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Tuesday, May 7, 2013

Laminopathies: Key components in the disease mechanism identified

May 7, 2013 ? Laminopathies are hereditary diseases that affect mainly the muscle tissue. These diseases include for example Emery-Dreifuss Muscular dystrophy, dilated cardiomyopathy, limb-girdle muscular dystrophy and Hutchison-Gilford progeria syndrome.

The underlying defect in these diseases is mutation in the genes encoding lamins or lamin-associated proteins. For example, many mutations in the lamin gene LMNA have been associated with different diseases.

Lamins are crucial components of the nuclear lamina that underlies the inner side of nuclear envelope, and provides mechanical stability to the nucleus. Lamina also participates in many different nuclear processes.

Two theories exist, why mutations in the lamina components cause disease. According to the first theory, mutations cause changes in the nuclear structure, which can lead to cell death in tissues that undergo harsh mechanical strain, such as the muscle. The second theory postulates that disturbed lamina causes changes in the gene expression patterns that are then deleterious for the cell.

A collaborative study between American and Finnish scientists bridge these two theories. The study shows that abnormal structure of the nuclear lamina, caused by laminopathy mutations, lead to changes in gene expression by disturbing the function of a specific transcription regulating protein.

The researchers found out that in laminopathy cells, the regulation of SRF (serum response factor), which controls the expression of many important genes, is disturbed. The molecular basis for this is that LMNA mutations that cause laminopathy alter the cellular localization of emerin, which is an important constituent of the nuclear envelope. Emerin regulates actin in the cell nucleus, and actin in turn is a critical regulator of SRF activator MKL1. Therefore, mis-localized emerin in laminopathies results in reduced activation of SRF by MKL1, and reduced expression of SRF target genes. Because many SRF target genes are critical for muscle function, this finding explains, why laminopathies affect mainly this tissue type. It also gives a mechanistic link between altered nuclear envelope structure and gene expression.

This study will give a glimmer of hope to the patients suffering from laminopathies, by identifying key components that underlie the disease mechanism. Restoring MKL1 activity in laminopathies might be a productive intervention mechanism for these devastating diseases.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Source: http://feeds.sciencedaily.com/~r/sciencedaily/top_news/top_health/~3/Pr2Jtv_X3LE/130507060839.htm

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Monday, May 6, 2013

Engineers manipulate a buckyball by inserting a single water molecule

May 6, 2013 ? Columbia Engineering researchers have developed a technique to isolate a single water molecule inside a buckyball, or C60, and to drive motion of the so-called "big" nonpolar ball through the encapsulated "small" polar H2O molecule, a controlling transport mechanism in a nanochannel under an external electric field. They expect this method will lead to an array of new applications, including effective ways to control drug delivery and to assemble C60-based functional 3D structures at the nanoscale level, as well as expanding our understanding of single molecule properties.

The study was published as a Physics Focus in the April 12 issue of Physical Review Letters.

"Buckyballs, more formally known as Buckminsterfullerenes, or fullerenes, are spherical, hollow molecular structures made of 60 carbon atoms, with the size of ~1 nm -- 6,000-8,000 times smaller than a regular red blood cell -- and, because of their highly symmetrical structure, very hydrophobic core, covalent nonpolar bonds, and more importantly, relatively non-toxicity to the human body, they are a perfect container for drug molecules," explains Xi Chen, associate professor of earth and environmental engineering, who led the research. He and his team believe their work is the first attempt to manipulate a nonpolar molecule (C60) or structure by an inserted polar molecule (H2O).

Chen says his findings may open a new way of controlling and delivering a nonpolar "big" molecule like C60 through the encapsulated "small" polar molecule like H2O. This could lead to important applications in nanotech and biotech areas, including drug delivery where researchers can "imprison" the polar drug molecules inside a hollow structure and then guide them to their targets.

And, from a fundamental point of view, he hopes that the isolated, encapsulated single molecule, like the H2O one in his study, will provide an important platform for revealing and probing inherent characteristics of a single molecule, free from its outside environment.

"The important role of hydrogen bonds in the properties of water, like surface tension and viscosity, and the precise interactions between a single water molecule and hydrogen bonds, are still unclear," Chen notes, "so our new technique to isolate a single water molecule free from any hydrogen bonds provides an opportunity for answering these questions."

