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'Attack on Malala a crime against humanity' | Pakistan Today | Latest ...

  • Ashraf vows to defeat mindset bent upon robbing country?s peace

RAWALPINDI?-?Prime Minister Raja Pervaiz Ashraf on Friday visited Malala Yousafzai at the hospital, saying the attack on her life was not a crime against an individual but against humanity and ?our core moral and social values?.

The prime minister enquired after the health of the girl and met her family as well.

He was told by the doctors that the next 36 hours were critical for Malala.

PML-Q President Chaudhry Shujaat Hussain, MQM?s Dr Farooq Sattar, ANP?s Haji Adeel and other ministers also enquired after Malala?s health along with the PM.

Ashraf said they had come to the hospital to pay tribute to the bravery and courage of Malala, who along with her friends was subjected to a cowardly attack by senseless people.

He said the nation stood united in condemning the brutality and degradation of those who perpetrated this crime and the poisoned mindset that sought to destroy the soul of the nation.

?The extremists attacked Malala for what she stands for, because they were scared of the power of her vision,? the PM said.

He said Malala had a simple message, ?The right for girls to be educated?.

Ashraf described Malala as a true Pakistani and the real face of Pakistan, vowing that they would not allow anyone to destroy the face of Pakistan.

?She has created a movement across Pakistan. Our girls want to follow her footprints,? he remarked.

The prime minister said he had often stated that we faced a threat from a bigoted and radicalised mindset that wanted to rob us of our cherished values of peace, pluralism, moderation, tolerance and passion for knowledge. The PM pledged to fight this mindset.

He said it was this mindset that was behind the martyrdom of Benazir Bhutto.

?I will not allow the future of our children to be endangered by the militant mindset; the enemies of Pakistan will never be allowed to succeed. We will uproot this menace of extremism and militancy and will not surrender the soul of the nation,? Ashraf said.

The prime minister said every Pakistani was praying for a complete recovery of Malala.

He said she was receiving the best-possible care and being treated by best professionals in the country.

Won?t allow terrorists to enforce their agenda: PM: Prime Minister Raja Parvez Ashraf said on Friday that a handful of terrorists would not be allowed to enforce their agenda on the country. Addressing a national conference on children?s rights, he condemned the attack on teenage education activist Malala Yousafzai in which she and her two fellow students were injured.

He said the attack on Malala was not against an individual, but an attempt to stifle our way of life.

He said such incidents would not deter the government?s resolve to protect common values and the future of country?s children. ?It gives me strength to note that the people from all walks of life and political spectrum have been unanimous in condemning this brutal act. This shows that the nation is united to preserve its values. Let us all pray for the speedy recovery of the young girls,? the PM said. He said the evil act exposes the hollowness of the extremists and the level they had sunk to.

He said the nation was under threat from an extremist mindset which wanted to rob it of its peace? moderation? tolerance and patience. ?We are fully aware of our international obligations in realizing the ideal of ensuring a world worthy for our children.

We are determined to continue our endeavours at national, regional and global levels in line with our international obligations,? he said, adding that the government was taking measures to combat violence against children. He said October 11 had also been declared as the day of children?s rights

Source: http://www.pakistantoday.com.pk/2012/10/13/news/national/attack-on-malala-a-crime-against-humanity/

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Windows 8 prices set, pre-orders begin

19 hrs.

Microsoft?opened its Windows 8 operating system for pre-orders on Friday, setting the price for an upgrade to the full version of the software at $70 for a DVD pack.

Users can also wait for launch on Oct. 26 to download the system onto their computers for $40, an offer price that will expire at the end of January. PCs running Windows XP, Vista and Windows 7 will be able to upgrade to Windows 8.

Shoppers can reserve the software pack at Microsoft's own stores, Amazon.com, Best Buy, Staples and elsewhere. Microsoft has not yet announced the price of the full software to install from scratch, as opposed to the upgrade. The current price for a comparable version of Windows 7 is $200.

Any customer who buys, or already bought, a Windows 7 PC between June 2 and the end of January 2013 will be able to get an upgrade to Windows 8 Pro for $15, a move designed to prevent a drop-off in PC sales before the launch of Windows 8.

Microsoft also said PC makers such as Acer, Asustek, Dell, HP, Samsung and Sony were also now taking pre-orders for machines with Windows 8 pre-installed.

