pro-
portion and total numbers of OX40-expressing CD4
1 D) and CD8
(Fig. 1 E) T cells peaked at 4 d.
Because excess T cell infiltration into the virally infected
lung compromises lung function and compliance, we next
examined the effect of reducing T cell costimulation via
OX40. Control-treated mice lost
weight, whereas those treated with OX40–Ig did not (Fig. 2
A). Visual inspection revealed that control-treated, influ-
enza-infected mice, especially at day 6, appeared hunched,
immobile, and severely cachexic, whereas OX40–Ig-treated
(Fig. 1 B)
? ? ?
25% of their initial body
mice were consistently indistinguishable from uninfected
controls (Fig. 2 B). The striking elimination of weight loss
and illness severity was accompanied by a reduction in pul-
monary inflammation including neutrophils (unpublished
data) and CD4
and CD8 T cells (Fig. 2 C). The total
number of OX40-expressing T cells was also reduced in
line with the general reduction in inflammation (unpub-
lished data). However, the percent of T cells expressing
OX40 was unaffected. This was not surprising because
OX40 expression is induced by CD28 and TCR signals and
does not rely on interaction with OX40L. OX40L expres-
sion has been observed on some T cells cultured in vitro
(21). Although reduced T cell numbers in our study may
reflect depletion after OX40–Ig binding, we do not believe
this to be the case because OX40–Ig did not enhance T cell
death in vitro (unpublished data) and an alternative OX40–
Ig fusion that does not fix complement or promote ADCC
produced an identical effect (Fig. 2 D). The benefit of ma-
nipulating OX40 costimulation is clearly evident in hema-
toxylin and eosin–stained sections of lung tissue. Cellular in-
filtration around the airways and blood vessels was markedly
reduced in OX40–Ig-treated mice compared with control
IgG–treated mice (Fig. 2, E and F, respectively).
Using flow cytometry and intracellular cytokine staining,
the number and proportion of CD8
TNF were found to be reduced in OX40–Ig-treated mice
(Fig. 3, A and B). Tetramer-binding CD8
C and E) and their production of TNF (Fig. 3 D) were se-
verely reduced by OX40–Ig treatment. Although TNF is
greatly increased systemically in some viral infections, we
did not observe elevated serum TNF by ELISA or cyto-
metric bead array after influenza virus infection (unpub-
lished data). Anti-TNF antibodies reduce weight loss and
cell recruitment during influenza infection (5). Precisely
? ?
T cells producing
T cells (Fig. 3,
Figure 2.
prevents illness and T cell inflamma-
tion during influenza infection. (A)
BALB/c mice (n ? 4) were infected
with influenza, treated with mouse
IgG or OX40–Ig on alternate days,
and weight loss was monitored and
expressed as percent of original
weight (P ? 0.05 days 2–6). Illness
was scored from 1–5 based on the
degree of immobility, cachexia, and
ruffled fur. The cumulative illness
score was calculated by treatment
group (B). (C) Total numbers of
BAL CD4? and CD8? T cells 6 d
after infection were determined by
multiplying the percent of positive
cells by flow cytometry with the total
viable cells recovered from the BAL
of IgG or OX40–Ig-treated mice.
(D) In an identical experiment, BAL
CD4? and CD8? T cell numbers
were determined in mice treated
with IgG, OX40–Ig, and OX40–
OX40–Ig treatment
mutIgG (gray symbols). Open symbols, OX40–Ig-treated mice; closed symbols, control IgG–treated mice. E and F show representative hematoxylin and
eosin–stained lung sections 7 d after influenza infection in OX40–Ig- (E) or IgG- (F) treated mice. All experiments were repeated two to three times
with five mice per group.
on March 18, 2013
Downloaded from
Published October 20, 2003
Page 4
The Journal of Experimental Medicine
Reduced Costimulation Prevents Lung Immunopathology
how this works, however, is unclear. Influenza virus repli-
cation is restricted to the respiratory epithelium. In this sit-
uation we believe that TNF indirectly causes weight loss by
enhancing cell recruitment and proliferation leading to air-
way occlusion. These results imply that OX40 signaling
plays a critical role during T cell–mediated immunopathol-
ogy elicited by influenza infection.