Since the discovery of C60 in the 1980s, scientists have been trying to solve the challenge of controlling a single C60. Several mechanical strategies involving AFM (atomic force microscopy) have been developed, but these are costly and time-intensive. The ability to drive a single C60 through a simple external force field, such as an electrical or magnetic field, would be a major step forward.

In the Columbia Engineering study, the researchers found that, when they encapsulated a polar molecule within a nonpolar fullerene, they could use an external electrical field to transport the molecule@fullerene structures to desired positions and adjust the transport velocity so that both delivery direction and time were controllable. Chen's team came up with the idea a year ago, and confirmed their surprising results through extensive atomistic simulations.

Chen plans to explore more properties of the H2O@C60 molecule and other similar structures, and to continue probing the interaction and communication of the encapsulated single water molecule with its surroundings. "Studying the communication of an imprisoned single water molecule with its outside environment such as adjacent molecules," he adds, "is like learning how a person sitting inside a room makes connections with friends outside, selectively on demand (i.e. with control) or randomly (without control) through, say, over the phone."

Disclaimer: Views expressed in this article do not necessarily reflect those of ScienceDaily or its staff.

Source: http://feeds.sciencedaily.com/~r/sciencedaily/top_news/top_technology/~3/HF5zw7gjqww/130506103310.htm

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BMC to go private in $6.9 billion deal led by Bain, Golden Gate

By Sayantani Ghosh

(Reuters) - Business software maker BMC Software Inc, whose anemic growth has been a source of frustration for its largest shareholder, said it would be taken private by a group led by Bain Capital and Golden Gate Capital for about $6.9 billion.

Elliott Management, which owns 9.6 percent of BMC and had been pushing for a sale for more than a year, had argued that BMC's management was neglecting the huge opportunity to expand into the fast-growing cloud computing market.

"Going private will be very positive for them because it will enable them to make the changes that were necessary, that were much difficult when you are a public company," Lazard Capital Markets analyst Joel Fishbein said.

BMC has some catching up to do in a market now dominated by Salesforce.com Inc and where Oracle Corp, SAP AG and Microsoft Corp are investing heavily.

BMC's revenue is expected to have grown just 3 percent in the year ended March 31 to $2.23 billion, after growth of just 5 percent the previous year. BMC reports fourth-quarter results on Tuesday.

Elliott, Paul Singer's activist hedge fund, succeeded in adding two directors to BMC's board last year after a proxy battle.

The offer price of $46.25 per share represents a premium of less than 2 percent to BMC's Friday close of $45.42.

The stock has risen 4.5 percent since March 21, when Reuters reported that private equity groups were looking to buy the company.

BMC shares were trading at $45.50, up 8 cents, by midday on the Nasdaq.

BMC has two main divisions. The enterprise services management business manages networks, databases and storage and brings in nearly two-thirds of total revenue, but has stagnated over the years.

The mainframe services management unit, which helps automate data center operations, has grown slowly but is a cash cow that could help the new owners maximize profits.

The private equity group also includes GIC Special Investments Pte Ltd, part of Singapore's sovereign wealth fund, and Insight Venture Partners, a New York investment firm that focuses on software and internet businesses.

"I think they will streamline the business, focus on the higher growth areas, either divest or spin off some of the unproductive businesses," Fishbein said, adding that he expects it will take 12-18 months to "right-size" the business.

Under the sale agreement, Houston-based BMC has a "go-shop" provision that allows it to seek alternative proposals within 30 days. Analysts said it was unlikely BMC would get better offers.

BMC, which also competes with CA Inc and Compuware Corp, said the deal is expected to close later this year. Credit Suisse, RBC Capital Markets and Barclays have agreed to provide debt financing for the deal.

Morgan Stanley & Co LLC and BofA Merrill Lynch were financial advisers to BMC, while Wachtell, Lipton, Rosen & Katz was legal counsel.

Qatalyst Partners, Credit Suisse, RBC Capital Markets and Barclays served as financial advisers to the buyers, while Kirkland & Ellis LLP acted as legal counsel.

Sidley Austin LLP was legal adviser to GIC and Willkie Farr & Gallager LLP was legal adviser for Insight Venture Partners.

