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Source: http://traffic-secrets.org/build-a-demarco-murray-jersey-policy-for-your-web-advertising-and-marketing

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HBT: Twins set to sign Mike Pelfrey for $4 million

CBSSports.com?s Jon Heyman is reporting that the Twins and Mike Pelfrey have come to terms on a one-year deal worth $4 million.

The deal includes $1.5 million in incentives for the rehabbing right-hander.

The soon-to-be 29-year-old Pelfrey had a 2.29 ERA in three starts for the Mets last season before undergoing Tommy John surgery. He went 15-9 with a 3.66 ERA in 2010, but he slipped to 7-13 with a 4.74 ERA in 2011. The Mets non-tendered him earlier this month rather than pay him $5 million-$6 million in arbitration.

Once healthy, Pelfrey will join fellow National League imports Vance Worley and Kevin Correia in a rotation that has just one sure returnee in Scott Diamond. The Twins could also add one more veteran to compete with holdovers Nick Blackburn, Liam Hendriks and Cole De Vries for an opening.

The gamble on Pelfrey is interesting, considering that the Twins let the similarly positioned Scott Baker go to the Cubs in free agency earlier this winter. Baker, likewise rehabbing from Tommy John surgery, signed for $5.5 million, plus incentives. And unlike Pelfrey, Baker has already proven he can cut it in the AL. The Twins got burnt last year by Jason Marquis, who had no AL experience and was roasted to the turn of an 8.47 ERA in seven starts before earning his release.

Source: http://hardballtalk.nbcsports.com/2012/12/16/twins-set-to-sign-mike-pelfrey-for-4-million/related

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Republicans Say There's No Budget, And Use That To Stall Senate

WASHINGTON -- After complaining much of the year that Senate Democrats have not passed a federal budget, Republicans are now using the budget they say doesn't exist to block legislation.

Democrats, indeed, have prevented a budget resolution from coming to the floor for a vote for more than three years, and Republicans have reminded them relentlessly of the failure, saying the Senate has abdicated its responsibility to lead.

Budget Committee Chairman Kent Conrad (D-N.D.) has maintained that the Budget Control Act passed last year to resolve the debt ceiling standoff is better than a normal budget resolution. It's actually budget law, he said -- the portion of the "fiscal cliff" that comes from spending cuts.

Nevertheless, Republican senators have incessantly decried the lack of a normal spending blueprint. Much of their caucus did so in an especially vivid demonstration on the Senate floor in September, before Congress took a break for the election.

Lately, however, the Republican senators have been citing the Budget Control Act as if it is a budget to block legislation, raising budget "points of order" on measures that spend more than authorized in the Budget Control Act. By Senate rules, such a point of order requires 60 votes to waive, much the same as overcoming a filibuster.

Perhaps the most vigorous adherent of the point-of-order strategy is Sen. Jeff Sessions (R-Ala.), the top Republican on the Budget Committee.

He raised a number of objections Thursday, stymying attempts to pass legislation to extend extra federal backing of large bank transactions.

?We will adhere to the budget agreement that we made with the American people 16 months ago,? Sessions said after his point of order succeeded, referring to the Budget Control Act.

?That budget point of order said that the legislation before us violates the budget, it spends too much and that we object,? Sessions said.

Sessions was among many in his party to declare there was no budget on Sept. 20, when most of the GOP caucus went to the Senate floor in protest.

"Today marks the 1,240th day since the Democratic leadership in the Senate adopted a budget. For three years, in a time of financial crisis, the Senate's Democratic majority has failed to comply with the United States code," Sessions said.

Sessions' spokesman, Stephen Miller, said the senator was referring not to an actual budget, but either to the 1974 Congressional Budget Act that allows points of order, or to the Budget Control Act simply as a set of spending limits, not a real budget.

"It is a fact beyond dispute that the Senate Democratic majority has no budget plan, has never offered a budget plan, has no intention of offering a budget plan and to say otherwise is to deny reality in the most obvious and desperate way," Miller said.

The lack of a normal budget resolution has not stopped the government from spending money because a resolution is basically a blueprint. The actual spending is specified in authorization bills and the funding is doled out via appropriations measures. Lacking a formally approved budget does make it more difficult for congressional spending, and it has been seen as politically advantageous for Democrats to mute that discussion.

A Democratic aide, speaking anonymously to avoid sparking a new public fight, saw the point of order trend as pure hypocrisy.

