Serena Williams holds the trophy after defeating Maria Sharapova, of Russia, in the final of the Sony Open tennis tournament, Saturday, March 30, 2013, in Key Biscayne, Fla. Williams won 4-6, 6-3, 6-0. (AP Photo/Lynne Sladky)
Serena Williams holds the trophy after defeating Maria Sharapova, of Russia, in the final of the Sony Open tennis tournament, Saturday, March 30, 2013, in Key Biscayne, Fla. Williams won 4-6, 6-3, 6-0. (AP Photo/Lynne Sladky)
Serena Williams celebrates after defeating Maria Sharapova, of Russia, 4-6, 6-3, 6-0, in the final match of the Sony Open tennis tournament, Saturday, March 30, 2013 in Key Biscayne, Fla. (AP Photo/Lynne Sladky)
Serena Williams celebrates after defeating Maria Sharapova, of Russia, 4-6, 6-3, 6-0, during the final match of the Sony Open tennis tournament, Saturday, March 30, 2013, in Key Biscayne, Fla. (AP Photo/Wilfredo Lee)
Serena Williams, right, and Maria Sharapova, of Russia, pose with their trophies after the final match at the Sony Open tennis tournament, in Key Biscayne, Fla., Saturday, March 30, 2013. Williams won 4-6, 6-3, 6-0. (AP Photo/Alan Diaz)
Serena Williams serves to Maria Sharapova, of Russia, during the final match of the Sony Open tennis tournament, Saturday, March 30, 2013, in Key Biscayne, Fla. (AP Photo/Lynne Sladky)
KEY BISCAYNE, Fla. (AP) ? Serena Williams broke the Key Biscayne women's record for most titles, and Maria Sharapova set a new standard for futility in finals.
Williams swept the final 10 games and earned her sixth championship in the event Saturday by rallying past Sharapova 4-6, 6-3, 6-0 at the Sony Open.
Sharapova completed a career Grand Slam by winning the French Open last year, but she's now 0-5 in Key Biscayne finals. After playing nearly flawless tennis for an hour, she began to miss with her serve, and Williams dominated rallies down the stretch.
Williams faltered only during the trophy ceremony.
"I felt good today," she told the crowd with the smile. "It's so good to be No. 6 now ? I mean, the six-time ? oh, gosh. Thank you."
Williams has won 11 consecutive matches against Sharapova, whose last victory in the rivalry came in 2004.
"Serena played a great match," Sharapova said. "I'm sure we'll be playing a few more times this year."
At 31, the No. 1-ranked Williams became the oldest female champion at Key Biscayne. She won the tournament for the first time since 2008 and surpassed Steffi Graf, a five-time champion.
Williams lives 2 hours up I-95 in Palm Beach Gardens and considers the tournament her home event.
On Sunday, 2009 champion Andy Murray will play first-time Key Biscayne finalist David Ferrer for the men's title.
The women's final began at high noon in sunny, mild weather, and the quality of play matched the conditions in the early going. The aggressive style of both finalists made for slam-bang points, and the occasional long rally had a near-capacity crowd gasping at the ferocity of the strokes.
Sharapova built her lead by keeping Williams on the defensive, and she kissed the line with a winner on consecutive points to break for a 3-2 advantage in the second set.
Then came the turnaround. Williams began to feast on Sharapova's tentative second serve and broke back at love, then took advantage of two double-faults by Sharapova to break again for a 5-3 lead.
Sharapova made 80 percent of her first serves early on but finished at 63. Williams converted all seven break-point chances and had a 35-13 advantage in winners.
"She definitely pushed me, and I definitely look forward to our next matches," Williams said. "It's going to be really fun for the fans and for us and for everyone."
Williams lost only 10 points in the final set and closed out the victory with a service winner, then was hopping, spinning, waving and grinning in jubilation as the crowd roared.
She became the first No. 1-seeded woman to win the title since she was champion nine years ago. She'll remain No. 1 and Sharapova No. 2 next week.
Sharapova also lost the final in 2005, '06, '11 and '12. Williams' other titles came in 2002, '03, '04, '07 and '08.