(Additional reporting by Supantha Mukherjee and Aditya Kondalamahanty in Bangalore; Editing by Saumyadeb Chakrabarty)

Source: http://news.yahoo.com/bmc-sell-itself-private-equity-group-6-9-133359712.html

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Trial of alleged neo-Nazi starts in Germany

Beate Zschaepe, member of the neo-Nazi group National Socialist Underground (NSU) enters the court room before the start of her trial in Munich, southern Germany, Monday, May 6, 2013. The highest-profile neo-Nazi murder trial in Germany in decades opened Monday amid tight security and intense media interest, with the five accused appearing in public for the first time since their arrest more than a year ago. Zschaepe, 38, is accused by prosecutor of complicity in the murder of eight Turks, a Greek and a policewoman between 2000 and 2007. If convicted she faces life imprisonment. Zschaepe is also accused of involvement in at least two bombings and 15 bank robberies carried out by her accomplices Uwe Mundlos and Uwe Boenhardt, who died in an apparent murder-suicide in November 2011. (AP Photo/Matthias Schrader)

A woman is held by police after she tried to force her way into the court in Munich, Germany, Monday, May 6, 2013, before the start of the trial of an alleged member of a German neo-Nazi cell. The highest-profile neo-Nazi murder trial in Germany in decades opened Monday amid tight security and intense media interest, with the five accused appearing in public for the first time since their arrest more than a year ago. The main defendant is Beate Zschaepe, 38, accused by prosecutor of complicity in the murder of eight Turks, a Greek and a policewoman between 2000 and 2007. If convicted she faces life imprisonment. Zschaepe is also accused of involvement in at least two bombings and 15 bank robberies carried out by her accomplices Uwe Mundlos and Uwe Boenhardt, who died in an apparent murder-suicide in November 2011. (AP Photo/dpa, Stephan Jansen)

Demonstrators hold photographs of NSU victims in front of the Higher Regional Court in Munich, Germany, 06 May 2013. Accused neo-Nazi terrorist Beate Zschaepe went on trial in Munich 06 May for her involvement in a series of racially motivated murders, bombings and robberies committed by an extreme right-wing underground group, the National Socialist Underground (NSU). The 38-year-old Zschaepe faces charges of being a founding member of a terrorist organization along with arson and attempted murder. The NSU group is believed to have carried out the execution-style murders of eight Turkish immigrants and one Greek man as well as a German policewoman over a period of seven years. Photo by: Karl-Josef Hildenbrand/picture-alliance/dpa/AP Images

Ralf Wohlleben, alleged supporter of the neo-Nazi group National Socialist Underground (NSU), waits for the start of a trial in Munich, southern Germany, Monday, May 6, 2013. The highest-profile neo-Nazi murder trial in Germany in decades opened Monday amid tight security and intense media interest, with the five accused appearing in public for the first time since their arrest more than a year ago. Zschaepe, 38, is accused by prosecutor of complicity in the murder of eight Turks, a Greek and a policewoman between 2000 and 2007. If convicted she faces life imprisonment. Zschaepe is also accused of involvement in at least two bombings and 15 bank robberies carried out by her accomplices Uwe Mundlos and Uwe Boenhardt, who died in an apparent murder-suicide in November 2011. (AP Photo/Matthias Schrader)

MUNICH (AP) ? An alleged German neo-Nazi accused of involvement in a 10-person killing spree appeared confident and calm Monday as her murder trial opened amid tight security, intense media interest and an immediate request by the defense for a new judge.

Beate Zschaepe ? said to be the sole surviving member of a gang behind the murders ? entered the court in a dark suit, her arms folded, before turning her back to the cameras and appearing to joke with her lawyers.

The hearing began with two motions from the defense lawyers alleging that the presiding judge was biased. Judge Manfred Goetzl put proceedings on hold until May 14 to consider the defense request that he recuse himself from the trial, which is the highest-profile neo-Nazi murder trial in Germany in decades and could last at least a year.

Zschaepe, 38, is accused by prosecutors of murder for alleged complicity in the killing of eight Turks, a Greek and a policewoman between 2000 and 2007. If convicted, she faces life imprisonment. Four others face lesser charges of assisting the cell.

