A New Approach to Treating Rheumatoid Arthritis

A new protein engineered to inhibit molecules that cause inflammation not only reduces symptoms of rheumatoid arthritis in mice but also may have potential to reverse the disease's course. Researchers hope the findings will point toward a new therapy for this crippling and difficult-to-treat disease, which occurs when the immune system attacks the body's own joints. Even medications that are most successful in halting joint inflammation are effective in only about half of the patients who try them.

Current drugs for rheumatoid arthritis inhibit tumor necrosis factor (TNF), an inflammatory molecule known to play a role in regulating the immune system and one that has been implicated in numerous diseases, from cancer to multiple sclerosis. However, these anti-TNF medications can also increase the risk of cancer, exacerbate other autoimmune conditions, and cost a patient as much as $20,000 per year. The new synthetic protein, described last week online in the journal Science, appears to target TNF in a far more specific fashion and could be produced at a small fraction of the cost.

A group of more than 20 scientists, led by NYU Langone Medical Center rheumatology researcher Chuanju Liu, found that a protein called progranulin binds to TNF receptors and that administering the protein to mice with rheumatoid arthritis reduced or even eliminated their symptoms. Then they determined which fragments of progranulin were responsible for binding to TNF and combined those fragments to engineer a protein that works even better to suppress disease. Mice with mild arthritis appeared to be disease-free after several weeks of regular injections of the modified progranulin, which the researchers dubbed Atsttrin.

"For early, mild arthritis, our molecule can completely prevent inflammation?it somehow reverses disease progression," Liu says. In mice with a more acute form of the disease, Atsttrin cut symptom severity in half. And, he says, because the protein can be grown in bacteria, rather than mammalian cells, it could be far less costly than current TNF inhibitors.

"The results are really spectacular," says Paul Anderson, a rheumatology expert at Harvard Medical School and Brigham and Women's Hospital in Boston, who was not involved in the study. "It looks like [they've found] a new pathway for the treatment of inflammatory arthritis." While results should be approached cautiously, since animal research doesn't necessarily translate to humans, the new treatment worked better in animals than the best drugs available to patients today, he says. "It provides a really strong foundation for moving on to the next step."

Liu has cofounded a company to do just that, and he is now a scientific advisor for the startup, called Atreaon, which has licensed his technology from NYU.

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A New Approach to Treating Rheumatoid Arthritis

A new protein engineered to inhibit molecules that cause inflammation not only reduces symptoms of rheumatoid arthritis in mice but also may have potential to reverse the disease's course. Researchers hope the findings will point toward a new therapy for this crippling and difficult-to-treat disease, which occurs when the immune system attacks the body's own joints. Even medications that are most successful in halting joint inflammation are effective in only about half of the patients who try them.

Current drugs for rheumatoid arthritis inhibit tumor necrosis factor (TNF), an inflammatory molecule known to play a role in regulating the immune system and one that has been implicated in numerous diseases, from cancer to multiple sclerosis. However, these anti-TNF medications can also increase the risk of cancer, exacerbate other autoimmune conditions, and cost a patient as much as $20,000 per year. The new synthetic protein, described last week online in the journal Science, appears to target TNF in a far more specific fashion and could be produced at a small fraction of the cost.

A group of more than 20 scientists, led by NYU Langone Medical Center rheumatology researcher Chuanju Liu, found that a protein called progranulin binds to TNF receptors and that administering the protein to mice with rheumatoid arthritis reduced or even eliminated their symptoms. Then they determined which fragments of progranulin were responsible for binding to TNF and combined those fragments to engineer a protein that works even better to suppress disease. Mice with mild arthritis appeared to be disease-free after several weeks of regular injections of the modified progranulin, which the researchers dubbed Atsttrin.

"For early, mild arthritis, our molecule can completely prevent inflammation?it somehow reverses disease progression," Liu says. In mice with a more acute form of the disease, Atsttrin cut symptom severity in half. And, he says, because the protein can be grown in bacteria, rather than mammalian cells, it could be far less costly than current TNF inhibitors.