"It's tough to lose in the final stage, because you work so hard to get there," Sharapova said. "But the more I give myself this opportunity, the better chance I have of winning."
JOHANNESBURG (Reuters) - South Africa's anti-apartheid hero Nelson Mandela is comfortable and able to breathe without problems as he continues to respond to treatment in hospital for a recurrence of pneumonia, President Jacob Zuma's office said on Saturday.
After the revered 94-year-old statesman and former South African president spent a third night in hospital, the presidency said doctors had drained excess fluid from his lungs to tackle the infection.
"This has resulted in him now being able to breathe without difficulty. He continues to respond to treatment and is comfortable," the statement added.
In the first detailed mention of his medical condition since his latest hospitalisation, the third in four months, the presidency said the Nobel Peace Prize laureate had "developed a pleural effusion which was tapped".
Previous bulletins since he was taken to hospital late on Wednesday have reported him responding well, in "good spirits".
They have appeared to indicate that the recurrence of the lung infection afflicting Mandela is being successfully treated.
Mandela, who became South Africa's first black president in 1994 and stepped down five years later, has been mostly absent from the political scene for the past decade. But he remains an enduring and beloved symbol of the struggle against racism.
Global figures such as U.S. President Barack Obama have sent get well messages and South Africans have included Mandela in their prayers on the Easter weekend, one of the most important dates of the Christian calendar.
Mandela is revered at home and abroad for leading the struggle against white minority rule, then promoting the cause of racial reconciliation when in power.
His fragile health has been a concern for years as he has withdrawn from the public eye and mostly stayed at his affluent homes in Johannesburg and in Qunu, the rural village in the destitute Eastern Cape province near where he was born.
"FATHER OF THE NATION"
South Africans of all ages and walks of life have been following the official medical bulletins closely.
"He is the father of the nation, our Abraham Lincoln, our George Washington," said South African economics student Curtis Richardson, 19, as he visited Nelson Mandela Square in an upscale Johannesburg shopping mall with friends.
Mandela remains an inspirational figure worldwide.
"If he dies, it will be a tragedy, because he's such a symbol," said Kagisho Paterson, 19, a visitor from Britain, snapping photos near a towering statue of Mandela in the square.
English Premiership League soccer team Sunderland AFC designated Saturday "Nelson Mandela Day" to kick off its new deal supporting the ex-president's charitable foundation. The partnership would start with fundraising efforts during the team's home clash with Manchester United, Sunderland added.
Mandela's ruling African National Congress (ANC) is still the dominant force in South African politics, but critics say it has lost the moral compass bequeathed it by the previous generation of anti-apartheid freedom fighters.
Under such leaders as Mandela and the late Walter Sisulu and Oliver Tambo, the ANC gained wide international respect when it battled white rule.
Once the yoke of apartheid was thrown off in 1994, it began governing South Africa in a blaze of goodwill from world leaders who viewed it as a beacon for a troubled continent and world.
Almost two decades later, this image has dimmed as ANC leaders have been accused of indulging in the spoils of office, squandering mineral resources and engaging in power struggles.
Mandela was in hospital briefly earlier this month for a check-up and spent nearly three weeks in hospital in December with a lung infection and after surgery to remove gallstones.
He has a history of lung problems dating back to when he contracted tuberculosis as a political prisoner.
A Nigerian visitor to Johannesburg, civil engineer Gregory Osugba, 35, called Mandela "an icon of greatness and freedom" for the entire African continent and the world.
"When he goes ... the symbol will remain," he said.
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WASHINGTON (AP) ? Prospects for a Senate deal on an ambitious rewrite of the nation's immigration laws improved markedly as business and labor appeared ready to set aside their differences over a new low-skilled worker program holding up the agreement.
The AFL-CIO and U.S. Chamber of Commerce had been fighting over wages for tens of thousands of low-skilled workers who would be brought in under the new program to fill jobs in construction, hotels and resorts, nursing homes and restaurants, and other industries. But on Friday, officials from both sides said there was basic agreement on the wage issue, and Sen. Chuck Schumer, D-N.Y., said a final deal on the low-wage worker dispute was very close.