?This is absolutely shameless hypocrisy from Senator Sessions and other Senate Republicans who want to have their cake and eat it too when it comes to the Budget Control Act," the aide said. "They love crowing about the Senate not passing a budget when they want to rile up their Tea Party base, but then they come to the floor with a straight face and talk about our bills violating the Senate budget they claim doesn?t exist.?

Michael McAuliff covers Congress and politics for The Huffington Post. Talk to him on Facebook.

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Source: http://www.huffingtonpost.com/2012/12/15/republicans-budget-stall-senate_n_2303345.html

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John Kerry Is Obama's Good Soldier On Foreign Policy

WASHINGTON -- Democratic Sen. John Kerry stands tall as President Barack Obama's good soldier.

The Massachusetts lawmaker has flown to Afghanistan and Pakistan numerous times to tamp down diplomatic disputes, spending hours drinking tea and taking walks with Afghan President Hamid Karzai or engaging in delicate negotiations in Islamabad.

It's a highly unusual role for a Senate Foreign Relations Committee chairman: envoy with a special but undefined portfolio.

Kerry has pushed the White House's national security agenda in the Senate with mixed results. He successfully ensured ratification of a nuclear arms reduction treaty in 2010 and most recently failed to persuade Republicans to back a U.N. pact on the rights of the disabled.

Throughout this past election year, he skewered Obama's Republican rival, Mitt Romney, at nearly every opportunity and was a vocal booster for the president's re-election. Kerry memorably told delegates at the Democratic National Convention in August: "Ask Osama bin Laden if he's better off now than he was four years ago."

Obama seems likely to reward all that work by nominating the 69-year-old Kerry, perhaps in the coming days, to succeed Secretary of State Hillary Rodham Clinton as the nation's top diplomat. The prospects for the five-term senator soared last week when U.N. Ambassador Susan Rice, a top contender for the post, withdrew from consideration to avoid a fierce fight with Senate Republicans.

A Kerry nomination has been discussed with congressional leaders, and consultations between the White House and congressional Democrats have centered on the fate of his Senate seat, according to officials familiar with the situation who were not authorized to publicly discuss the talks. If the seat were in play, it could boost the prospects for recently defeated Republican Sen. Scott Brown to win back a job in Washington.

At the same time, Obama is considering one of Kerry's former Senate colleagues, Republican Chuck Hagel of Nebraska, for the Pentagon's top job.

The selection of Kerry would close a political circle with Obama. In 2004, it was White House hopeful Kerry who asked a largely unknown Illinois state senator to deliver the keynote address at the Democratic convention in Boston, handing the national stage to Obama. Kerry lost that election to President George W. Bush. Four years later, Obama was the White House hopeful who succeeded where Kerry had failed.

Senate colleagues in both parties say Kerry's confirmation would be swift and near certain, another remarkable turnaround. Eight years ago, the GOP ridiculed Kerry as a wind-surfing, flip-flopper as he tried and failed to unseat Bush.

"If he is nominated, he comes into the position with a world of knowledge. He's someone who certainly understands how the legislative process works and I think he will be someone that Congress will want to work with in a very positive way," said Sen. Bob Corker of Tennessee, who is poised to become the top Republican on the Foreign Relations Committee next year.

Sen. Kelly Ayotte, R-N.H., a member of the Senate Armed Services Committee, said "there's no question he has a very strong depth of knowledge of these issues. Certainly qualified."

Sen. John McCain, R-Ariz., has taken to jokingly referring to Kerry as "Mr. Secretary."

Kerry and McCain, defeated presidential candidates who returned to the Senate, have joined forces repeatedly during the past few decades. In July 1995, the two decorated Vietnam War veterans provided political cover to President Bill Clinton when he normalized U.S. relations with Vietnam. Clinton had been dogged by questions about his lack of military service.

Last year, Kerry and McCain were outspoken in pushing for a no-fly zone over Libya as Moammar Gadhafi's forces attacked rebels and citizens. This month, they stood together in arguing for the disabilities treaty against staunch Republican opposition and complaints that it could undermine U.S. national sovereignty.

The pact fell five votes short of ratification, and Kerry called it "one of the saddest days I've seen" in his years in the Senate.

"Today I understand better than ever before why Americans have such disdain for Congress and just how much must happen to fix the Senate so we can act on the real interests of our country," he said, his frustration evident.

Kerry has traveled extensively for the administration, to Afghanistan in May as a strategic partnership agreement loomed large in the decade-plus war. He was in Pakistan last year in the midst of a diplomatic crisis after Raymond Davis, a CIA-contracted American spy, was accused of the killing two Pakistanis.