Zschaepe is also accused of involvement in at least two bombings and 15 bank robberies allegedly carried out by her accomplices Uwe Mundlos and Uwe Boenhardt, who died in an apparent murder-suicide in November 2011.

Prosecutors allege the trio had formed the self-styled National Socialist Underground after evading arrest on lesser charges in 1998 and managed to remain largely off the authorities' radar for the following 13 years despite committing a string of violence crimes.

Hundreds of reporters lined up outside the Munich courthouse in the hope of gaining one of the few available seats in the packed courtroom. Police erected security barriers in anticipation of possible protests by far-right and far-left extremist groups.

Aside from Zschaepe, the four other defendants are:

? Ralf Wohlleben, 38, and Carsten Schultze, 33, are accused of being accessories to murder in the killing of the nine male victims. Prosecutors allege that they supplied the trio with the handgun and silencer used in the killings. Wohlleben was once a member of the far-right National Democratic Party, which has seats in two state parliaments in eastern Germany.

? Andre Eminger, 33, is accused of being an accessory in two of the bank robberies and in a 2001 bombing in Cologne. He is also accused of two counts of supporting a terrorist organization.

? Holger Gerlach, 39, is accused of three counts of supporting a terrorist organization.

Like Zschaepe, the co-defendants were known to German authorities before the existence of the NSU ? whose name alludes to the official name of Adolf Hitler's National Socialist German Workers' Party ? came to light.

Many of Germany's 3 million Turks have asked how the country's well-funded security services, with their network of informants in the far-right scene, could have overlooked the group's existence for so long. For years, police suspected the immigrant victims of being involved with foreign gangs linked to gambling and drugs.

Families of those killed and survivors of the bomb attacks in particular have said they are hoping not just for justice, but answers to questions such as how the group chose its victims, none of whom were high-profile targets.

One of Zschaepe's three lawyers has claimed that his client faces "execution by media."

Wolfgang Stahl told public broadcaster SWR last week that Zschaepe was being portrayed as "evil incarnate, a murderer, a member of a murder gang, a Nazi bride or a Nazi killer" in a way that could prejudice the trial judges.

Her lawyers have said she will remain silent during the lengthy trial. Under German law Zschaepe won't have to make a plea until the end, though her lawyers have said they will contest the prosecution charges.

___

Frank Jordans contributed from Berlin. He can be reached at http://www.twitter.com/wirereporter

Associated Press

Source: http://hosted2.ap.org/APDEFAULT/cae69a7523db45408eeb2b3a98c0c9c5/Article_2013-05-06-Germany-Neo-Nazi%20Trial/id-b5b8d6d9c6e84ef3879b3260e1791cef

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Sunday, May 5, 2013

Thunder Edge Grizzlies In Game 1: Kevin Durant Lifts OKC To 93-91 Win Over Memphis (VIDEO)

OKLAHOMA CITY ? Derek Fisher turned a tough situation for the Oklahoma City Thunder into the worst-case scenario for the Grizzlies.

With the Thunder down by one in the final minute, Fisher poked the ball away from Memphis' Mike Conley, springing three-time NBA scoring champion Kevin Durant into the open court with a chance to put Oklahoma City on top.

Durant pulled up and connected on a jumper with 11.1 seconds left for the last of his 35 points, lifting the Thunder to a 93-91 victory over the Grizzlies on Sunday in Game 1 of the Western Conference semifinals.

"I just wanted to get up the floor as quick as possible and find a shot," said Durant, who finished second in league MVP voting announced Sunday. "That was the only shot I could find and, by the grace of God, it went in."

Game 2 is Tuesday night in Oklahoma City.

Thabo Sefolosha kept the Grizzlies from going back ahead, deflecting a pass that Conley was able to corral ? but only after diving out of bounds. Reggie Jackson then hit a pair of free throws for a three-point lead, and Quincy Pondexter couldn't force overtime after getting fouled while attempting a 3-pointer with 1.6 seconds left.

Pondexter, a 72 percent career free-throw shooter, missed the first free throw. He made his second attempt before intentionally missing the third, but Durant swatted the rebound away and Marc Gasol's attempt at a buzzer-beater was late.