"The results are really spectacular," says Paul Anderson, a rheumatology expert at Harvard Medical School and Brigham and Women's Hospital in Boston, who was not involved in the study. "It looks like [they've found] a new pathway for the treatment of inflammatory arthritis." While results should be approached cautiously, since animal research doesn't necessarily translate to humans, the new treatment worked better in animals than the best drugs available to patients today, he says. "It provides a really strong foundation for moving on to the next step."

Liu has cofounded a company to do just that, and he is now a scientific advisor for the startup, called Atreaon, which has licensed his technology from NYU.

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Alan Turing collection saved

Back in issue 89 of Custom PC, you may remember that our own ex-news hound Gareth Halfacree wrote about his efforts to raise funds in order to purchase a rare collection of Alan Turing's papers. Through the power of Twitter and a generous donation from Google of $100,000, Gareth raised just under £90,000 for the Bletchley Park Trust so that it might purchase the documents for public display.

The collection, originally property of Professor Max Newman, a friend and colleague of Turing's at Bletchley Park, includes offprints of 15 of Turing's 18 published works, along with Newman's annotations. The collections is so significant because very little remains of Turing's work or personal belongings, with much of Bletchley Park's documents and records destroyed after World War II.

However, with a guide price of between £300,000 and £500,000, the collection looked set to end up in the hands of a private collector. Happily, though, this price was not met when the collection went up for auction last November, and the collection sat un-purchased, awaiting later sale.

Then, a couple of weeks ago, the National Heritage Memorial Fund, which aims to save the most outstanding parts of our national heritage at risk of loss to the nation, stepped in with additional funding of £213,437. Once this was added to Bletchley Park's own funds, the group was able to meet the list price and purchase the collection privately.

Simon Greenish, CEO of the Bletchley Park Trust said 'The acquisition of this hugely important collection has been made possible only by the astonishing support demonstrated by the public, the media, Google, the National Heritage Memorial Fund and Christies the auctioneers whose help in brokering the purchase is gratefully acknowledged. We're delighted to have the collection here at Bletchley Park, which is surely its most fitting home, and it will be an incredible addition to the visitor experience.'

The collection with go on display later this year in the Bletchley Park Museum. All of which just goes to show that it's possible for us to make a difference. We'd very much like to congratulate Gareth on this achievement, and also thank the National Heritage Memorial Fund for getting involved with the extra cash.

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Taking Control of Cars From Afar

Researchers who have spent the last two years studying the security of car computer systems have revealed that they can take control of vehicles wirelessly.

The researchers were able to control everything from the car's brakes to its door locks to its computerized dashboard displays by accessing the onboard computer through GM's OnStar and Ford's Sync, as well as through the Bluetooth connections intended for making hands-free phone calls. They presented their findings this week to the National Academies Committee on Electronic Vehicle Controls and Unintended Acceleration, which was brought together partly in response to last year's scandal over supposed problems with the computerized braking systems in Toyota Priuses.

The team, including Tadayoshi Kohno, an assistant professor of computer science at the University of Washington, and Stefan Savage, a professor of computer science at the University of California, San Diego, had previously shown that they could take control of a car's computer systems, provided that they had physical access to the vehicle's onboard diagnostics port?a federally mandated access point located under the dashboard in almost all modern cars.

With the new work, the researchers systematically analyzed ways they could get at a car's computer systems without having physical access. They used a 2009 mass-production sedan equipped with fewer computer systems than many high-end cars. For each attack that succeeded, they confirmed that they could take complete control of all of the car's internal computer systems.

The researchers attacked the car's Bluetooth system, which allows a driver to make hands-free cell-phone calls. They found a vulnerability in the way the Bluetooth system was implemented that allowed them to execute code to take control of the car. To do this, the researchers used a smart phone already paired with the car or found a way to illicitly authorize a new smart-phone connection.