Sen. Chris Coons, D-Del., a member of the Foreign Relations Committee, traveled to Pakistan around that time and recalled Kerry's influence.

"I arrived in Islamabad I think five days after Ray Davis had been taken into a jail in the Punjab and was at very real risk of being hauled out of the jail and lynched," Coons said. "Sen. Kerry was about to show up and negotiate on behalf of the administration. And it was clear that both the diplomats and the military folks we met with viewed him as a real man of credibility and experience who was likely to contribute meaningfully to those negotiations."

Davis pleaded self-defense. After weeks of wrangling between the U.S. and Pakistan, he was released in exchange for "blood money" paid to the dead men's relatives.

This year, Kerry has presided over committee hearings on treaties and other major issues, but there has been little legislative work. He didn't draw much attention to the committee, avoiding possible embarrassments for the administration in an election year.

Corker said he would have liked for the committee to devote more time to events in Libya, Syria and other countries.

"I think he's tried to accommodate our concerns and at the same time seek a balance ... giving the administration the headroom they needed to do what he and the administration felt was best. I understand that," he said, speaking of Kerry.

Coons said Kerry's deliberate work is often behind the scenes.

"The role of the chairman ... is not always getting your picture taken with George Clooney, standing around with heads of state, going to receptions in Foggy Bottom," he said. "It's also lots and lots of time listening to folks who've got concerns whether it's on behalf of the defense community, the business community, the diplomatic community and being the person who's at the intersection of all that and trying to keep the Senate productively engaged in a very dangerous world with a lot of emerging threats."

___

Associated Press writer Steve Peoples in Boston contributed to this report.

___

Related on HuffPost:

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Source: http://www.huffingtonpost.com/2012/12/16/john-kerry-obama_n_2311839.html

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Movie Reviews: The Hobbit, Playing for Keeps, Hyde Park and ...

Editor's Note: All reviews and information aggregated from Moviefone.

The Hobbit: An Unexpected Journey

?"Charming, spectacular, technically audacious? in short, everything you expect from a Peter Jackson movie. A feeling of familiarity does take hold in places, but this is an epically entertaining first course." From?Matthew Leyland of Total Film.?Full Review.??

"As epic, grandiose, and emotionally appealing as the previous pictures, The Hobbit doesn't stray far from the mold, but it's a thrilling ride that's one of the most enjoyable, exciting and engaging tentpoles of the year." From?Rodrigo Perez of The Playlist.?Full Review.??

"I'm holding the filmmaker responsible for getting us all back again - to feelings of excitement and delight. Vital as they are, Gollum and Bilbo can only do so much to keep us enchanted. Is Jackson able to sustain the magic in two more installments? I peer into Tolkien's Misty Mountains and embrace the journey. From?Lisa Schwarzbaum of Entertainment Weekly.?Full Review.

Do you plan on seeing this movie? Have you seen it already? Leave a review of the film with a comment below.?

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Playing the Field

"Jessica Biel all but steals the show as Stacie." From?Roger Ebert of Chicago Sun-Times.?Full Review.

"As a movie, it's not much. But it's the best showcase for his charm that Butler has ever had." From Mick LaSalle of San Francisco Chronicle.?Full Review

"At some point you hope the actor (Butler) will find a movie that will give him the right material to make hearts truly beat faster. Until then, it appears we'll have to settle for films with more flaws than his characters. From Betsy Sharkey of Los Angeles Times.?Full Review.

Do you plan on seeing this movie? Have you seen it already? Leave a review of the film with a comment below.?

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Hyde Park on Hudson

"In beauty, tone, technical achievement and cinematic artistry on every level, Hyde Park on Hudson is a movie unto itself - funny, believable, historic and hugely entertaining." From?Rex Reed of New York Observer.?Full Review.

"This isn't a serious historical film. It plays different instruments than Spielberg's "Lincoln." Murray, who has a wider range than we sometimes realize, finds the human core of this FDR and presents it tenderly." From?Roger Ebert of Chicago Sun-Times.?Full Review.

"This hugely entertaining movie is about the wisdom and - with trenchant wit and sympathy - the human flaws in one of America's most idealized heads of state." From?Ella Taylor of NPR.?Full Review.

Do you plan on seeing this movie? Have you seen it already? Leave a review of the film with a comment below.?