The world's largest software company did not mention its own Surface tablet PC, which is expected on the market at the same time as Windows 8. Microsoft has not revealed the price of the product it hopes will challenge Apple's iPad.

?(Reporting By Bill Rigby; Editing by Bernard Orr)?

(c) Copyright Thomson Reuters 2012. Check for restrictions at:?http://about.reuters.com/fulllegal.asp?

Source: http://www.nbcnews.com/technology/technolog/microsoft-sets-windows-8-prices-opens-pre-orders-1C6443234

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VP debate tees up closing issues for Romney, Obama

Vice President Joe Biden, center, and his wife Jill Biden, meet with Republican vice presidential candidate, Rep. Paul Ryan, R-Wis., right, his wife Janna Ryan, left, and son Charlie Ryan, center, on stage after the vice presidential debate, at Centre College in Danville, Ky., Thursday, Oct. 11, 2012. (AP Photo/Pablo Martinez Monsivais)

Vice President Joe Biden, center, and his wife Jill Biden, meet with Republican vice presidential candidate, Rep. Paul Ryan, R-Wis., right, his wife Janna Ryan, left, and son Charlie Ryan, center, on stage after the vice presidential debate, at Centre College in Danville, Ky., Thursday, Oct. 11, 2012. (AP Photo/Pablo Martinez Monsivais)

Remarking on the vice presidential debate, President Barack Obama tells reporters, "I think Joe Biden did great. I couldn't be prouder," as he returns to the White House in Washington after a day of campaign events in Miami, Thursday night, Oct. 11, 2012. (AP Photo/J. Scott Applewhite)

Vice President Joe Biden answers a question during the vice presidential debate at Centre College, Thursday, Oct. 11, 2012, in Danville, Ky. (AP Photo/Mark Humphrey)

Republican vice presidential nominee Rep. Paul Ryan of Wisconsin answers a question during the vice presidential debate at Centre College, Thursday, Oct. 11, 2012, in Danville, Ky. (AP Photo/Mark Humphrey)

Supporters of Republican vice presidential nominee Rep. Paul Ryan, of Wisconsin, gather at the Holiday Inn Express in Janesville, Wis. to watch his debate with Vice President Joe Biden on Thursday, Oct. 11, 2012. (AP Photo/The Janesville Gazette, Mark Kauzlarich)

(AP) ? In a spirited debate that laid out stark choices, Joe Biden and Paul Ryan teed up pointed arguments on the economy, social policy and America's place in the world that President Barack Obama and GOP rival Mitt Romney now will drive forward into the campaign's final stretch.

With just 25 days to go in Campaign 2012 and throngs of people already voting, Obama and Romney will try to answer two questions that their running mates posed to the tens of millions of Americans who watched Thursday's hard-fought, 90-minute debate.

"Who do you trust?" Biden asked.

"Wouldn't it be nice to have a job-creator in the White House?" asked Ryan.

Biden, eager to make up for the president's lackluster performance in his first debate with Romney, played the aggressor throughout. And the president gave his running mate a quick thumbs up for delivering with the energy and feeling that he did not.

"His passion for making sure that the economy grows for the middle class came through so I'm really proud of him," Obama said after watching the debate aboard Air Force One on the way home after a day of campaigning in battleground Florida.

Ryan came back at the vice president with harsh talking points, a flurry of statistics and a sharp economic warning: In another Obama term, he said, "Watch out, middle class, the tax bill's coming to you."

Romney, who watched the debate at the end of a campaign day in North Carolina, got on the phone to Ryan immediately afterward to congratulate him. Ann Romney told a rally in the western Michigan town of Hudsonville on Friday that the debate showed why her husband chose Ryan as his running mate.

"What he saw in Paul was a level head, very smart. You can tell, it came through, the kind of character that this man has," Mrs. Romney said.

Attention now shifts to the two remaining debates between Obama and Romney: Tuesday's "town hall" style faceoff in Hempstead, N.Y., and a final showdown, over foreign policy, on Oct. 22 in Boca Raton, Fla.

And the campaigns get right back into the thick of it on Friday, looking for ways large and small to shift more voters their direction in the small number of states whose electoral votes are still up for grabs: Colorado, Florida, Iowa, Ohio, New Hampshire, Nevada, North Carolina, Virginia and Wisconsin.

Romney headed to Virginia and after was linking up with Ryan in Ohio. Biden and wife Jill will woo young voters at the University of Wisconsin-La Crosse. Obama will spend a rare day in Washington, preparing for the next two debates and taking campaign contest winners out to eat.