That likely would clear the way for Schumer and seven other senators in a bipartisan group to unveil legislation the week of April 8 to overhaul the U.S. immigration system, strengthening the border, cracking down on employers, allowing in tens of thousands of new high- and low-skilled workers and providing a path to citizenship for the estimated 11 million illegal immigrants already in the country.
"We're feeling very optimistic on immigration: Aspiring Americans will receive the road map to citizenship they deserve and we can modernize 'future flow' without reducing wages for any local workers, regardless of what papers they carry," AFL-CIO spokesman Jeff Hauser said in a statement. "Future flow" refers to future arrivals of legal immigrants.
Under the emerging agreement between business and labor, a new "W'' visa program would bring tens of thousands of lower-skilled workers a year to the country. The program would be capped at 200,000 a year, but the number of visas would fluctuate, depending on unemployment rates, job openings, employer demand and data collected by a new federal bureau pushed by the labor movement as an objective monitor of the market.
The workers would be able to change jobs and could seek permanent residency. Under current temporary worker programs, personnel can't move from employer to employer and have no path to permanent U.S. residence and citizenship. And currently there's no good way for employers to bring many low-skilled workers to the U.S. An existing visa program for low-wage nonagricultural workers is capped at 66,000 per year and is supposed to apply only to seasonal or temporary jobs.
The Chamber of Commerce said workers would earn actual wages paid to American workers or the prevailing wages for the industry they're working in, whichever is higher. The Labor Department determines prevailing wage based on customary rates in specific localities, so that it varies from city to city.
There was also disagreement about how to deal with certain higher-skilled construction jobs, such as electricians and welders, and it appears those will be excluded from the deal, said Geoff Burr, vice president of federal affairs at Associated Builders and Contractors. Burr said his group opposes such an exclusion because, even though unemployment in the construction industry is high right now, at times when it is low there can be labor shortages in high-skilled trades, and contractors want to be able to bring in foreign workers. But unions pressed for the exclusion, Burr said.
The low-skilled worker issue had loomed for weeks as perhaps the toughest matter to settle in monthslong closed-door talks on immigration among the senators, including Republicans John McCain of Arizona and Marco Rubio of Florida. The issue helped sink the last major attempt at immigration overhaul in 2007, when the legislation foundered on the Senate floor after an amendment was added to end a temporary worker program after five years, threatening a key priority of the business community.
The amendment passed by just one vote, 49-48. President Barack Obama, a senator at the time, joined in the narrow majority voting to end the program after five years.
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Mar. 29, 2013 ? While compared to men, women continue to be underrepresented in math and science courses and careers, is this disparity a true reflection of male and female student ability? According to a study to be released tomorrow in Psychology of Women Quarterly, a SAGE journal, male and female students earn similar grades in math and science while Asian American students of both genders outperform all other races.
Researchers Nicole Else-Quest, Concetta Mineo and Ashley Higgins studied 367 White, African American, Latino/Latina, and Asian American 10th grade male and female students in math and science. The study results indicated that while male and female adolescents earned similar grades in math and science, Asian American students outperformed all other ethnic groups, with Asian American males in particular receiving the highest scores. Furthermore, the researchers found that Latino and African American male students received the lowest scores in math and science.
"Asian American male adolescents consistently demonstrated the highest achievement compared to other adolescents, mirroring the 'model minority' stereotype," the researchers wrote. "In contrast, the underachievement of Latino and African American males is a persistent and troubling trend."
The researchers also studied the students' perceptions of their abilities in math and science. Male students reported a greater perception of their own ability in math as well as higher expectations of success, while female students reported greater value of science than their male counterparts. These findings did not vary across ethnicities.
The researchers also took into account the effects of family income and education on school achievement. Still, self-concept, task value, and expectations of success were strong predictors of student achievement in math and science.