Nowadays many cars come equipped with cellular connections that perform safety functions, such as automatically calling for help if the driver is in a crash. The researchers found that they could take control of this system by breaking through its authentication system. First, they made about 130 calls to the car to gain access, and then they uploaded code using 14 seconds of audio. The researchers also found other ways to gain access, for example via the car's media player.

"We were surprised to find that the attack surface was so broad," Kohno says, referring to the wide variety of ways the researchers were able to gain access to the car's computer systems.

The team analyzed possible attack scenarios as well. For example, they showed that high-tech car thieves could search for desired models of cars, identify their locations, and unlock them, all without any forced entry. They could conduct malicious surveillance, such as forcing a car to send out its GPS location at regular intervals. They could also sabotage a car, by disabling its brakes, for example.

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Yammer Gets Workers Hooked First, then Woos Bosses

Some vendors of made-for-business social-network software woo companies from the top down. Jive and IBM's Lotus Connections, for example, try to sell management on all-encompassing tools such as blogs, wikis, or Facebook-esque profile pages that work well with software already in place at most corporations.

However, the startup Yammer took a bottom-up approach with its collaboration service: it tries to entice rank-and-file employees first and bosses later.

Yammer lets people make microblog posts in a format similar to Twitter or Facebook updates; the users can also message each other, create online groups of colleagues to collaborate, and upload documents. Any person with a company's e-mail address can join Yammer free. The first person within a company to join can quickly set up a network for the entire company; as coworkers join, Yammer automatically includes them in that company's network. No involvement from the IT or human resources departments is necessary.

This isn't to say management is excluded. Eventually, "executives get involved and they start posting," says David Sacks, Yammer's CEO and founder. But Sacks lets the software-not a sales associate?convince management that social networks can streamline communications and make people more productive. He also argues that this model spares companies from the risk of investing in expensive software that might not get used much by employees.

Stowe Boyd, an analyst and advisor to companies building social technologies, says Yammer's method of getting into a company is "revolutionary, subversive." "Companies turn around and find out that they've got 500 people using Yammer, and they want to take control of it," he says.

For the IT department to gain control, a company has to buy a premium version of Yammer. The premium version also has such features as the ability to link Yammer with employee contact lists and corporate software. Companies generally pay $5 per employee per month for the premium version. (It's hard to compare this cost with that of rival applications; companies such as Jive and IBM generally customize prices depending on the customer.)

Two million employees at more than 100,000 companies have used Yammer; Sacks says between 15 and 20 percent of those workers are using premium versions.

The join-as-you will structure of Yammer worked well for AAA's collection of more than 50 regional, independent driving clubs across the United States. Some clubs use it for daily operations and others only for occasional communications, says Janie Graziani, public relations manager of new media and technology at AAA. And the employees who were already reliant on AAA's intranet system didn't have to change their ways. "Yammer is just a 'use this if it's useful to you and your work' thing," Graziani says. "We haven't told people to use it instead of your e-mail."

Although Yammer might spread easily in many organizations, the ad hoc way it's adopted can also create information silos or confusion within a company if too many people are using different tools, says David Coleman, founder of Collaborative Strategies, an industry analysis and advisory services firm. Coleman says he has advised companies that struggled with streamlining their communication tools.

He also says the software will have to show that it increases a company's profits if it's going to keep selling itself. "Collaboration itself just for the benefit of interacting really doesn't have a huge amount of value," says Coleman. "What it really needs to do is sell the outcomes or the goals that come out of the collaboration."

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Campaigning as All Things to All Republicans

Few audiences are too small for Mr. Pawlenty, who turns up at Tea Party rallies, church forums and beer and pizza parties with College Republicans. He even hit the ice to play hockey here, with a local television crew following closely along.

Mr. Pawlenty, a former governor of Minnesota, is trying to make equal appeals to the diverse constituencies of the Republican Party as he introduces himself as a potential candidate. He stands out among the major contenders in trying to assertively court all factions that will help select a nominee to challenge President Obama.