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Killing Them Softly

"The film is terribly smart in every respect, with ne'er-a-false note performances and superb craft work from top to bottom." From?Todd McCarthy of The Hollywood Reporter.?Full Review.?

"This is an unrepentantly cynical take on the hope-and-change promised to the US in 2008; this year's election race makes it look even bleaker, an icily confident black comedy of continued disillusion." From?Peter Bradshaw of The Guardian.?Full Review.

"Killing them Softly is a lurid and nasty little nihilistic hitman noir, with an ingenuity that sneaks up on you." From?Owen Gleiberman of Entertainment Weekly.?Full Review.

Do you plan on seeing this movie? Have you seen it already? Leave a review of the film with a comment below.?

?

Source: http://eureka-wildwood.patch.com/articles/movie-reviews-the-hobbit-playing-for-keeps-hyde-park-and-killing-them-softly

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UN court orders release of Argentine ship in Ghana

BERLIN (AP) ? A United Nations court ordered the immediate release Saturday of an Argentine navy training ship and crew detained in Ghana two months ago at the request of an American hedge fund.

The ARA Libertad training ship was seized Oct. 2 in the port of Tema as collateral for unpaid bonds dating from Argentina's economic crisis a decade ago.

Argentina appealed to the Hamburg, Germany-based U.N.'s International Tribunal for the Law of the Sea for the ship's release, arguing that as a warship the Libertad is immune from being seized.

In an expedited ruling that sided with Argentina's argument, the court ordered that Ghana "forthwith and unconditionally release the frigate ARA Libertad" and ensure the ship and its crew can leave Ghanaian waters. It also ordered that the vessel should be resupplied as needed.

Detaining the ship was "a source of conflict that may endanger friendly relations among states," the court said.

The ruling leaves untouched the parties' rights to seek further international arbitration on the matter.

Ghana courts ordered the ship detained on a claim by Cayman Islands-based NML Capital Ltd. Its owner, American billionaire Paul Singer, leads a group demanding payment in full, plus interest, for dollar-based Argentine bonds bought at fire sale prices after Argentina's 2001-2002 economic collapse forced a sharp devaluation of its currency.

The vast majority of bondholders accepted about 30 cents on the dollar years ago, and that is roughly what the holdouts led by Singer initially paid for the bonds.

Source: http://news.yahoo.com/un-court-orders-release-argentine-ship-ghana-145551007--finance.html

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Beck looks for new connection with 'Song Reader'

NASHVILLE, Tenn. (AP) ? Beck Hansen wants you to think about the way music has changed over the last century and what that means about how human beings engage each other these days.

Laboring over the intricate and ornate details of his new "Song Reader" sheet music project, he was struck by how social music used to be ? something we've lost in the age of ear buds.

"You watch an old film and see how people would dance together in the '20s, '30s and '40s. You'd go out and people would switch partners and it was a way of social interaction," Hansen said. "It's something that was part of what brought people together. Playing music in the home is another aspect of that that's been lost. Again, I'm not on a campaign to get people to take up songs and play music in their home or anything. But it is interesting to me, the loss of that, what it means."

Beck hopes the "Song Reader" inspires some of us to pick up instruments and limber our vocal cords. It includes 20 songs annotated on sheet music that's been decorated in the style popular in the early 20th century when the songwriting industry was a thriving enterprise with billions of songs sold.

The 42-year-old singer notes in the book's preface that Bing Crosby's "Sweet Leilani" sold an estimated 54 million copies in 1937, meaning about 40 percent or more of the U.S. population was engaged in learning how to play that song. They were touching it directly, speeding it up, slowing it down, changing the lyrics and creating something new.

"There's popular bands now that people know the words to their songs and can sing along, but there's something about playing a song for yourself or for your friends and family that allows you to inhabit the song and by some sort of osmosis it becomes part of who you are in a way," he said. "So when I think of my great-grandparents' generations, music defined their lives in a different way than it does now."

Beck proposed the idea to McSweeney's Dave Eggers in 2004 and it soon blossomed into something more ambitious as the artist wrapped his mind around the challenge of not just writing a song, but presenting it in a classic way that also engages fans who might not be able to read music or play their own instruments.

They quickly agreed it would make no money, but it seemed like an idea worth exploring.

"And it seemed like only Beck would have thought of it," Eggers said in an email to the Associated Press. "It's a very generous project, in that he wrote a bunch of songs and just gives them to the world to interpret. That's a very expansive kind of generosity and inclusiveness that we're happy to be part of. On a formal level, we love projects like this, that are unprecedented, and that result in a beautiful object full of great art and great writing. And it all started with Beck. It's a testament to his groundbreaking approach to everything he does."