"Despite gender similarities in math and science achievement, female adolescents tend to believe their science, technology, engineering, and mathematics (STEM) abilities are just not as strong as those of their male classmates," says Professor Else-Quest, a lead author and developmental psychologist at the University of Maryland, Baltimore County. "We believe these attitudes are important in students' choices about persevering in math and science and pursuing STEM careers. Moreover, we need to expand our approach to this issue and study affective variables such as anxiety, boredom or apathy, enjoyment, and pride, given prior findings of the importance of these emotions in academic achievement contexts."
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CHATTANOOGA, Tenn. ? Authorities in southeastern Tennessee are searching for a man who was thrown from an experimental aircraft while he was learning to fly from an instructor.
The Chattanooga Times Free Press reports ( ) that police in Collegedale and the Hamilton County Sheriff's Office on Friday were searching the ground for the man, who has not been identified. http://bit.ly/11YgGrn
Collegedale Municipal Airport employee Lowell Sterchi said the man was being trained by an instructor in his Zodiac 601 aircraft at about 2,500 feet when the canopy came off.
The man's seat belt was not fastened and he was thrown out from the plane over the East Brainerd and Apison areas of the county.
Sterchi said the instructor, who Sterchi would not identify, landed the plane and was not physically hurt. Sterchi said the Federal Aviation Administration and the National Transportation Safety Board have been notified.
ALBANY, N.Y. (AP) ? A formal complaint filed with New York's lobbying board asks it to investigate whether Artists Against Fracking, a group formed by Yoko Ono and son Sean Lennon, is violating the state's lobbying law.
The complaint obtained by The Associated Press was made by the Independent Oil & Gas Association to the state Joint Commission on Public Ethics.
The energy trade group based its request for an investigation on an AP report that found that Artists Against Fracking and its advocates didn't register as lobbyists. Registration requires several disclosures about spending and activities.
A spokesman for Artists Against Fracking says the group's activities are protected because they were made during a public comment period. He also says celebrities involved in the group are protected because they are longtime activists, not lobbyists.
Clumps of ?-synuclein protein in nerve cells are hallmarks of many degenerative brain diseases, most notably Parkinson's disease.
"No one has been able to determine if Lewy bodies and Lewy neurites, hallmark pathologies in Parkinson's disease can be degraded," says Virginia Lee, PhD, director of the Center for Neurodegenerative Disease Research, at the Perelman School of Medicine, University of Pennsylvania.
"With the new neuron model system of Parkinson's disease pathologies our lab has developed recently, we demonstrated that these aberrant clumps in cells resist degradation as well as impair the function of the macroautophagy system, one of the major garbage disposal systems within the cell."
Macroautophagy, literally self eating, is the degradation of unnecessary or dysfunctional cellular bits and pieces by a compartment in the cell called the lysosome.
Lee, also a professor of Pathology and Laboratory Medicine, and colleagues published their results in the early online edition of the Journal of Biological Chemistry this week.
Alpha-synuclein (?-syn ) diseases all have clumps of the protein and include Parkinson's disease (PD), and array of related disorders: PD with dementia , dementia with Lewy bodies, and multiple system atrophy. In most of these, ?-syn forms insoluble aggregates of stringy fibrils that accumulate in the cell body and extensions of neurons.
These unwanted ?-syn clumps are modified by abnormal attachments of many phosphate chemical groups as well as by the protein ubiquitin, a molecular tag for degradation. They are widely distributed in the central nervous system, where they are associated with neuron loss.
Using cell models in which intracellular ?-syn clumps accumulate after taking up synthetic ?-syn fibrils, the team showed that ?-syn inclusions cannot be degraded, even though they are located near the lysosome and the proteasome, another type of garbage disposal in the cell.
The ?-syn aggregates persist even after soluble ?-syn levels within the cell are substantially reduced, suggesting that once formed, the ?-syn inclusions are resistant to being cleared. What's more, they found that ?-syn aggregates impair the overall autophagy degradative process by delaying the maturation of autophagy machines known as autophagosomes, which may contribute to the increased cell death seen in clump-filled nerve cells. Understanding the impact of ?-syn aggregates on autophagy may help elucidate therapies for ?-syn-related neurodegeneration.
###
University of Pennsylvania School of Medicine: http://www.uphs.upenn.edu/news/
Thanks to University of Pennsylvania School of Medicine for this article.