Delayed OX40–Ig Treatment Inhibits Weight Loss in In-
fluenza-infected Mice with Established Illness and Does Not
Affect Viral Clearance or Recall Responses.
OX40–Ig treatment during influenza virus infection until
the mice had lost 20% of their original weight. Such de-
layed treatment still reversed the decline of weight com-
Next, we delayed
pared with controls (Fig. 4 A; P
appeared perfectly healthy. Plaque assays performed on
lung homogenates in a time course study did not reveal any
delay in influenza virus clearance when OX40–Ig was ad-
ministered on day 0 (Fig. 4 B) or 3 d after infection (un-
published data).
The rather surprising lack of an effect of OX40–Ig on
virus clearance might be partially explained by stimulation
of B cells. OX40 interaction with OX40L imparts a bidi-
rectional signal to the T cell and the APC (22). Although
soluble OX40 fusion proteins reduce the signal to the T
cell, signaling to the APC remains intact and may even be
enhanced. OX40–Ig treatment may therefore induce anti-
0.05 days 5–7) and mice
Figure 3.
binding of CD8? T cells. (A) Influenza-infected
mice were treated with IgG or OX40–Ig and
lung cells were stained for CD8 and intracellular
TNF. Total numbers were calculated by multi-
plying total viable cells by the percent of CD8?/
TNF? cells. Mean percent (left) and total numbers
(right) ? SEM from five mice per group are
shown. Representative plots of lung CD8 versus
TNF in lymphocytes 7 d after infection in
IgG- (left) or OX40–Ig- (right) treated mice
(B). (C and E) Lung cells were removed from
IgG- or OX40–Ig-treated, influenza-infected
mice 0, 2, 5, 7, and 10 d after infection and
stained with anti–CD8-PercP, tetramer-APC,
and anti–TNF-FITC. Total numbers were cal-
culated by total viable cells ? percent CD8?/
Tetramer? (C) or CD8?/Tetramer?/TNF? (D).
Results are mean values ? SEM of five mice per
group. Representative plots of CD8 versus
tetramer are shown in E in IgG- (left) or
OX40–Ig- (right) treated mice 7 d after infection.
All results are representative of at least two inde-
pendent experiments containing five mice per
group. Open symbols, OX40–Ig-treated mice;
closed symbols, IgG-treated mice.
OX40–Ig reduces TNF and tetramer
Figure 4.
and T cell proliferation, increases apoptosis, but
does not inhibit viral clearance or recall responses.
(A) Mice (n ? 3) were infected with influenza
virus on day 0 and treated with IgG or OX40–Ig
on days 3, 4, and 5 after infection. Weight loss is
expressed as percent of original weight. (B) Mice
(n ? 4) were infected with influenza and
treated with either IgG or OX40–Ig. On days
2, 5, 7, and 11 after infection, lung tissue was
homogenized and viral titre was quantified by
plaque assay. (C–E) Mice (n ? 4) were infected
with influenza and treated with IgG or OX40–
Ig as in B. 3 wk later mice were challenged with
influenza and on days 2, 5, and 7 after infection,
CD4? (C), CD8? (D), and CD8? tetramer? (E)
T cells were enumerated in lung tissue. (F and
G) Proliferating MLN CD4 and CD8 T cells
(F, by BrdU incorporation) and apoptotic annexin
V–stained lung cells (G) were assessed in control-
or OX40–Ig-treated mice 4 and 7 d, respectively,
after influenza infection. Closed symbols, IgG
control; open symbols, OX40–Ig. Mean
values ? SEM are shown and are representa-
tive of two separate experiments.
OX40–Ig reduces established illness
on March 18, 2013
Downloaded from
Published October 20, 2003
Page 5
The Journal of Experimental Medicine
Humphreys et al.
viral antibodies and elicit compensatory effects. However,
analysis of influenza-specific antibody 4, 7, 11, 15, and 19 d
after infection showed no differences in nasal IgA responses
or serum IgG1 and IgG2a (unpublished data).