With so little time left in the countdown to Nov. 6, "every day, every hour counts," said Rahm Emanuel, the Chicago mayor who served as Obama's first White House chief of staff. "Everything counts."

The president has set aside a serious chunk of time for preparation after being faulted for underestimating the importance of his first debate with Romney. He'll be hunkered down in Williamsburg, Va., from Saturday until Tuesday rehearsing with Sen. John Kerry, D-Mass, acting as a proxy for Romney.

Romney's return to Ohio this weekend signals the importance of a state seen by both sides as decisive to the whole election. Obama holds the edge there, polls show.

Obama had to hope that Biden's solid showing on Thursday was enough to shift a campaign dynamic that has had the momentum moving Romney's way since the first debate. Romney, for his part, had to hope Ryan's performance would keep up the good karma for the GOP.

The running mates clearly sensed that the stakes were higher than usual for their faceoff, and both played hardball throughout, frequently interrupting one another and challenging one another's assertions.

On television's split screens, Biden's body language ? a montage of pained smiles, winces, head shakes and eye rolls ? often screamed incredulity when Ryan was speaking.

"I know you're under a lot of duress to make up for lost ground," Ryan shot back at Biden at one point, "but I think people would be better served if we don't keep interrupting each other."

In one of the night's lighter moments, Ryan helpfully provided a translation of one of Biden's putdowns.

"This is a bunch of stuff," Biden said of Ryan's dismissive characterization of the president's Iran policy.

"What does that mean, a bunch of stuff?" asked moderator Martha Raddatz of ABC News.

"It's Irish," Ryan offered.

"It is," Biden agreed, to laughter from the audience. "We Irish call it malarkey."

At another point, Ryan used Biden's own history of gaffes to explain away Romney's much-criticized comment dismissing the 47 percent of Americans who pay no income taxes, a comment Biden brought up repeatedly after Obama had failed to mention it in his debate.

"I think the vice president very well knows that sometimes the words don't come out of your mouth the right way," Ryan said.

There were spirited exchanges on taxes, abortion, Medicare, Libya, and more. It may not have broken new ground, but the conversation gave viewers a clear illustration of the sharp choices before them come Election Day.

"In case you haven't noticed, we have strong disagreements," Biden said in his closing statement. And then he distilled the Democrats' campaign pitch into a simple bid to give anxious Americans "a little bit of peace of mind."

Ryan then spoke of the "big choice" in this election, and argued that Obama had had his chance and failed.

"This is not what a real recovery looks like," he said. "You deserve better."

For all the political back-and-forth during the past two months, the race essentially stands where it was in August, before the two national political conventions, with the two candidates running about even in national polls.

There's been no shortage of drama in between: the revelation of Romney's caught-on-tape comment about the 47 percent, Biden's remark that the middle class has been "buried" in the past four years, Obama's weak showing in the first debate, the ongoing tussle over the administration's handling of the attack that left four Americans dead in Benghazi, Libya, and more.

With turnout critical, both campaigns are devoting considerable energy to ensuring that supporters are registered to vote and taking advantage of the early voting options available in many states. Nearly a million Americans already have voted.

The Democrats' monthlong "gotta vote" bus tour will be in Milwaukee on Friday, just in time to rev up supporters for the opening of Wisconsin's early voting season on Monday.

And both sides are keeping up the push for campaign contributions to keep the battleground-state airwaves full of political ads. Within a few hours of the debate, Romney, Obama and Biden all emailed supporters asking for more cash.

___

Benac reported from Washington.

___

Follow Nancy Benac on Twitter: http://www.twitter.com/nbenac

Associated Press

Source: http://hosted2.ap.org/APDEFAULT/89ae8247abe8493fae24405546e9a1aa/Article_2012-10-12-Presidential%20Campaign/id-9d87be87916d44c6a6ebad27a60f394b

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96% The Imposter

All Critics (95) | Top Critics (26) | Fresh (91) | Rotten (4)

In the annals of forged identity flicks, this is a towering Everest, dwarfing the deceivers in the likes of Catch Me If You Can and F for Fake.

This is edge-of-your-seat stuff and the difficulty is in the telling of the tale. To give any of this film away is a crime. You simply have to see it for yourself.

The most fascinating aspect of the movie is why the missing boy's family believed the imposter's story.

You may begin to wonder if you aren't being conned by the movie yourself.