"We couldn't get stops. That's why we lost," said Gasol, who had 20 points and 10 rebounds. "We didn't lose because of free throws."

Kevin Martin scored 25 for Oklahoma City, which trailed for much of the game but was able to avoid repeating its Game 1 loss from when these two teams met in the West semifinals two years ago. The Thunder were able to rally and win that series in seven.

Fisher, a five-time NBA champion who only joined the Thunder after asking to be released by Dallas for family reasons earlier in the season, turned this game around with his defense.

Conley had gotten past him on a drive to the basket when Fisher reached in from behind and knocked the ball free. It was just the stop Oklahoma City needed.

"He makes plays, whether it's tipping the ball out and getting a steal or hitting the big shot to start the fourth," Durant said. "Or just his leadership in the huddles and the locker room is big for us. We need that."

Zach Randolph chipped in 18 points and 10 rebounds for the Grizzlies, and Pondexter and Conley scored 13 apiece. As a team, Memphis went 14 for 24 on free throws. Oklahoma City, which was the league's top foul shooting team with the third-best mark in NBA history, was 22 of 25.

"Obviously, we have to make free throws, especially myself," said Pondexter, who was slapped on his right arm by Jackson on his attempt at the tying 3-pointer. "We've just got to take this as a learning experience and move on."

The series opener was a competitive new chapter in an increasingly fierce rivalry, but there weren't any scuffles this time. They had combined for nine technical fouls in three meetings during the regular season, including one confrontation that got Randolph and Kendrick Perkins ejected.

After letting a seven-point lead slip away in the first half, Memphis surged back ahead with a 15-4 run early in the third quarter that featured two driving layups and a jumper by Conley. The lead stretched to 70-58 when Conley hit a free throw following 3-pointers on back-to-back possessions by Pondexter and Tayshaun Prince.

The Thunder started to rally before Pondexter's buzzer-beater from the half-court logo to finish the third quarter bumped the lead up to 73-64. That didn't stop Oklahoma City's comeback, though.

Fisher opened the final period with a 3-pointer and Martin converted a three-point play and a 3-pointer as the Thunder went on a 9-2 run, prompting Memphis coach Lionel Hollins to call a timeout with the lead down to 75-73 with 10:08 left.

"That shot at the buzzer, that's a great shot on his part. That's one of those things that it could have really took us back a little," Thunder coach Scott Brooks said, "but we still fought through that shot and kept competing when we were down."

After the timeout, the Grizzlies got their lead back up to seven before Durant sandwiched a pair of driving buckets around Fisher's 3-pointer in a 7-0 burst that tied it at 84 with 3:47 to play.

The Grizzlies went back up 90-87 when Serge Ibaka missed one of two free throws and Gasol followed with a hook shot with 1:08 to go.

"If you're up 3 and you've got a minute and a half, you've got to get a stop," Gasol said. "We couldn't get a stop."

Notes: Durant also finished second in the MVP race last season and in 2009. He got 93 of the 121 second-place votes in the balloting announced Sunday. ... The Thunder made their first nine shots in their only win of the season against Memphis, the best start to a game by an NBA team this season. They missed their first 10 in this one. ... Nick Collison was called for a flagrant foul after leveling Prince on a baseline drive in the second quarter. ... In the three regular-season games, the Grizzlies attempted 52 more shots largely because they had 24 more offensive rebounds. Memphis had just one more offensive rebound in this one and two more shots.

Related on HuffPost:

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Source: http://www.huffingtonpost.com/2013/05/05/kevin-durant-thunder-grizzlies-video-game-1_n_3219887.html

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Iran calls for stand against Israel after Syria attack

DUBAI (Reuters) - Iran called on the region to unite against Israel after a reported attack on Syria and said it was ready to train the Damascus government's army.

Israel carried out its second air strike in days on Syria early on Sunday, targeting Iranian-supplied missiles headed for Lebanon's Hezbollah, a Western intelligence source said.

Tehran on Sunday denied the attack was aimed at "its missiles destined for Hezbollah resistance fighters in Lebanon," according to the Islamic state's English-language Press TV.

Iran has supported its ally Syrian President Bashar al-Assad in his efforts to suppress a rebellion that has raged for more than two years and which Tehran and Damascus say is being waged by Western-backed "terrorists".