?I want to be every person?s candidate ? that?s my goal,? Mr. Pawlenty said. ?The notion that you can?t do more than one thing at a time, I think, is a flawed premise.?

At a recent Tea Party Patriots rally, he pronounced, ?The government?s too damn big!? To an evangelical audience, he declared, ?The Constitution was designed to protect people of faith from government, not to protect government from people of faith.? And to Republicans in New Hampshire, he closed with a gentle plea: ?Please leave with hope and optimism.?

It is an uncertain gambit for Mr. Pawlenty, who rose through the ranks of state politics over nearly two decades and now faces the tumult of a Republican presidential primary in which the path to the nomination is far from clear. And seeking to keep a foot in all Republican camps, rather than concentrating on a more targeted slice of voters, could leave the impression that he is trying too hard.

His record as a fiscally conservative governor in a politically divided state is solid, but he still faces stiff competition winning over Tea Party supporters. An evangelical Christian, Mr. Pawlenty has yet to build a loyal following among religious conservatives. He lacks a deep fund-raising network and his name recognition is low, but he was among the finalists Senator John McCain was considering for his running mate in 2008.

Yet in a prospective field whose most prominent members have some heavy baggage as well as higher profiles, one of Mr. Pawlenty?s strongest assets could be the opportunity to sell himself on his own terms ? in policy and personal style.

Unlike Newt Gingrich, he does not have the political scars that come with a long career under intense scrutiny. He does not enjoy the intensity of support directed at Sarah Palin, nor does he generate the passion of her detractors. And Mitt Romney?s efforts to remake himself as more of a social conservative provide an object lesson in handling questions about authenticity.

?I think the people who get tossed around in this process are people who don?t have their compass set, who don?t have their feet firmly planted on the ground,? Mr. Pawlenty said in an interview. ?And then they start to just grab for the wind and they flop around. That?s not me.?

He is taking an old-fashioned approach, hoping to earn respect for showing up nearly everywhere. He seldom leaves a room before talking to all who are waiting. Then he makes time for reporters, unlike some of his rivals, particularly Mr. Romney, a former Massachusetts governor, who exited through a side door at an appearance last week as journalists approached.

Mr. Pawlenty, 50, has been a fixture at Republican events in Iowa and New Hampshire for more than a year. He barely climbs above the margin of error in national polls ? three percentage points or so ? but those surveys do not measure the importance of face-to-face introductions he has been making.

The knock on Mr. Pawlenty, according to conversations with voters, is that his speeches sound sincere but do not always sizzle. At a faith forum last week in Iowa, he displayed vigor. But the next day at the Statehouse, the talk among several Republicans was that it seemed he had suddenly developed a Southern accent as he tried connecting to voters by speaking louder and with more energy.

The political blog of Radio Iowa heard it too and noted, ?Pawlenty seems to be adopting a Southern accent as he talks about his record as governor.? As he spoke of the country?s challenges, he dropped the letter G, saying: ?It ain?t gonna be easy. This is about plowin? ahead and gettin? the job done.?

Mr. Pawlenty is positioning himself as a leading alternative to Mr. Romney, who starts the race with a significant fund-raising advantage in his second bid for the party?s nomination. But that is the most sought-after role in the Republican field, one that Gov. Haley Barbour of Mississippi is also hoping to fill.

Mr. Pawlenty has benefited from Senator John Thune of South Dakota and Representative Mike Pence of Indiana opting to stay out of the race. But his efforts to win Tea Party support may be complicated by a fellow Minnesotan, Representative Michele Bachmann, who spent the weekend in New Hampshire, testing her own presidential bid.

At a Republican gathering here last week, as people waited for handshakes and autographs, Diana Lachance of Derry stood about three feet from Mr. Pawlenty as she told a reporter, ?I love Michele Bachmann!? She said that she appreciated Mr. Pawlenty?s sincerity, but that she needed to learn more about him.