Beverly Dollarhide, Nicholas's mother, says of the period after her son's disappearance, "My main goal in life at that time was not to think." Apparently, the filmmakers have taken a cue from her.

Layton's dazzling film is an exciting, edge-of-your-seat experience superior to any Hollywood mystery you're likely to see for a long time.

Superbly crafted documentary about a missing teenager who mysteriously resurfaces after three years, prompting a riveting, better-than-fiction Cold Case-style drama.

If only the movie didn't almost glamorise Bourdin's action, they'd have been onto a real masterpiece.

If you are a fan of true crime stories or the workings of the human mind, The Imposter will blow you away.

... both interesting and repellent.

An unnerving experience and a brilliant piece of documentary filmmaking that peels back the layers on one of the most perplexing stories

Layton layers "The Imposter" with powerful images in the dramatic re-creations, as well as a brooding soundscape and a concise pacing that distributes its information with the reserve of a good mystery writer.

"The Imposter" may be the first movie since "Penn and Teller Get Killed" whose title may need its own spoiler alert.

Every bit as engaging as it is well-shot, it proves once more that truth is, indeed, stranger than fiction.

A mixture of documentary, mystery and thriller, which recounts an astonishing true story that gets more outrageous with each revelation

Strange and intriguing, searching for that elusive essence known as 'the perfect truth.'

Rather like watching a magician pulling off a trick which your eyes cannot see, The Imposter offers its own strange kind of magic.

The story is astonishing enough on its own, and The Imposter succeeds in enhancing its immediacy and intensity.

As his story unfolds, one gets the uncomfortable sensation that a joke is being played. But on whom?

One of the year's most provocative pictures.

Incredibly well-made and with a story you won't forget, "The Imposter" is one of the better docs of the season.

The Imposter emerges as a brilliantly slippery film that demands brain-stretching consideration. Astonishing, indeed.

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Source: http://www.rottentomatoes.com/m/the_imposter_2012/

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Total Recall: Christopher Walken's Best Movies

We count down the best-reviewed work of the Seven Psychopaths star.

Christopher Walken

From junior soap star to Oscar-winning film actor, Saturday Night Live mainstay, and music video legend, Christopher Walken has carved out one of the most cheerfully inimitable career paths in Hollywood since making his screen debut nearly 60 years ago. This weekend, the amazingly prolific actor -- who's acted in nearly 30 films over the last 10 years alone -- pops up in Seven Psychopaths, so we decided to take the opportunity to take a fond look back at some of his most critically beloved performances. Break out your cowbells, it's time for Total Recall!


81%

Ever wondered what the word "latrine" means? Look no further than Biloxi Blues. In one of the most colorfully memorable scenes from Mike Nichols' adaptation of the Neil Simon play, Walken's marvelously named Sergeant First Class Merwin J. Toomey provides a rather in-depth definition for his latest batch of U.S. Army recruits. This being a family site, we can't reprint the whole thing; suffice it to say that it's pronounced, as Toomey puts it, "La-trine, from the French." The interplay between Walken and Biloxi's star, Matthew Broderick, was what set the movie apart for the New York Times' Vincent Canby, who chortled, "With superb performances by Mr. Broderick and Christopher Walken, who plays Mr. Simon's nearly unhinged, very funny variation on the drill sergeant of movie myth, Biloxi Blues has a fully satisfying life of its own."


84%

Adding a cop mustache, co-starring support from Sean Penn, and a Madonna hit on the soundtrack to Walken's arsenal, 1986's At Close Range dramatized the tragic real-life story of a Pennsylvania crime family whose patriarch (played by Walken) returns from exile to darken the lives of his grown sons (Sean and Chris Penn). In spite of its compelling story and excellent cast -- which included Mary Stuart Masterson, Kiefer Sutherland, and Crispin Glover -- the movie didn't make much of an impact at the box office, but it resonated with critics like Roger Ebert, who wrote that "Penn and Walken [are] at the top of their forms in roles that give them a lot to work with."


84%

If you're filming a musical and you need someone to play a singing, dancing pimp, there's really only one person to call. Walken added a little bit of off-kilter genius to 1981's Pennies from Heaven, screenwriter Dennis Potter's adaptation of his hit BBC miniseries about an unhappy married couple during trying economic times; here, directed by Herbert Ross and starring Steve Martin as a Depression-era sheet music salesman, it went down as one of the decade's more ignominious flops at the box office, although it's gained something of a cult following over the years -- and it's always been a favorite among critics like Mark Athitakis of Flimcritic.com, who called it "Dark as night but perfectly lit, a little sad but with a song in its heart."