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The B-2 stealth bomber's history of hitting China's Belgrade embassy in 1999 makes it's training mission over South Korea an even more pointed message to North Korea's Kim Jong-un.
By Anna Mulrine,?Staff writer / March 28, 2013
The Pentagon sent its distinctive bat-wing-shaped B-2 stealth bombers, pictured here in 2003, flying low over the Korean Peninsula this week, making it's training mission over South Korea.
Courtesy of Rebeca M. Luquin/U.S. Department of Defense/Reuters/File
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The Pentagon sent its distinctive bat-wing-shaped B-2 stealth bombers flying low over the Korean Peninsula this week ? dropping munitions over a remote South Korean island ? in what US military officials initially described as a routine training exercise.
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But the B-2 bomber runs ? along with the US military?s unusually frank announcement of this fact ? were designed to send a far more pointed warning to North Korea, and more precisely to the country?s young dictator, Kim Jong-un, who lately has been increasingly bellicose in his words and actions, say senior US officials.
Kim?s ?provocative actions? and ?belligerent tone? have ?ratcheted up the danger, and I think we have to understand that reality,? Defense Secretary Chuck Hagel said Thursday afternoon in his first joint press conference with the chairman of the Joint Chiefs of Staff, Gen. Martin Dempsey.
This danger includes the nation?s third nuclear test in February and threats to aim long-range artillery and rockets at US and allied troops.
The B-2 bomber can fly some 6,500 miles, drop smart bombs, and is nuclear-capable.
It is also the same US aircraft that infamously hit the Chinese Embassy in Belgrade, Yugoslavia, in 1999.
While this was described as an accident at the time, conventional wisdom among many defense analysts today is that China?s Peoples Liberation Army forces in the embassy basement were sending out intelligence?information to President Slobodan Milosevic of Yugoslavia, whose military was committing atrocities.
The B-2 bomber does, after all, have the most precisely targeted munitions in any military arsenal, accurate to within two meters, the defense analysts point out.?
Yet regardless of whether this theory about the 1999 B-2 bombing is true, the point is that the Chinese and North Korean government believe it to be true, says Patrick Cronin, senior director of the Asia-Pacific Security Program at the Center for a New American Security.
For that reason, the training run involving the B-2 bombers ?is a subtle signal to China and North Korea to say ?Look, war can really happen. We?re not going to be deterred, and we?re going to go after high-value target sites.? ?
But does the US know enough about Kim?s rationality to bring out the B-2 bombers, which could further provoke North Korea?
?There are a lot of unknowns here,? Mr. Hagel conceded Thursday. ?But we have to take seriously every provocative, bellicose word and action that this new young leader has taken so far since he?s come to power.?
Given those unknowns, then, is it wise to eye-poke an unpredictable ? possibly irrational ? new dictator?
?I don?t think we?re poking,? Hagel said. ?I don?t think we?re doing anything extraordinary, or provocative, or out of the orbit of what other nations do to protect their own interests.?
The point, both General Dempsey and Hagel reiterated, is not just to flex US military muscles for North Korea?s benefit, but more importantly to reassure US allies that the Pentagon has their back.
?The reaction to the B-2 that we?re most concerned about it not necessarily the reaction that it might elicit in North Korea,? Dempsey said Thursday. ?Those exercises are mostly to assure our allies that they can count on us to be prepared.?
You won't find people in North Korea checking Facebook or Twitter for the latest updates on the tense situation created by its leader, Kim Jong Un. That's because the nation of 24 million is largely shut out from the Internet. Few outside the government and military have ever been online.
"In North Korea, we don't see evidence that much of anyone has access," Jim Cowie, chief technology officer and co-founder of Renesys, which does global Internet measurement, told NBC News.
"You don't see banks or factories or universities attached to the Internet," he said. "In North Korea, Internet is extremely limited. They don't have those resources. There's basically one service provider and that is state-controlled."
The country's Internet access physically comes through from China, he said, supplemented "sometimes" by a satellite provider.
"We don't have first-hand knowledge of who has access," Cowie said, but Internet use is "very tightly restricted."