Iranian Foreign Ministry spokesman Ramin Mehmanparast urged countries in the region to stand against the "assault", the Fars news agency reported on Sunday.

Iranian army ground forces commander Ahmad Reza Pourdastan said on Sunday Iran was ready to support its ally.

"Syria has a powerful army and with the structure and experience it has against the Zionist regime (Israel) it can definitely defend itself and there is no need for intervention by other countries," Pourdastan said, according to Fars.

"But if they need training we can help them," he added.

Iran has denied supporting Assad militarily, although Western diplomats have said Iranian weapons pour into Syria via Iraq, Turkey, and Lebanon.

Ali Akbar Velayati, an adviser to Iran's Supreme Leader Ayatollah Ali Khamenei, said in January Tehran would consider an attack on Syria an attack on itself.

(Reporting By Yeganeh Torbati; Editing by Andrew Heavens)

Source: http://news.yahoo.com/iran-condemns-israeli-attack-syria-081045833.html

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Next Iran president likely to have gentler touch

In this Thursday, May 2, 2013 photo, Iran's former nuclear negotiator, Hasan Rohani, a potential front-runner in the presidential race, center right, is greeted by a supporter, in a campaign rally in Tehran, Iran. For eight years, Iran?s President Mahmoud Ahmadinejad has played the role of global provocateur-in-chief: questioning the Holocaust, saying Israel should be erased from the map and painting U.N resolutions as worthless. Now, a race is beginning to choose his successor -- candidate registration starts Tuesday for a June 14 vote -- and it looks like an anti-Ahmadinejad referendum is shaping up. (AP Photo/Vahid Salemi)

In this Thursday, May 2, 2013 photo, a group of supporters of Hasan Rohani, an Iranian potential front-runner in the presidential race, cheer, in his campaign rally in Tehran, Iran. For eight years, Iran?s President Mahmoud Ahmadinejad has played the role of global provocateur-in-chief: questioning the Holocaust, saying Israel should be erased from the map and painting U.N resolutions as worthless. Now, a race is beginning to choose his successor -- candidate registration starts Tuesday for a June 14 vote -- and it looks like an anti-Ahmadinejad referendum is shaping up. (AP Photo/Vahid Salemi)

In this Thursday, May 2, 2013 photo, Iran's former nuclear negotiator, Hasan Rohani, a potential front-runner in the presidential race, waves to his supporters in a campaign rally in Tehran, Iran. For eight years, Iran?s President Mahmoud Ahmadinejad has played the role of global provocateur-in-chief: questioning the Holocaust, saying Israel should be erased from the map and painting U.N resolutions as worthless. Now, a race is beginning to choose his successor -- candidate registration starts Tuesday for a June 14 vote -- and it looks like an anti-Ahmadinejad referendum is shaping up. (AP Photo/Vahid Salemi)

In this photo taken on Thursday, April 22, 2010, Iranian presidential hopeful, Ali Akbar Velayati, adviser to the Iranian supreme leader Ayatollah Ali Khamenei, left, talks with President Mahmoud Ahmadinejad, prior to departure of Ahmadinejad to Africa, at the Mehrabad airport, in Tehran, Iran. For eight years, Iran?s President Mahmoud Ahmadinejad has played the role of global provocateur-in-chief: questioning the Holocaust, saying Israel should be erased from the map and painting U.N resolutions as worthless. Now, a race is beginning to choose his successor -- candidate registration starts Tuesday for a June 14 vote -- and it looks like an anti-Ahmadinejad referendum is shaping up. (AP Photo/Vahid Salemi)

In this photo taken on Monday, May 9, 2011, Iranian presidential hopeful, Ali Akbar Velayati, adviser to the Iranian supreme leader Ayatollah Ali Khamenei, left, stands next to President Mahmoud Ahmadinejad, prior to departure of Ahmadinejad to Turkey, at the Mehrabad airport, in Tehran, Iran. For eight years, Iran?s President Mahmoud Ahmadinejad has played the role of global provocateur-in-chief: questioning the Holocaust, saying Israel should be erased from the map and painting U.N. resolutions as worthless. Now, a race is beginning to choose his successor -- candidate registration starts Tuesday for a June 14 vote -- and it looks like an anti-Ahmadinejad referendum is shaping up. (AP Photo/Vahid Salemi)

TEHRAN, Iran (AP) ? For eight years, Iran's President Mahmoud Ahmadinejad has played the role of global provocateur-in-chief: questioning the Holocaust, saying Israel should be erased from the map and painting U.N resolutions as worthless. His provocative style grated inside Iran as well ? angering the country's supreme leader to the point of warning the presidency could be abolished.