Beck hopes fans will record their own versions and upload them to the Internet so those songs grow into something more universal.

As for his own recorded music, that's a little more complicated.

Beck's not sure where he's headed at the moment. He recorded an album in 2008, but set it aside to work with Charlotte Gainsbourg on "IRM," which he wrote and produced. He's also been writing songs for soundtracks and special projects and producing artists like Thurston Moore, Stephen Malkmus and Dwight Yoakam. All that has left him feeling creatively satisfied, but he does acknowledge it's been a while since he released 2008's Danger Mouse-produced "Modern Guilt."

He says in many ways he's reached a crossroads he's not yet sure how to navigate.

"This last year I've been thinking about whether I'd finish those songs (from 2008), whether they're relevant or worthy of releasing. I know that doesn't sound very definitive," he said, laughing, "but that's the kind of place I'm in ? in this kind of limbo ? and, um, yeah."

The "Song Reader" spurred Beck to think about his own work in a new light as well. Spending six months finishing off the project after working on it sporadically over the years, he was struck by how much craft went into the creation of each song and how quickly music can come into existence today.

"There is so much music out there, to me," he said. "I don't know if it's just where I am in my own music making or if it's a product of the amount of music out there, but I feel like a piece of music does have to have a certain validity to be put out there and to ask people to listen. ... I feel like it's impossible for everyone to keep up, you know, so I guess I've been feeling like maybe there's something to picking what you're going to put out, about being more particular about what you put out."

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Online:

http://beck.com

___

Follow AP Music Writer Chris Talbott: http://twitter.com/Chris_Talbott.

Source: http://news.yahoo.com/beck-looks-connection-song-reader-153006272.html

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Obama's 'red line' may be giving Assad an opening

WASHINGTON (AP) ? President Barack Obama's chemical weapons position on Syria may have given Bashar Assad an unintended opening: The embattled Syrian leader appears willing to use other deadly tactics, including Scud missiles, without fear of U.S. retaliation.

The White House casts Assad's escalation against rebel forces as a sign of his growing desperation as his opposition gets stronger and enjoys more international support, including from the United States. But some human rights groups and Middle East experts say Obama's "red line" has given Assad a green light to launch attacks on his own people through other conventional means.

Obama has said Syria's use or movement of its chemical weapons stockpile would change his "calculus" about a conflict the U.S. has been loath to intervene in militarily.

Max Boot, a senior fellow at the Council on Foreign Relations and former adviser to Republican presidential campaigns, said Obama publicly staking out a red line like that "has the unintended consequence of seeming to ratify anything short of the use of chemical weapons."

More than 40,000 people have died during Assad's two-year crackdown on rebels, according to activists. Opposition fighters have seized large swaths of territory in northern Syria along the border with Turkey and appear to be expanding their control outside Damascus, pushing the fight closer to Assad's seat of power in the capital.

As Assad has come under greater pressure, he has steadily escalated his methods for fighting insurgents. U.S. officials said the Syrian regime launched more than a half-dozen Scud missiles in recent days. It's the first time the Assad government has used such weapons.

Further testing Obama's red line, recent U.S. intelligence reports showed the Syrian regime may be readying its chemical weapons and could be desperate enough to use them. Those reports drew a sharp warning from Obama, but administration officials said the intelligence fell short of the president's threshold for more direct U.S. intervention in the conflict.

Despite Assad's escalating attacks, officials also say the president is not considering reevaluating his red line on Syria. He first articulated it in August, and officials say the U.S. defines movement as Assad handing over the weapons to a terrorist group like Hezbollah.

Obama has never publicly stated how the U.S. would respond if Assad does cross the red line and deploy or prepare to deploy its chemical weapons. Current and former U.S. officials who have been briefed on the matter say options being considered include aerial strikes or limited raids by regional forces to secure the stockpiles. They say the administration remains reluctant to dispatch U.S. forces to Syria, but a U.S. special operations training team is in neighboring Jordan, teaching troops there how to safely secure chemical weapons sites, together with other troops from the region.

"Our policy remains what it was," White House press secretary Jay Carney said Thursday. "We believe that providing continued support to the Syrian people and non-lethal support to the opposition is the right approach."