89%

Walken earned a Saturn Award nomination for his role in David Cronenberg's The Dead Zone, an adaptation of the Stephen King novel about a psychic (played by Walken) who discovers that a Presidential candidate (Martin Sheen) will trigger nuclear war if elected -- and sets about planning a one-man assassination attempt. Unlike a number of 1980s King adaptations, The Dead Zone proved successful with audiences as well as critics; Luke Y. Thompson of New Times called this "The classic Walken role, by which all subsequent ones are measured" and argued that it's "Possibly the best Stephen King adaptation too."


91%

We don't normally include single-scene roles in Total Recall, but Christopher Walken's appearance in True Romance is something special -- in fact, the character he plays in the movie, Vincenzo Coccotti, boasts his own Wikipedia entry, thanks to the memorably racist monologue delivered by Dennis Hopper during their few moments of shared screentime. And as for the rest of the movie, which stars Christian Slater and Patricia Arquette as a couple on the run from bloodthirsty mobsters? It isn't bad either. As TIME's Richard Corliss observed at the time, "If shoot-'em-up, gobble-'em-down movies like The Fugitive and Jurassic Park are rated PG-13 these days, what does an R-rated action adventure look like? Like True Romance: violent to a fault, glam to the max."

Source: http://www.rottentomatoes.com/m/1925991/news/1925991/

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Cells control energy metabolism via hedgehog signalling pathway

[ Back to EurekAlert! ] Public release date: 12-Oct-2012
[ | E-mail | Share Share ]

Contact: J. Andrew Pospisilik
pospisilik@immunbio.mpg.de
49-761-510-8757
Max-Planck-Gesellschaft

Scientists discover novel diabetes and obesity therapy, and potential cause of major side effects from hedgehog inhibitors used as a cancer treatment

This press release is available in German.

Cancer, diabetes, and excess body weight have one thing in common: they alter cellular metabolism. Scientists from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg and the Medical University of Vienna together with an international research team have jointly resolved a new molecular circuit controlling cellular metabolism. The previously unknown signalling pathway, acting downstream of the hedgehog protein enables muscle cells and brown fat cells to absorb sugars without relying on insulin. Substances that selectively activate the signalling pathway could thus be utilized in the treatment of diabetes and obesity. With their results, the researchers are also able to explain why various new anti-cancer agents have induced mysterious pronounced side effects in the clinics.

Hedgehog was initially identified as an important protein for embryonic development across various organisms. Without hedgehog, the physiological partitions of the embryo become indistinct. However, hedgehog also influences replication, migration and specialisation of cells that is, the processes that also play a role in carcinogenesis. Mutation of genes also occurs concomitantly in various types of cancer, such as pancreatic, gastric or intestinal carcinomas. Above and beyond this, hedgehog inhibits the formation of "bad" white adipose tissue. Brown or "good" fat that serves to control body temperature, however, remains unaffected.

Hedgehog is therefore a very promising target for medications that fight cancer, diabetes and excess body weight. The US Food and Drug Administration (FDA) approved the first hedgehog inhibitor, Vismodegib, for treatment of cancer this year. There are presently at least six further agents being tested in clinical studies. Surprisingly, the first patient cohorts receiving Vismodegib have shown serious side effects, such as weight loss and muscle cramps, to the extent that more than half of the participants in the studies had to discontinue use.

The new research results appear to explain the mysterious cramps and suggest an easy, safe and already available adjunct therapy to resolve the complication. The researchers discovered a new hedgehog signalling pathway that is independent of the activation of transcription factors and genes known thus far. Cells control their primary energy metabolism, including the glucose, fatty acid and amino acid metabolisms, via this pathway.

The membrane protein known as Smo plays an important role here. Smo controls the known signalling pathway through transcription factors, as well as the new pathway via a much faster AMP-kinase enzyme and calcium dependent pathway. Smo is activated if hedgehog binds to a specialised receptor in the cell membrane. In the signalling pathway that has now been discovered, calcium flows through the membrane channels into the cell and activates calcium-dependent enzymes that in turn activate the AMP-kinase. This completely rewires metabolism. The cell can rapidly absorb large quantities of glucose using the AMP-kinase and other enzymes, rebalancing anabolism and catabolism.