Now, a race is beginning to choose his successor and it looks like an anti-Ahmadinejad referendum is shaping up. Candidate registration starts Tuesday for the June 14 vote.

Leading candidates assert that they will be responsible stewards, unlike the firebrand Ahmadinejad, who cannot run again because he is limited to two terms. One criticized Ahmadinejad for "controversial but useless" statements. Others even say the country should have a less hostile relationship with the United States.

Comments from the presumed front-runners lean toward less bombast and more diplomacy. They are apparently backed by a leadership that wants to rehabilitate Iran's renegade image and possibly stabilize relations with the West.

The result however may be more a new tone rather than sweeping policy change. Under Iran's theocratic system, Ayatollah Ali Khamenei wields supreme power, making final decisions on nuclear and military questions. However, the president acts as the public face of the country, traveling the world. A new president might embark on an international image makeover and open the door to less antagonistic relations with Iran's Arab neighbors and the West.

The vote comes at a critical time in Iran, a regional powerhouse with about 75 million people and some of the largest oil reserves in the world. Nuclear talks between Iran and world powers are at an impasse while the Islamic Republic barrels ahead with a uranium enrichment program that many are convinced is intended for atomic weapons. Iran also serves as the key ally of Syria's President Bashar Assad, a mainstay so far helping keep him in power as rebels fight to oust him.

It is also in the middle of an apparent shadow war with Israel. Tehran has blamed Israel for deadly attacks on its nuclear scientists. Israel in turn has alleged Iranian attack plots on its diplomats or citizens around the world, including one where two Iranians were convicted of planning to attack Israeli, American and other targets in Kenya on Thursday. Israeli Prime Minister Benjamin Netanyahu has warned repeatedly that Iran must be stopped from acquiring nuclear weapons, through use of force if need be.

While polls in Iran are unreliable, the tenor of the candidates' speeches reflects a sense among the public that Ahmadinejad's belligerent stance toward the rest of the world has not helped.

"Ahmadinejad has followed a policy of confrontation. He made a lot of enemies for Iran. What were the results?" asked Tehran taxi driver Namdar Rezaei, 40. "The next government should pursue a policy of easing tensions with the outside world."

All the main candidates ? including a top adviser and a former nuclear negotiator ? are closely linked to the ruling clerics, since opposition groups have mostly been crushed. They reflect the mood of Khamenei, himself a former president, who wants nothing more than to end the internal political rifts opened by Ahmadinejad.

On Wednesday, Khamenei told prominent clerics to avoid "divisive" comments during the election. It is the clerics who will select a small group of hopefuls, probably no more than six, for the ballot.

The ultimate goal is to find ways to ease painful Western sanctions that have evicted Iran from international banking networks, brought public complaints over rising prices and cut vital oil exports by more than half. But what still stands in the way is a complicated dance: Maintaining uranium enrichment while addressing Western fears that Iran could move toward atomic weapons ? a charge it denies.

For more than two years, Ahmadinejad has openly defied Khamenei in an attempt to expand the authorities of the presidency. The disputes reached a meltdown point in late 2011, when Khamenei's loyalists mounted an impeachment campaign. Khamenei stepped in to call it off, but warned that Iran could one day eliminate the presidency for a system where the parliament picks a prime minister instead.

"This is a chance for Iran to bring a new tone after eight years of Ahmadinejad," said Ehsan Ahrari, a Virginia-based strategic affairs analyst. "There seems to be a real interest in the ruling system to quiet things down."

Of course, Ahmadinejad is not likely sit on the sidelines after he leaves office. He still carries significant populist support across Iran, particularly in rural areas that benefited from aid from his government. Whichever candidate he backs could get an Election Day bump.