James Kirkpatrick, who met Mr. Pawlenty last summer, became the first Republican county chairman in Iowa to support him. He said Mr. Pawlenty?s appeal included his ability to perform well in the Midwest, including Minnesota, which last voted for a Republican presidential candidate in 1972. ?When other candidates come up,? Mr. Kirkpatrick said, ?I ask them, ?What states can you bring to the table?? ?

Mr. Pawlenty presents himself to audiences as a Republican who trimmed government and stood up to labor unions, prevailing in a 44-day transit strike that led to pension and benefits changes for bus drivers. He tells his up-by-the-bootstraps story about growing up in a working-class neighborhood, his mother dying when he was 16, working in a grocery store and being the first person in his family to go to college.

Mr. Pawlenty has been considering a presidential bid for so long that he is already on his second stump speech. Last year, he opened nearly every appearance with a quip about ?my red-hot, smoking wife, the first lady of Minnesota.? That crowd pleaser has been replaced by a pair of partisan jokes, with the punch line aimed at Mr. Obama.

?I do have to give him credit on at least one thing,? Mr. Pawlenty told a New Hampshire audience. ?He?s accomplished something that is really almost impossible: he has proven that somebody can win a Nobel Prize and deserve it less than Al Gore.?

As the crowd laughed lightly, he added: ?I?m not one of those who question President Obama?s birth certificate, but I do question what planet he?s from.?

Mr. Pawlenty, a year older than Mr. Obama, is one of the youngest prospective Republican candidates. He is sensitive to questions about his experience, which came to light here when a voter asked how he believed the president had handled Libya and other foreign policy challenges.

?For a governor, I?ve got an unusual amount of foreign policy or international security experience,? he said. ?I?ve been to Iraq five times. I?ve been to Afghanistan three times. I?ve been all over the Middle East, including Israel, Turkey, Jordan, Kuwait and other places.?

After the soliloquy about himself, Mr. Pawlenty answered the question.

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Lenovo ThinkPad X220 Ultraportable Review

Over the past year I've had the opportunity to review nearly half a dozen Lenovo notebooks including models from the consumer-level IdeaPad line as well as the business-oriented ThinkPad series.

Living up to its reputation, I've generally been pleased with Lenovo's overall build quality and performance. The recently reviewed IdeaPad U260 was a real work of art and excelled in nearly every category except for one -- it narrowly missed Intel's Sandy Bridge processor refresh which would have offered even better all-around CPU and GPU performance.

Today we'll be looking at our first notebook based on Intel's second generation Core processors, the ThinkPad X220.

The X220 was just introduced this month and represents Lenovo's latest ultraportable ThinkPad. Feature highlights include a 12.5" 1366x768 IPS display, a solidly built thin frame and starting weight of 3 pounds, all without sacrificing on performance courtesy of Intel's new mobile processors. The ThinkPad X series refresh is available in various configurations, from the Core i3-2310M all the way up to the high-end i7-2620M (the series fastest dual-core mobile processor). The ThinkPad X220 also includes a full-size keyboard and an all-new oversized touchpad with integrated mouse-click buttons.

Our review unit came equipped with a dual-core Core i5-2520M clocked at 2.5GHz (four thread capable with Hyper-Threading). This processor packs Intel's new HD 3000 graphics core and has max TDP of only 35W. Other specs include 4GB of PC3-10700 DDR3, a Hitachi 320GB 7200RPM hard drive, Intel Centrino Advanced-N 6205 wireless, Bluetooth, a 6-cell Li-ion battery and as mentioned before a 12.5" IPS display.

The prospect of using a SSD for this type of system makes a lot of sense, however Lenovo has kept a standard hard drive likely to keep base price of the system accessible. According to the system's spec sheet they will let you fit a SSD out of the box, including Intel's popular solid state offerings.

Standard with the ThinkPad X220 is a 6-cell battery that connects at the back of the unit. In addition Lenovo sent us a slim 6-cell external battery that mounts onto the bottom of the notebook, they call it a battery slice. Road warriors looking to get a full day's use from their system will certainly be interested to see how well this unit performs.