The ability of mice to respond to reinfection was not af-
fected by OX40–Ig treatment despite the significant re-
duction in T cell immunity during the first infection. A
time course analysis after rechallenge did not reveal any
statistical differences between the numbers of CD4
4 C) or CD8
(Fig. 4 D) T cells and those binding MHC
class I tetramer (Fig. 4 E). In both OX40–Ig-treated and
control mice influenza virus was cleared 5 d after rechal-
lenge. On day 2, virus titres were similar (1,080
control and 1,546
246 plaque-forming units/lung in the
OX40–Ig-treated group). The lack of an effect on recall
responses is surprising and may suggest that sufficient im-
mune memory was generated during the first infection.
Influenza virus promotes a very large inflammatory re-
sponse. It is likely that not all of the inflammatory cells are
required to contain infection. The reduced inflammatory
infiltrate may therefore still contain enough cells to seed
the memory pool. No studies to date have addressed the
number of antigen-specific cells required to eliminate a vi-
ral infection. In this study we show that a threefold reduc-
tion in T cells remains efficient and does not cause disease.
Alternatively, efficient rechallenge responses may reflect
recruitment of naive cells or the fact that OX40–Ig treat-
ment was only administered to day 10 during the first in-
fection. After day 10 some memory T cell responses may
have been generated.
Impaired T Cell Responses in OX40–Ig-treated Mice Is a
Consequence of Reduced Proliferation and Enhanced Apoptosis.
The reduction of T cells by OX40–Ig could represent re-
duced proliferation or increased apoptosis. Rather than ar-
tificially examining proliferation in vitro, we gave mice
BrdU in their drinking water during infection. BrdU is in-
corporated into proliferating cells and can be detected by
flow cytometry using an anti-BrdU antibody. Analysis of
MLN cells 4 d after infection revealed that OX40–Ig treat-
ment had significantly reduced both CD4
cell proliferation (Fig. 4 F). This effect was only observed at
the peak of proliferation and not during the later stages of
infection (unpublished data).
OX40 binding to its ligand induces the anti-apoptotic
proteins Bcl-2 and Bcl-xL (8) and prevents activation-
induced cell death (23). Reduced T cell numbers in OX40–
Ig-treated mice may therefore result from increased cell
death. The frequency of apoptotic CD4
was identified by annexin V staining and flow cytometry.
Administration of OX40–Ig significantly enhanced the pro-
portion of apoptotic CD4
(Fig. 4 G) but not CD8
(unpublished data) in the airways during the later stages of
infection (days 7 and 10), implying that OX40 costimula-
tion is required to prolong pulmonary T cell survival.
The reduction in T cell infiltrate is similar to that ob-
served in influenza virus–infected OX40
Using such mice it is difficult to ascertain whether the
improved outcome is due to reduced T cell function or
288 for
and CD8
and CD8
T cells
? ?
T cells
mice (11).
an alteration of APC activation through OX40L. Our
studies compliment and extend this in several important
ways: (a) we show that both CD4
affected, (b) that inflammatory cytokines are reduced,
and (c) that proliferation is reduced and cell death in-
The reduction of both T cell numbers and proinflamma-
tory cytokine secretion after OX40–Ig treatment raises the
question of why lung viral replication is still effectively
controlled? There are three plausible explanations: (a) in-
nate immune mechanisms such as NK cells, which were
not affected by OX40–Ig treatment (unpublished data),
may mediate viral clearance. However, the role of NK cells
in immunity to influenza virus infection is unclear. In-
creased susceptibility to influenza virus in the senescence-
accelerated mouse is associated with impaired activity of
NK cells, but CD8
T cells are also defective in this model
(24). (b) Influenza virus is highly inflammatory and a mod-
erate reduction in the vigor of the inflammatory response
might be beneficial without affecting virus clearance. This
hypothesis is consistent with the efficient control of other
viruses in OX40 knockout mice (25, 11). (c) Because
OX40 is expressed 1–2 d after antigen activation, influenza
virus infection might be controlled by earlier T cell–APC
The delayed expression of OX40 makes it an ideal target
during immunopathological conditions because it enables
initial T cell priming and containment of viral replication.