Further, rather promoting efficient energy metabolism through mitochondria, the new hedgehog signalling pathway prompts much less efficient via lactic acid fermentation a process with which cancer cells use to acquire their energy without oxygen, for example (Warburg effect).

Even more surprising, the new pathway is stimulated promiscuously by both classical activators and inhibitors of the old, "canonical" hedgehog pathway. This finding potentially flips the interpretation of tens, if not hundreds of research papers in the field. Still not clear, this could be one additional reason why hedgehog inhibitors are so effective, in essence they starve the cancer cells from the inside.

Counterintuitive inhibitor-based activation of the hedgehog and Smo-calcium/AMP-kinase signalling pathways interferes with anabolic metabolism. "Activation of the AMP-kinase and increased catabolism could explain the exaggerated weight loss of the participants in the clinical studies. More importantly though, the influx of calcium into muscle cells leads to instant contraction, and must be triggering the cramps," explains Andrew Pospisilik from the Max Planck Institute in Freiburg.

Importantly, Hedgehog inhibitors do not have to lead to these side effects. "We targeted the Smo protein with various substances and found out that there are inhibitors that do not evoke an increase in calcium or glucose values, and critically, these same inhibitors fail to cause muscle cells to contract in culture. The development of medications such as these, which have minimal side effects, is therefore entirely possible," says Pospisilik.

In addition, again using fat cells, the scientists find that cells dramatically increase the glucose quantity they can absorb without relying on insulin. Glucose-tolerance tests on mice confirmed the findings. This was accomplished by administering a specific amount of glucose via the food and measuring the blood glucose concentration afterwards. Mice that had previously been treated with the classic hedgehog inhibitor cyclopamine had correspondingly lower blood glucose than untreated animals. Apparently, cyclopamine increases the glucose absorption, but only in the brown adipose tissue and various types of muscle tissue. Thus, researchers measured an increase in body temperature of around one degree a sign of higher activity in brown adipose tissue.

"Agents that only activate the Smo-calcium/AMP-kinase hedgehog signalling pathway are therefore candidates as medications for treating excess body weight, as well as type-1 and type-2 diabetes. Similar to the broad hedgehog inhibitors, they possess the potential to induce muscle cramps. Thanks to our findings, we now know that a new agent must first be tested on muscle cells before it is used on humans," says Harald Esterbauer from the Medical University of Vienna.

###

Original Publication:

Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat

Raffaele Teperino, Sabine Amann, Martina Bayer, Sean L. McGee, Andrea Loipetzberger, Timothy Connor, Carsten Jaeger, Bernd Kammerer, Lilli Winter, Gerhard Wiche, Kevin Dalgaard, Madhan Selvaraj, Jeremy Reiter, Michael Gaster, Robert S. Lee-Young, Mark A. Febbraio, Claude Knauf, Patrice D. Cani, Fritz Aberger, Josef M. Penninger, J. Andrew Pospisilik, and Harald Esterbauer Cell, 12 October 2012



[ Back to EurekAlert! ] [ | E-mail | Share Share ]

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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.


[ Back to EurekAlert! ] Public release date: 12-Oct-2012
[ | E-mail | Share Share ]

Contact: J. Andrew Pospisilik
pospisilik@immunbio.mpg.de
49-761-510-8757
Max-Planck-Gesellschaft

Scientists discover novel diabetes and obesity therapy, and potential cause of major side effects from hedgehog inhibitors used as a cancer treatment

This press release is available in German.

Cancer, diabetes, and excess body weight have one thing in common: they alter cellular metabolism. Scientists from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg and the Medical University of Vienna together with an international research team have jointly resolved a new molecular circuit controlling cellular metabolism. The previously unknown signalling pathway, acting downstream of the hedgehog protein enables muscle cells and brown fat cells to absorb sugars without relying on insulin. Substances that selectively activate the signalling pathway could thus be utilized in the treatment of diabetes and obesity. With their results, the researchers are also able to explain why various new anti-cancer agents have induced mysterious pronounced side effects in the clinics.

Hedgehog was initially identified as an important protein for embryonic development across various organisms. Without hedgehog, the physiological partitions of the embryo become indistinct. However, hedgehog also influences replication, migration and specialisation of cells that is, the processes that also play a role in carcinogenesis. Mutation of genes also occurs concomitantly in various types of cancer, such as pancreatic, gastric or intestinal carcinomas. Above and beyond this, hedgehog inhibits the formation of "bad" white adipose tissue. Brown or "good" fat that serves to control body temperature, however, remains unaffected.