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Weekend tech reading: EA sneaks SecuROM in Dragon Age II

EA fails to disclose SecuROM in Dragon Age II Those of you who know me, know that I love Dragon Age: Origins and the Dragon Age universe. You also know that I loathe DRM, especially SecuRom. You can imagine how dismayed I was when I read a Reclaim Your Game report today revealing that despite not disclosing the fact anywhere on the game packing or even in the 28-page EULA, disc-based copies of Dragon Age II contain the destructive, intrusive DRM known as SecuRom. Vivid Gamer

Japan scrambles to avert meltdowns as nuclear crisis builds Japanese officials were struggling Sunday with a growing nuclear crisis and the threat of multiple meltdowns, as more than 170,000 people were evacuated from the quake- and tsunami-savaged northeastern coast where police fear more than 10,000 people may have already died. A partial meltdown was already likely under way at one nuclear reactor... The Globe and Mail

Windows 8 taskbar update leaks out in another image It's not every day that a new Windows 8 image surfaces. While the image presented above does not reveal anything new, it is a second look at the upcoming improvements that Windows 8 will provide. Ever since Windows 8 hit milestone 3, more users on various forums have been reporting that they have finally been issued a version of the platform for testing purposes. Neowin

DICE: Our competitors are getting lazy. We're coming for them. Battlefield 3 developer DICE has thrown down the gauntlet in the raging battle for first-person shooter supremacy, warning its rivals: We're coming for you. Speaking in the latest issue of Official PlayStation Magazine - which is arriving with subscribers now - DICE GM, Karl-Magnus Troedsson was more than confident in his stunning FPS, cautioning the competition: "they had better watch out". CVG

Pwn2Own day 2: iPhone, BlackBerry beaten After successful attacks on Safari and Internet Explorer 8 on Wednesday, the second day of Pwn2Own saw the iPhone 4 and then the BlackBerry Torch 9800 successfully exploited. The annual security competition allows researchers to win any systems that they successfully compromise, and also awards them cash rewards if those security flaws are still present in the latest version of the software. Ars Technica

TSA to retest airport body scanners for radiation The Transportation Security Administration announced Friday that it would retest every full-body X-ray scanner that emits ionizing radiation 247 machines at 38 airports after maintenance records on some of the devices showed radiation levels 10 times higher than expected. USA Today

iPad 2 Wi-Fi teardown The iPad has come back to iFixit! And this time, it has a 2 at the end of its name, hence the iPad 2! After a much awaited debut, the iPad 2 is expected to fill in the gaps left by the first generation iPad. iFixit

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A New Approach to Treating Rheumatoid Arthritis

A new protein engineered to inhibit molecules that cause inflammation not only reduces symptoms of rheumatoid arthritis in mice but also may have potential to reverse the disease's course. Researchers hope the findings will point toward a new therapy for this crippling and difficult-to-treat disease, which occurs when the immune system attacks the body's own joints. Even medications that are most successful in halting joint inflammation are effective in only about half of the patients who try them.

Current drugs for rheumatoid arthritis inhibit tumor necrosis factor (TNF), an inflammatory molecule known to play a role in regulating the immune system and one that has been implicated in numerous diseases, from cancer to multiple sclerosis. However, these anti-TNF medications can also increase the risk of cancer, exacerbate other autoimmune conditions, and cost a patient as much as $20,000 per year. The new synthetic protein, described last week online in the journal Science, appears to target TNF in a far more specific fashion and could be produced at a small fraction of the cost.

A group of more than 20 scientists, led by New York University rheumatology researcher Chuanju Liu, found that a protein called progranulin binds to TNF receptors and that administering the protein to mice with rheumatoid arthritis reduced or even eliminated their symptoms. Then they determined which fragments of progranulin were responsible for binding to TNF and combined those fragments to engineer a protein that works even better to suppress disease. Mice with mild arthritis appeared to be disease-free after several weeks of regular injections of the modified progranulin, which the researchers dubbed Atsttrin.