In contrast, blockade of CD28, which is constitutively ex-
pressed by T cells, significantly delays influenza clearance
(26). The lung microenvironment requires careful immune
homeostasis. Excessive inflammation compromises gaseous
exchange by occluding the airways and inducing mucus
production. This is more apparent in the lungs than other
mucosal sites. The gut, for example, can accommodate rel-
atively large cell numbers while retaining its primary func-
tion. Evidence from murine models suggests that a re-
duction, but not elimination, of the lung inflammatory
infiltrate is beneficial. Depletion of inflammatory cytokines
or CD8T cells, or T cell subsets (27) all reduce
weight loss without preventing virus clearance. Collec-
tively, this implies that the problem is caused by the num-
ber of T cells present and not their phenotype. Manipula-
tion of OX40 therefore presents a novel therapeutic
strategy for treatment of immunopathological conditions
by reducing the number of activated T cells while leaving
the naive repertoire intact.
and CD8
T cells are
? ?
The authors would like to thank Paul Hitchen (Imperial College
London) for help with determining the LPS content of OX40L–Ig
fusion proteins, Lorraine Lawrence (Department Leukocyte Biology,
Imperial College) for processing of samples for analysis of BrdU, and
Professor Ita Askonas for critical review of the manuscript.
This work was supported by The Medical Research Council and
The National Asthma Campaign.
Submitted: 5 March 2003
Revised: 19 August 2003
Accepted: 16 September 2003
on March 18, 2013
Downloaded from
Published October 20, 2003
Page 6
The Journal of Experimental Medicine
Reduced Costimulation Prevents Lung Immunopathology
1. Murray, C.J., and A.D. Lopez. 1997. Global mortality, dis-
ability, and the contribution of risk factors: global burden of
disease study.
2. Curwen, M., K. Dunnell, and J. Ashley. 1990. Hidden influ-
enza deaths.
Br. Med. J.
3. Doherty, P.C., D.J. Topham, R.A. Tripp, R.D. Cardin, J.W.
Brooks, and P.G. Stevenson. 1997. Effector CD4
T-cell mechanisms in the control of respiratory virus
Immunol. Rev.
4. Enelow, R.I., A.Z. Mohammed, M.H. Stoler, A.N. Liu, J.S.
Young, Y.H. Lou, and T.J. Braciale. 1998. Structural and
functional consequences of alveolar cell recognition by
) T lymphocytes in experimental lung disease.
5. Hussell, T., A. Pennycook, and P.J.M. Openshaw. 2001. In-
hibition of tumour necrosis factor reduces the severity of vi-
rus-specific lung immunopathology.
6. Gramaglia, I., A.D. Weinberg, M. Lemon, and M. Croft.
1998. Ox-40 ligand: a potent costimulatory molecule for sus-
taining primary CD4 T cell responses.
7. Maxwell, J.R., A. Weinberg, R.A. Prell, and A.T. Vella.
2000. Danger and OX40 receptor signaling synergize to en-
hance memory T cell survival by inhibiting peripheral dele-
J. Immunol.
8. Rogers, P.R., J. Song, I. Gramaglia, N. Killeen, and M.
Croft. 2001. TI-OX40 promotes Bcl-xL and Bcl-2 expres-
sion and is essential for long-term survival of CD4 T cells.
9. Flynn, S., K.M. Toellner, C. Raykundalia, M. Goodall, and
P. Lane. 1998. CD4 T cell cytokine differentiation: the B cell
activation molecule, OX40 ligand, instructs CD4 T cells to
express interleukin 4 and upregulates expression of the che-
mokine receptor, Blr-1.
J. Exp. Med.
10. Stuber, E., M. Neurath, D. Calderhead, H.P. Fell, and W.
Strober. 1995. Cross-linking of OX40 ligand, a member of the
TNF/NGF cytokine family, induces proliferation and differen-
tiation in murine splenic B cells.