Obama long has called for Assad to leave power, and the U.S. this week formally recognized the rebel-led Syrian Opposition Council as the country's sole legitimate representative. But the U.S., weary after years of war in Afghanistan and Iraq, wants to avoid sending American troops into Syria to stem the violence and risk getting drawn into another protracted Middle East conflict.

Officials say Obama settled on the use or proliferation of chemical weapons as his red line because there would be international consensus that such a step would be unacceptable. But those assertions have only increased frustrations among many in the region who question why Assad's other actions have not generated similar promises of international action.

"We hear a lot from people on the ground who say, 'So we won't be killed by chemical weapons, but killing us with a machine gun is OK?" said Nadim Houry, a Beirut-based official with the international organization Human Rights Watch.

Secretary of State Hillary Rodham Clinton said last week "there is no doubt that there's a line between even the horrors that they've already inflicted on the Syrian people and moving to what would be an internationally condemned step of utilizing their chemical weapons."

The Assad government insists it would not use such weapons against Syrians, though it carefully does not admit to having them. The regime is party to the 1925 Geneva Protocol banning chemical weapons in war.

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Follow Julie Pace at http://twitter.com/jpaceDC

Source: http://news.yahoo.com/obamas-red-line-may-giving-assad-opening-225450253.html

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The Invention of an Illness

Foie gras.

Foie gras?essentially fatty liver?is delicious. Is it a disease?

Photo by Lilyana Vynogradova/iStockPhoto.

Diseases come and diseases go?which, when you think about it, they really shouldn't. Outside of diseases that have been eradicated, this inconstancy suggests a certain fallibility and fashion running through medicine, a discipline we'd prefer to be a reliable science. Take chlorosis. For hundreds of years doctors understood it perfectly. It afflicted young women, coloring their complexion with an unmistakeable trace of green. Unrequited love was the cause?or, to put it in the physical terms used more often, the lingering and harmful persistence of female virginity. In 1936, chlorosis was officially demolished as a condition. Unsatisfied physical longing as a cause of green-tinged skin disappeared from the medical world.

It's no surprise to find our ancestors getting things wrong?they were, after all, an ignorant and prejudiced lot. But could it be that our world has not yet reached a stage of mental and cultural perfection? Might we be making similar mistakes, inventing diseases that don't really exist? And if we are, does it matter?

Consider these questions in relation to something which, before 1980, wasn't described as a disease. You might call it the human version of foie gras. Or, if you felt diseases benefited from being described in Greek (a lingering medical conviction, and one I confess to sharing), you'd name it hepatic steatosis or even steatohepatitis. If you favored plain language, you'd call it fatty liver disease. Whatever name you chose, you'd be referring to a condition which has gone from unknown to pandemic within a few decades, all without any change in human hepatic physiology. Fatty liver disease affects up to a quarter of us. Its harms?a significantly increased risk of death among them?are taken seriously by hepatologists and other doctors. But it may not be a real disease at all.

Contemplate for a moment one of the ethical quirks of the debate about foie gras. Even if you accept that force-feeding geese is cruel, you can still produce foie gras as ethically sound as any meat product. One of the functions of the liver is the storage of energy, and birds that go on long migrations lay down fat in preparation. Slaughter a goose just before it's expecting to take off across the globe, and you can extract a foie with the gras a gourmand desires. Fatty livers in geese, then, aren't necessarily a disease?they can be a healthy consequence of the animal storing energy it's expecting to need.

Something similar happens in humans, with the key problem being that our tendency to lay down calories is out of proportion with our likelihood of using them up. We're good at storing up fat?padding out our bellies, our bottoms, our livers, and the rest of our generally overfed and under-exercised bodies. We're evolutionarily adapted for boom and bust, for periods of plenty and periods of want. Faced with a constant supply of food, we eat it. We put on weight and then we put on more. That's a real challenge, but just possibly I'm not the first to break this news. We know that obesity is unhealthy and that it's on the rise. It's something we're bad at dealing with, both emotionally and practically. We even agonize over it morally. Doctors and society tend to blame the overweight for their condition with a disapproval that we don't apply, say, to mountaineers who fall and break bones. As medics, we're also lousy at actually helping. A lot of research money goes into weight-loss drugs, which at best are minimally effective and tend to have nasty side effects. Relatively little goes into figuring out how to engineer societies to eat less and exercise more?and even when it does, we worry how much of that sort of societal engineering we should be doing. The appropriate boundary between invading individual freedom and promoting public health can be pretty unclear.