"For early, mild arthritis, our molecule can completely prevent inflammation?it somehow reverses disease progression," Liu says. In mice with a more acute form of the disease, Atsttrin cut symptom severity in half. And, he says, because the protein can be grown in bacteria, rather than mammalian cells, it could be far less costly than current TNF inhibitors.

"The results are really spectacular," says Paul Anderson, a rheumatology expert at Harvard Medical School and Brigham and Women's Hospital in Boston, who was not involved in the study. "It looks like [they've found] a new pathway for the treatment of inflammatory arthritis." While results should be approached cautiously, since animal research doesn't necessarily translate to humans, the new treatment worked better in animals than the best drugs available to patients today, he says. "It provides a really strong foundation for moving on to the next step."

Liu has cofounded a company to do just that, and he is now a scientific advisor for the startup, called Atreaon, which has licensed his technology from NYU.

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Official Exits State Dept. After Jabs at Pentagon

Mr. Crowley?s comments, which were made to a small group at the Massachusetts Institute of Technology, stirred a political tempest in Washington and were rejected by President Obama at a news conference on Friday. Mr. Obama said the Pentagon had assured him that its procedures in Private Manning?s confinement were ?appropriate and are meeting our basic standards.?

White House officials were infuriated by the episode, administration officials said, which one described as ?the last straw? in a series of incautious remarks by Mr. Crowley. A retired Air Force officer, Mr. Crowley, 59, had a rocky tenure at the State Department, failing to establish close ties to Secretary of State Hillary Rodham Clinton.

In a one-paragraph statement, Mrs. Clinton said she accepted Mr. Crowley?s resignation with regret and praised him for his ?deep devotion to public policy and public diplomacy.?

Mr. Crowley, in his statement, did not retract his critical comments about the Pentagon, which he said ?were intended to highlight the broader, even strategic impact of discrete actions undertaken by national security agencies every day and their impact on our global standing and leadership.?

His remarks were first reported in a blog by a BBC correspondent, Philippa Thomas, who said Mr. Crowley had added that Private Manning deserved to be in jail. Mr. Crowley declined to comment further.

Private Manning?s lawyer has complained about his treatment, including sometimes being deprived of his clothing, as a maximum security prisoner under restrictions intended to prevent self-injury, even though his supporters said there was no evidence that he was suicidal.

Mr. Crowley had been in a tenuous position for some time, several officials said, and was discussing another assignment with Mrs. Clinton and her chief of staff, Cheryl D. Mills, even before his Manning remarks. He did not travel on Mrs. Clinton?s plane, which is highly unusual for a spokesman and added to the perception that he did not have access to her inner circle.

Public statements from Mr. Crowley, a seasoned public affairs officer, raised hackles in the Pentagon and the White House several times. On Friday, in the wake of the earthquake in Japan, he sent out a message on ?Twitter that said: ?We?ve been watching a hopeful tsunami sweep across the Middle East. Now we?re seeing a tsunami of a different kind sweep across Japan.?

Other officials said the message was insensitive, and Mr. Crowley pulled it from Twitter.

He also came under fire in a State Department audit while managing the public affairs bureau.

For the last few months, Mr. Crowley had devoted much of his time to dealing with the fallout from the release of State Department cables by WikiLeaks. Officials credited him with handling that difficult task well, and he has developed strong opinions about the role of the government and the news media through this episode, some of which he voiced in his M.I.T. talk.

Last month, Michael Hammer, a former spokesman for the National Security Council, became Mr. Crowley?s deputy ? a move that was widely perceived as setting the stage for Mr. Crowley?s departure. Mrs. Clinton said that Mr. Hammer, a career diplomat, would serve as the chief spokesman on an acting basis, and officials said he was likely to become Mr. Crowley?s permanent replacement.

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