11. Kopf, M., C. Ruedl, N. Schmitz, A. Gallimore, K. Lefrang,
B. Ecabert, B. Odermatt, and M.F. Bachmann. 1999. OX40-
deficient mice are defective in Th cell proliferation but are
competent in generating B cell and CTL responses after virus
Immunity. 11:699–708.
12. Jember, A.G., R. Zuberi, F.T. Liu, and M. Croft. 2001. De-
velopment of allergic inflammation in a murine model of
asthma is dependent on the costimulatory receptor OX40. J.
Exp. Med. 193:387–392.
13. Malmstrom, V., D. Shipton, B. Singh, A. Al-Shamkhani,
M.J. Puklavec, A.N. Barclay, and F. Powrie. 2001. CD134L
expression on dendritic cells in the mesenteric lymph nodes
drives colitis in T cell-restored SCID mice. J. Immunol. 166:
14. Higgins, L.M., S.A. McDonald, N. Whittle, N. Crockett,
J.G. Shields, and T.T. Macdonald. 1999. Regulation of T cell
activation in vitro and in vivo by targeting the OX40-OX40
ligand interaction: amelioration of ongoing inflammatory
bowel disease with an OX40-IgG fusion protein, but not
J. Clin.
Eur. J. Immunol.
J. Immunol.
with an OX40 ligand-IgG fusion protein. J. Immunol. 162:
15. Weinberg, A.D., K.W. Wegmann, C. Funatake, and R.H.
Whitham. 1999. Blocking OX-40/OX-40 ligand interaction
in vitro and in vivo leads to decreased T cell function and
amelioration of experimental allergic encephalomyelitis. J.
Immunol. 162:1818–1826.
16. Taylor, L., M. Bachler, I. Duncan, S. Keen, R. Fallon, C.
Mair, T.T. McDonald, and H. Schwartz. 2002. In vitro and
in vivo activities of OX40 (CD134)-IgG fusion protein iso-
forms with different levels of immune-effector functions. J.
Leukoc. Biol. 72:522–529.
17. Hussell, T., L.C. Spender, A. Georgiou, A. O'Garra, and
P.J.M. Openshaw. 1996. Th1 and Th2 cytokine induction in
pulmonary T-cells during infection with respiratory syncytial
virus. J. Gen. Virol. 77:2447–2455.
18. Wang, Q., N. Strong, and N. Killeen. 2001. Homeostatic
competition among T cells revealed by conditional inactiva-
tion of the mouse Cd4 gene. J. Exp. Med. 194:1721–1730.
19. Alwan, W.H., F.M. Record, and P.J.M. Openshaw. 1992.
CD4? T cells clear virus but augment disease in mice in-
fected with respiratory syncytial virus: comparison with the
effects of CD8? cells. Clin. Exp. Immunol. 88:527–536.
20. Stevenson, P.G., S. Hawke, and C.R. Bangham. 1996. Pro-
tection against lethal influenza virus encephalitis by intrana-
sally primed CD8? memory T cells. J. Immunol. 157:3065–
21. Baum, P.R., R.B. Gayle, III, F. Ramsdell, S. Srinivasan,
R.A. Sornensen, M.L. Watson, M.F. Seldin, E. Baker, G.R.
Sutherland, and K.N. Clifford. 1994. Molecular characteriza-
tion of murine and human OX40/OX40 ligand systems:
identification of a human OX40 ligand as the HTLV-1-regu-
lated protein gp34. EMBO J. 13:3992–4001.
22. Stuber, E., and W. Strober. 1996. The T cell–B cell interac-
tion via OX40-OX40L is necessary for the T cell–dependent
humoral immune response. J. Exp. Med. 183:979–989.
23. Weinberg, A.D., A.T. Vella, and M. Croft. 1998. OX-40:
life beyond the effector T cell stage. Semin. Immunol. 10:471–
24. Dong, L., I. Mori, M.J. Hossain, and Y. Kimura. 2000. The
senescence-accelerated mouse shows aging-related defects in
cellular but not humoral immunity against influenza virus in-
fection. J. Infect. Dis. 182:391–396.