Those with fatty liver disease won't know for certain they have the disease without a scan, be it ultrasound or some other modality. Usually fatty liver disease causes no symptoms. Yet those who have it are more likely to suffer heart attacks and strokes, more likely to develop liver cirrhosis, more likely to have high blood pressure and diabetes. Their health is improved from lowering their blood pressure and cholesterol levels, from dieting and exercising, and even (if they're particularly obese) from having a gastric bypass or similar surgery to help them lose weight. So why isn't it necessarily a real disease?

The problem comes into focus when you realise these same hazards and recommendations can be invoked for any other manifestation of being overweight. Take fatty elbow disease. As far as I'm aware, I'm the first to describe it, but I think it could take off. It's associated with being overweight and underactive and it carries with it the same range of real risks. Sufferers are often asymptomatic, unaware of their illness, although I admit that it can be picked up without much use of an MRI scanner. Shortly I'll be writing to the New England Journal of Medicine to expose the problem. I'll demand action to raise the profile of fatty elbow disease, with programs to screen elbows nationwide and make patients aware of their affliction. I'll accept lucrative posts advising drug companies and seek out a celebrity patient or two. I'll attend so many lavish conference dinners I may develop the disease myself.

Yet there's a problem. When you say that patients are unaware of their condition, you're suggesting, in a vital way, that maybe they're not actually patients. The word comes from pathos, meaning one who suffers. These people are not literally dis-eased, at least not until I disturb their ease by pointing out they suffer from FED. (I feel a flush of parental pride contemplating how technical and impressive it sounds as an acronym.) Do I do people a favor by revealing to them their unsuspected diagnosis? I'm not sure I do. Most people are aware that it's not ideal to be overweight, to have high blood pressure and high cholesterol, to undertake too little physical exercise. Fatty elbow disease gives me another tool to beat them up with, to add to their sense of guilt. Who knows, they may turn out to have fatty liver disease also, and fatty hip disease, too?they could be suffering under the delusion of reasonable health, when all along they're a walking bag of medical problems. I worry, though, that I'm just dishing out disease labels for my own benefit, not for the good of the people I'm meant to be caring for. For the foreseeable future, the mortality rate for life is expected to remain at around 100 percent. Staying alive as long as possible is great, and worrying about illness is reasonable, but all life is limited and it's important to enjoy what we've got. Health, like beauty, is terrifically subjective. Tell someone who's feeling fine that they've got fatty liver disease, and you're subtracting from their sense of well-being. Maybe not much, but you're doing so all the same, and I'm not sure it's merited. Remember that shady border between intruding on freedom and promoting health? You may have just crossed it.

Fatty liver disease appears to be a manifestation of what could be called?with justification?Modern Life. We eat too much and we do too little, and one of the things that follows is that we put on weight. As a doctor, I know too little about how to help people deal with that. But banal advice doesn't cut it, nor does piling on the guilt. The existence of chlorosis said something about our ancestors? ambivalence toward female sexuality. Fatty liver disease, I suspect, comes from our mixed feelings over modern lifestyles and who to blame for them. It's not good for us to spend too much time eating and sitting and not enough fasting or running around, but is it really a disease? I think we're unsure and bad at facing up to our uncertainty. Moral ambivalence, more than calories, might be driving our contemporary pandemic of fatty liver disease.

Source: http://feeds.slate.com/click.phdo?i=b8d151f0926d159c7c93ab7c5dd11c9e

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Reality check for DNA nanotechnology

Friday, December 14, 2012

Two major barriers to the advancement of DNA nanotechnology beyond the research lab have been knocked down. This emerging technology employs DNA as a programmable building material for self-assembled, nanometer-scale structures. Many practical applications have been envisioned, and researchers recently demonstrated a synthetic membrane channel made from DNA. Until now, however, design processes were hobbled by a lack of structural feedback. Assembly was slow and often of poor quality. Now researchers led by Prof. Hendrik Dietz of the Technische Universitaet Muenchen (TUM) have removed these obstacles.

One barrier holding the field back was an unproven assumption. Researchers were able to design a wide variety of discrete objects and specify exactly how DNA strands should zip together and fold into the desired shapes. They could show that the resulting nanostructures closely matched the designs. Still lacking, though, was the validation of the assumed subnanometer-scale precise positional control. This has been confirmed for the first time through analysis of a test object designed specifically for the purpose. A technical breakthrough based on advances in fundamental understanding, this demonstration has provided a crucial reality check for DNA nanotechnology.