Hedgehog is therefore a very promising target for medications that fight cancer, diabetes and excess body weight. The US Food and Drug Administration (FDA) approved the first hedgehog inhibitor, Vismodegib, for treatment of cancer this year. There are presently at least six further agents being tested in clinical studies. Surprisingly, the first patient cohorts receiving Vismodegib have shown serious side effects, such as weight loss and muscle cramps, to the extent that more than half of the participants in the studies had to discontinue use.

The new research results appear to explain the mysterious cramps and suggest an easy, safe and already available adjunct therapy to resolve the complication. The researchers discovered a new hedgehog signalling pathway that is independent of the activation of transcription factors and genes known thus far. Cells control their primary energy metabolism, including the glucose, fatty acid and amino acid metabolisms, via this pathway.

The membrane protein known as Smo plays an important role here. Smo controls the known signalling pathway through transcription factors, as well as the new pathway via a much faster AMP-kinase enzyme and calcium dependent pathway. Smo is activated if hedgehog binds to a specialised receptor in the cell membrane. In the signalling pathway that has now been discovered, calcium flows through the membrane channels into the cell and activates calcium-dependent enzymes that in turn activate the AMP-kinase. This completely rewires metabolism. The cell can rapidly absorb large quantities of glucose using the AMP-kinase and other enzymes, rebalancing anabolism and catabolism.

Further, rather promoting efficient energy metabolism through mitochondria, the new hedgehog signalling pathway prompts much less efficient via lactic acid fermentation a process with which cancer cells use to acquire their energy without oxygen, for example (Warburg effect).

Even more surprising, the new pathway is stimulated promiscuously by both classical activators and inhibitors of the old, "canonical" hedgehog pathway. This finding potentially flips the interpretation of tens, if not hundreds of research papers in the field. Still not clear, this could be one additional reason why hedgehog inhibitors are so effective, in essence they starve the cancer cells from the inside.

Counterintuitive inhibitor-based activation of the hedgehog and Smo-calcium/AMP-kinase signalling pathways interferes with anabolic metabolism. "Activation of the AMP-kinase and increased catabolism could explain the exaggerated weight loss of the participants in the clinical studies. More importantly though, the influx of calcium into muscle cells leads to instant contraction, and must be triggering the cramps," explains Andrew Pospisilik from the Max Planck Institute in Freiburg.

Importantly, Hedgehog inhibitors do not have to lead to these side effects. "We targeted the Smo protein with various substances and found out that there are inhibitors that do not evoke an increase in calcium or glucose values, and critically, these same inhibitors fail to cause muscle cells to contract in culture. The development of medications such as these, which have minimal side effects, is therefore entirely possible," says Pospisilik.

In addition, again using fat cells, the scientists find that cells dramatically increase the glucose quantity they can absorb without relying on insulin. Glucose-tolerance tests on mice confirmed the findings. This was accomplished by administering a specific amount of glucose via the food and measuring the blood glucose concentration afterwards. Mice that had previously been treated with the classic hedgehog inhibitor cyclopamine had correspondingly lower blood glucose than untreated animals. Apparently, cyclopamine increases the glucose absorption, but only in the brown adipose tissue and various types of muscle tissue. Thus, researchers measured an increase in body temperature of around one degree a sign of higher activity in brown adipose tissue.

"Agents that only activate the Smo-calcium/AMP-kinase hedgehog signalling pathway are therefore candidates as medications for treating excess body weight, as well as type-1 and type-2 diabetes. Similar to the broad hedgehog inhibitors, they possess the potential to induce muscle cramps. Thanks to our findings, we now know that a new agent must first be tested on muscle cells before it is used on humans," says Harald Esterbauer from the Medical University of Vienna.