25. Pippig, S.D., C. Pena-Rossi, J. Long, W.R. Godfrey, D.J.
Fowell, S.L. Reiner, M.L. Birkeland, R.M. Locksley, A.N.
Barclay, and N. Killeen. 1999. Robust B cell immunity but
impaired T cell proliferation in the absence of CD134
(OX40). J. Immunol. 163:6520–6529.
26. Lumsden, J.M., J.M. Roberts, N.L. Harris, R.J. Peach, and F.
Ronchese. 2000. Differential requirement for CD80 and
CD80/CD86-dependent costimulation in the lung immune
response to an influenza virus infection. J. Immunol. 164:
27. Walzl, G., S. Matthews, S. Kendall, J.C. Gutierrez-Ramos,
A.J. Coyle, P.J. Openshaw, and T. Hussell. 2001. Inhibition
of T1/ST2 during respiratory syncytial virus infection pre-
vents T helper cell type 2 (Th2)- but not Th1-driven immu-
nopathology. J. Exp. Med. 193:785–792.
on March 18, 2013
Downloaded from
Published October 20, 2003


text:
New England Patriots Cut Roster Down to 53
In what has been a busy day for the New England Patriots organization, they finally get their roster down to a total of 53 players.
Of the 22 players released receiver Deion Branch, 11-year veteran and MVP of Super Bowl XXXIX, headlined the cuts. Other notable players released from the team include center Dan Koppen, who was one of the three lasting players from the New England Patriots first Super Bowl win, safeties Sergio Brown and James Ihedigbo and quarterback Brian Hoyer.
Other players who didn't make the team include WR Jesse Holley, DL Marcus Harrison,OL Matt Kope, LB Niko Koutouvides, S Derrick Martin, LB Jeff Tarpinian, S Malcolm Williams, FB Eric Kettani, DL Aaron LAvarias, TE Alex Silvestro and WR Kerry Taylor.
As far as players who entered the league this year whether via draft or as a rookie free agent, WR Jeremy Ebert, OL Derek Dennis, TE Tyler Urban, OL Dustin Waldron, OL Jeremiah Warren and OL Darrion Weems.
Outside of players whom were cut, the second biggest news coming out of the Patriots camp was that rookie running back Jeff Demps, most known for competing in the Olympics, has been placed on injured reserved. Demps was removed from the final preseason game against the New York Giants due to a league injury which led to a precautionary MRI.
This move to place Demps on injured reserve may be a way of showing the rookie that he will remain on the team for time to come as the running back position is jam-packed from top to bottom.
Do not be taken by surprise if you see some of these names return, as the Patriots will most likely add a few of these released players to their practice squad.
2015 NFL Draft: Houston Texans 7-Round Mock
The Houston Texans have had a solid season, bouncing back from having the worst record in the NFL. Another good draft could make them a potential playoff team in 2015. Read More
Giants' Coughling Visits Jaguars For 300th Game
New York Giants head coach Tom Coughlin's 300th career game in Jacksonville highlights a remarkable coaching career. Read More
Giants Need To Pressure Jags QB Blake Bortles
The New York Giants will need to get on Blake Bortles early and often to beat the Jacksonville Jaguars in Week 13. Read More
Elvis Dumervil Having Great Season For Ravens
Baltimore Ravens linebacker Elvis Dumervil is having a fantastic season thus far and has a shot to make franchise history in Week 13. Read More
Andre Branch Could Give Jaguars A Boost
Getting defensive end Andre Branch back this week should be big for the Jacksonville Jaguars. Read More
Cowboys Must Hope For Wild Card Berth
After a monumental 33-10 loss to the Philadelphia Eagles, the Dallas Cowboys are more than likely hoping for a wild card berth to make the playoffs. Read More
Lance Briggs' Career May Be Coming To End
The Lance Briggs' placement on the Chicago Bears' injured reserve list could mean the end of a great career. Read More
Lance Briggs Career as a Bear Likely Over
Lance Briggs, the All-Pro linebacker of the Chicago Bears, has likely played his last game in Chicago, ending this season on injured reserve. Read More
Grimes' INT a Close Second To ODB's Catch
Brent Grimes isn't wrong to think his amazing INT was better than Odell Beckham's one-handed TD grab. Read More
Weston Richburg Returns to Giants' O-Line
Rookie Weston Richburg gets a second chance to prove he has what it takes to make it on the New York Giants offensive line. Read More
Ray Rice Signing Will Be Media Driven
With Ray Rice allowed to re-enter the league, will the media or a desperate team power his signing? Read More
Jaguars Will Have Tough Time Defending RB Jennings
The Jacksonville Jaguars will have a tough time stopping New York Giants running back Rashad Jennings. Read More


text:
- Webster
- Downtown
- Edwardsville
- Shoppe
- Catering & Parties
- About Robust
- News
Just enter your recipient's email address and an optional gift message, and your holiday shopping is all done! Good for all Robust locations.