In a separate set of experiments, the researchers discovered that the time it takes to make a batch of complex DNA-based objects can be cut from a week to a matter of minutes, and that the yield can be nearly 100%. They showed for the first time that at a constant temperature, hundreds of DNA strands can fold cooperatively to form an object ? correctly, as designed ? within minutes. Surprisingly, they say, the process is similar to protein folding, despite significant chemical and structural differences. "Seeing this combination of rapid folding and high yield," Dietz says, "we have a stronger sense than ever that DNA nanotechnology could lead to a new kind of manufacturing, with a commercial, even industrial future." And there are immediate benefits, he adds: "Now we don't have to wait a week for feedback on an experimental design, and multi-step assembly processes have suddenly become so much more practical."

Atomically precise control

To test the assumption that discrete DNA objects could be assembled as designed with subnanometer precision, TUM biophysicists collaborated with scientists at the MRC Laboratory of Molecular Biology in Cambridge, UK. They produced a relatively large, three-dimensional DNA-based structure, asymmetrical to help determine the orientation, and incorporating distinctive design motifs.

Subnanometer-resolution imaging with low-temperature electron microscopy enabled the researchers to map the object ? which comprises more than 460,000 atoms ? with subnanometer-scale detail. Because the object incorporates, in effect, a whole library of different design elements, it will also serve as a resource for further study. The results, reported in Proceedings of the National Academy of Sciences, not only demonstrate atomically precise assembly, but also show that such structures, formerly thought to be jelly-like and flexible, are rigid enough to be probed by electron microscopy.

Fast processing, near-100% yields

In contrast, DNA objects with 19 different designs ? including plate-like, gear-like, and brick-like shapes ? were used for a second series of experiments at TUM, reported in the latest issue of Science. Here the researchers' main focus was on the dynamics of DNA folding and unfolding. The usual self-assembly process is often described as a "one-pot reaction": Strands of DNA that will serve as the template, instructions, and building material for a designed object are placed together at a relatively high temperature where they will remain separate; the temperature is gradually lowered, and somewhere along the line the DNA strands zip together to form the desired structures.

Observing this process in unprecedented detail, the TUM researchers discovered that all of the action takes place within a specific and relatively narrow temperature range, which differs depending on the design of the object. One practical implication is that, once the optimal temperature for a given design has been determined, DNA self-assembly ? nanomanufacturing, in essence ? could be accomplished through fast processes at constant temperatures. Following up on this lead, the researchers found that they could "mass-produce" objects made from hundreds of DNA strands within minutes instead of days, with almost no defective objects or by-products in the resulting batch.

"Besides telling us that complex DNA objects are manufacturable," Dietz says, "these results suggest something we hardly dared to imagine before ? that it might be possible to assemble DNA nanodevices in a cell culture or even within a living cell."

From the viewpoint of fundamental biology, the most intriguing result of these experiments may be the discovery that DNA folding resembles protein folding more closely than anticipated. Chemically and structurally, the two families of biomolecules are quite different. But the researchers observed clearly defined "cooperative" steps in the folding of complex DNA objects, no different in principle from mechanisms at work in protein folding. They speculate that further experiments with self-assembly of designed DNA objects could help to unravel the mysteries of protein folding, which is more complex and less accessible to direct study.

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Xiao-chen Bai, Thomas G. Martin, Sjors H. W. Scheres, Hendrik Dietz. Cryo-EM structure of a 3D DNA-origami object. Proceedings of the National Academy of Sciences of the USA, Dec. 4, 2012, 109 (49) 20012-20017; on-line in PNAS Early Edition, Nov. 19, 2012. DOI: 10.1073/pnas.1215713109

Jean-Philippe J. Sobczak, Thomas G. Martin, Thomas Gerling, Hendrik Dietz. Rapid folding of DNA into nanoscale shapes at constant temperature. Science, vol. 338, issue 6113, pp. 1458-1461. DOI: 10.1126/science.1229919

See also: Martin Langecker, Vera Arnaut, Thomas G. Martin, Jonathan List, Stephan Renner, Michael Mayer, Hendrik Dietz, and Friedrich C. Simmel. Synthetic lipid membrane channels formed by designed DNA nanostructures. Science, vol. 338, issue 6109, pp. 932-936. DOI: 10.1126/science.1225624

Technische Universitaet Muenchen: http://www.tum.de

Thanks to Technische Universitaet Muenchen for this article.

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Source: http://www.labspaces.net/125935/Reality_check_for_DNA_nanotechnology

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