###

Original Publication:

Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat

Raffaele Teperino, Sabine Amann, Martina Bayer, Sean L. McGee, Andrea Loipetzberger, Timothy Connor, Carsten Jaeger, Bernd Kammerer, Lilli Winter, Gerhard Wiche, Kevin Dalgaard, Madhan Selvaraj, Jeremy Reiter, Michael Gaster, Robert S. Lee-Young, Mark A. Febbraio, Claude Knauf, Patrice D. Cani, Fritz Aberger, Josef M. Penninger, J. Andrew Pospisilik, and Harald Esterbauer Cell, 12 October 2012



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Source: http://www.eurekalert.org/pub_releases/2012-10/m-cce101212.php

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Massive "dry cleaner bag" to lift skydiver

In this July 25, 2012 photo provided by Red Bull Stratos, a balloon lifts up during the second manned test flight for Red Bull Stratos in Roswell, N.M. It?s described as a ?40-acre dry cleaner bag,? that, when first filled, will stretch 55 stories high. On Monday, this special ultra-thin helium balloon is scheduled to liftoff from Roswell, N.M., to carry "Fearless Felix" Baumgartner 23 miles into the stratosphere for what he hopes will be a history-making, sound barrier-breaking skydive. (AP Photo/Red Bull Stratos)

In this July 25, 2012 photo provided by Red Bull Stratos, a balloon lifts up during the second manned test flight for Red Bull Stratos in Roswell, N.M. It?s described as a ?40-acre dry cleaner bag,? that, when first filled, will stretch 55 stories high. On Monday, this special ultra-thin helium balloon is scheduled to liftoff from Roswell, N.M., to carry "Fearless Felix" Baumgartner 23 miles into the stratosphere for what he hopes will be a history-making, sound barrier-breaking skydive. (AP Photo/Red Bull Stratos)

In this Feb. 23, 2012 photo provided by Red Bull Stratos, pilot Felix Buamgartner of Austria shows a piece of the balloon material during the Red Bull Stratos egress training in Lancaster, Calif. It?s described as a ?40-acre dry cleaner bag,? that, when first filled, will stretch 55 stories high. On Monday, this special ultra-thin helium balloon is scheduled to liftoff from Roswell, N.M., to carry "Fearless Felix" Baumgartner 23 miles into the stratosphere for what he hopes will be a history-making, sound barrier-breaking skydive. (AP Photo/Red Bull Stratos, Joerg Mitter)

(AP) ? It's described as a "40-acre dry cleaner bag," that, when first filled, will stretch 55 stories high.

On Tuesday, this special ultra-thin helium balloon is scheduled to lift off from Roswell, N.M., to carry Felix Baumgartner 23 miles into the stratosphere for what he hopes will be a history-making, sound barrier-breaking skydive.

WHAT'S THE BALLOON MADE OF?

Strips of plastic film that are 0.0008 inches thick, or thinner than a Ziploc bag. If laid flat, this plastic would cover 40 acres.

WHO MADE IT?

ATA Aerospace of Albuquerque. Company officials said they were not authorized by Red Bull Stratos, which is funding the jump, to talk to the media. A fact sheet says it is designed after previous balloons used for over 60 years on high-altitude flights.

WHAT ARE THE RISKS?

Helium balloons can easily be torn by the wind, so the launch will not take place unless wind speeds are less than 2 mph.

HAS IT BEEN TESTED?

No. Balloons of this type are so delicate that once out of the box they must be used immediately. The launch crew must wear clothing that can't snag it. Handlers must wear cotton gloves. Balloons used in test jumps were similar but smaller because they didn't have to go as high.

HOW DOES IT WORK?

Helium is lighter than air, so the size depends on the weight of the payload and the altitude it must reach.

HOW BIG IS IT?

It can hold nearly 30 million cubic feet of helium, enough to hoist the 3,000-pound capsule carrying Baumgartner.

HOW LONG IS THE ASCENT?

2 ? to 3 hours.

WHAT HAPPENS TO IT AFTER?

It will be separated from the capsule and parachute to earth.

___

Online:

http://www.redbullstratos.com/technology/high-altitude-balloon/

Associated Press

Source: http://hosted2.ap.org/APDEFAULT/b2f0ca3a594644ee9e50a8ec4ce2d6de/Article_2012-10-08-Supersonic%20Skydiver-Balloon/id-059e6295edec489f8777a19346b3f55b

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American Home Improvement Ideas: Controlling Pests Without ...

A colorful infographic about the hazards that are associated with the chemical pesticides. Chemical pesticides might be effective against the pests but one cannot ignore the dangers that arise from them for the human health and the environment. Instead of using chemical pesticides, you should opt for these techniques to control unwanted guests in the form of pests and insects.


Author Bio: Henry Layla is a freelance blogger and Home Improvement enthusiast. He has worked closely with Home Pest Control Company, Charleston, South Carolina, offering practical pest controlling & extermination services.

Source: http://home-improvementservices.blogspot.com/2012/10/controlling-pests-without-pesticides.html

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