Robust Wine Bar Royalty Rewards Club Webster: Sign up & receive $10 off w/purchase of $50 or more!
New Jane Jenni Mugs in our Shoppe now! #theRobustLife #mugs #WG instagram.com/p/vpa7mBrv8E/
This is our kind of sippy cup. #shoppe #therobustwinelife #gifts instagram.com/p/vpZ9UuLv2l/
Hipsters, take note. #TheRobustLife ... See MoreSee Less
The Most Hipster Way To Open A Bottle Of Wine
Jonathan Ross, a sommelier at Eleven Madison Park, is responsible for resurrecting the old world tradition of using heated tongs to open wine. Placing the red hot metal around the neck, it mak
1 day ago ·View on Facebook


text:
Rugby Union
Select a team
Six Nations
- England
- France
- Ireland
- Italy
- Scotland
- Wales
Aviva Premiership
- Bath
- Exeter
- Gloucester
- Harlequins
- Leicester
- London Irish
- London Welsh
- Newcastle
- Northampton
- Sale
- Saracens
- Wasps
The Rugby Championship
- Australia
- New Zealand
- South Africa
Guinness PRO12
- Cardiff Blues
- Connacht
- Dragons
- Edinburgh
- Glasgow
- Leinster
- Munster
- Ospreys
- Scarlets
- Treviso
- Ulster
- Zebre
Top 14
- Bayonne
- Bordeaux-Begles
- Brive
- Castres
- Clermont Auvergne
- Lyon
- Montpellier
- Racing Metro
- Stade Francais
- Toulon
- Toulouse
- Grenoble
- La Rochelle
- Oyonnax
Mathieu Bastareaud
France select Frederic Michalak at fly-half for second Test against New Zealand
Thursday 13th June 09:39
France have named Frederic Michalak at fly-half for Saturday's second Test against New Zealand in Christchurch.
France centre Mathieu Bastareaud seeking redemption against New Zealand
Wednesday 5th June 10:00
Mathieu Bastareaud is intent on proving his worth to France in Saturday's opening Test against New Zealand.
Mathieu Bastareaud one step closer to France return in Six Nations
Monday 28th January 19:59
Mathieu Bastareaud has made the second cut for a place in the France squad for the Six Nations after coach Philippe Saint-Andre further trimmed his initial selection.
Bastareaud signs Stade deal
Wednesday 24th March 14:44
France star Mathieu Bastareaud has signed a three-year contract with Top 14 outfit Stade Francais.
Phil Edwards explains why England's World Cup dreams will not be over if they lose their next two games
If England are to have any chance of launching a successful assault on the Everest that is next year's World Cup, then the widespread feeling seems to be that they simply have to win their next two games.
Pro12 Highlights
Highlights of all the Pro12 action, including Ulster's win over the Ospreys and Treviso's draw with Leinster.
Back Ireland to continue their winning ways
It has been fairly even between Ireland and Australia in the last six meetings, three wins to Australia, two Irish victories and a draw, but recent form comes down in Ireland's favour, with eight wins from nine contrasting to Australia's three victories in nine.
Experts & Blogs
Phil Edwards
Read the thoughts and opinions of Phil Edwards with skysports.com