He is now trying to push his top adviser and in-law, Esfandiar Rahim Mashaei, onto the ballot, but will likely be rejected by the Guardian Council, the group that vets all candidates. Ahmadinejad has been traveling around Iran for weeks, sometimes along with Mashaei.

After the internal political upheavals he triggered, the clerics are expected to stick with safe and loyal candidates, and the candidates know it and are playing to that dynamic.

Tehran's mayor, Mohammad Bagher Qalibaf, chided Ahmadinejad for "controversial but useless" statements that undermined Iran's international standing.

"Where did the case of the Holocaust take us? We were never against Judaism. It's a religion. ... No one could accuse us of being anti-Semitic," he told Iran's Tasnim news agency last month. "But suddenly, without consideration for the results and implications, the issue of the Holocaust was raised. How did this benefit Iran or the Palestinians?"

Another prominent candidate, Ali Akbar Velayati, took a clear shot at Ahmadinejad by saying Iran needs a "principlist" as the next president ? meaning a conservative who will not question the authority of Khamenei or the ruling clerics.

Velayati, a senior adviser to Khamenei, has joined in an unusual three-way alliance with Qalibaf and parliament member Gholam Ali Haddad Adel. Each has promised to give key posts to the two others should he win the presidency.

"If we do not succeed, we have to try for another eight years in order to take back the country's management," Velayati said in a February speech in the seminary city of Qom.

Velayati has deferred to Khamenei on any possible overtures to the U.S. But Qalibaf and others suggest they would urge the leadership to remain open for direct talks.

"Confrontation with the U.S. is not a value by itself," Qalibaf said. "At the same time, an alliance with or bowing to the U.S. won't meet our interests, too. These are two extremist views. We should follow a realistic approach. Dialogue (with the U.S.) is not a taboo."

Mohsen Rezaei, a former chief of Iran's powerful Revolutionary Guard chief who is seeking another chance at the presidency after losing four years ago, says only that he favors a "win-win dialogue."

"That means we won't lose and they (West) won't think Iran is a threat to the world," he said.

And candidate Hasan Rowhani, Iran's former nuclear negotiator and Khamenei's top national security representative, also disparaged Ahmadinejad's grandstanding style, saying Iran needs a "government of prudence."

Another candidate, former Interior Minister Mostafa Pourmohammadi, said even restoring diplomatic ties with Washington is not out of the question as long as Iranian "interests are ensured."

"I believe there is no need for Iran to be at war with the U.S. forever," he said. "Iran has the capacity to protect and ensure its national interests while having ties with the U.S."

Ahmadinejad foe Akbar Hashemi Rafsanjani, a former president, appears unlikely to make one last presidential run, despite speculation to the contrary. The official IRNA news agency quoted Rowhani on Wednesday saying the 78-year-old Rafsanjani "will definitely not" be a candidate.

However, Rafsanjani still wields considerable clout, and his endorsement will carry weight. Earlier this week, Rafsanjani urged his nation to lower tensions with Iran's archenemy Israel, which is considering military action over Tehran's nuclear program.

"We are not at war with Israel," Rafsanjani was quoted as saying by several Iranian newspapers, including the pro-reform Shargh daily. He said Iran would not initiate war against Israel, but "if Arab nations wage a war, then we would help."

Ahmadindejad's role in this election stands in sharp contrast to the last, where he was front and center and backed by the clerics. Accusations that his re-election was clumsily rigged by a clerical establishment panicked by the possibility of reformers coming to power led to massive demonstrations and reprisals spanning weeks, the most serious unrest in Iran since the 1979 Islamic Revolution itself.

The election was so contentious that the two main opposition leaders of 2009, Mir Hossein Mousavi and cleric Mahdi Karroubi, remain under house arrest. The remnants of the opposition appear increasingly unlikely to persuade their one major hope, former President Mohammad Khatami, not to seek a comeback run. That leaves them with the choice of boycotting the vote or picking from an establishment-friendly lineup.

While this election is unlikely to spark the same fireworks, a desire for change remains.

"Why shouldn't we be in good terms with the outside world? Why tensions at home and abroad?" asked 35-year-old real estate agent Shahram Rashidi in Tehran. "That's why we really need a totally different president this time."

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Murphy reported from Dubai, United Arab Emirates.