So much so that North Korea was named one of 12 "enemies" of the Internet last year by Reporters Without Borders, which monitors censorship globally. "We still consider North Korea as an enemy of the Internet," Delphine Hagland, the group's director in Washington, D.C., told NBC News. Other countries making that list included China, Iran, Syria and Vietnam.
There aren't many other sources of information available in North Korea, which according to the CIA World Factbook, has "no independent media," with "radios and TVs ... pre-tuned to government stations."
About 1 million people in North Korea have cellphones, but they are not phones with Internet access.
There may be some exceptions, said Hagland. North Koreans who live near the border with China "can have the (illegal) option of connecting to the Chinese mobile network."
In its report, Reporters Without Borders also noted the existence of what's sometimes called a "sneakernet" ? that is, people handing off data to one another via physical media, rather than across a network. The North Korea-China border is "sufficiently porous to allow mobile phones, CDs, DVDs and USB flash drives containing articles and other content to be smuggled in from China."
North Korea did, for a very short time recently, allow tourists who were staying at one hotel to have Internet access via their 3G cellphones. But that access was yanked within less than a month, according to a report in Wired UK.
That brief mobile Internet availability was not tied to Google executive chairman Eric Schmidt's visit to the country, along with former New Mexico governor Bill Richardson. The two had gone to North Korea in January to seek the release of American detainee Kenneth Bae ? which did not happen ? as well as to promote Internet freedom.
Nearly two years ago, the United Nations said that access to the Internet should be considered a basic human right. But North Korea has not gotten ? or has ignored ? that memo.
Schmidt, who met with North Korean scientists and software engineers, said after his visit that the country runs a risk of being left behind economically if it does not provide Internet access.
"Once the Internet starts, citizens in a country can certainly build on top of it, but the government has to do something,? he told NBC News' Ed Flanagan at that time. ?They have to make it possible for people to use the Internet, which the government in North Korea has not yet done.?
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FILE - In this Jan. 21, 2013 photo, Emma Clyman, 5, of Manhattan, holds a sign that reads "No More Newtowns" outside city hall park during the One Million Moms for Gun Control Rally in New York. Despite a proposal backed by over 8 in 10 people in polls, gun control supporters are struggling to win over moderate Democrats in their drive to push expanded background checks of firearms purchasers through the Senate next month. (AP Photo/John Minchillo, File)
FILE - In this Jan. 21, 2013 photo, Emma Clyman, 5, of Manhattan, holds a sign that reads "No More Newtowns" outside city hall park during the One Million Moms for Gun Control Rally in New York. Despite a proposal backed by over 8 in 10 people in polls, gun control supporters are struggling to win over moderate Democrats in their drive to push expanded background checks of firearms purchasers through the Senate next month. (AP Photo/John Minchillo, File)
FILE - In this May 19, 2011 file photo, Chairman Mark Pryor, D-Ark., speaks during a hearing of the Subcommittee on Consumer Protection, Product Safety, and Insurance on cell phone privacy on Capitol Hill in Washington. Despite a proposal backed by over 8 in 10 people in polls, gun control supporters are struggling to win over moderate Democrats like Pryor in their drive to push expanded background checks of firearms purchasers through the Senate next month. (AP Photo/Alex Brandon, File)
FILE - In this Nov. 6, 2012 file photo, Sen.-elect Heidi Heitkamp, D-N.D., address her supporters in Bismarck, N.D. Despite a proposal backed by over 8 in 10 people in polls, gun control supporters are struggling to win over moderate Democrats like Heitkamp in their drive to push expanded background checks of firearms purchasers through the Senate next month. (AP Photo/Will Kincaid, File)
WASHINGTON (AP) ? It would seem a lobbyist's dream: rounding up votes for a proposal backed by more than 8 in 10 people in polls. Yet, gun control supporters are struggling to win over moderate Democrats in their drive to push expanded background checks for firearms purchasers through the Senate next month.
Backed by a $12 million TV advertising campaign financed by New York Mayor Michael Bloomberg, gun control groups scheduled rallies around the country Thursday aimed at pressuring senators to back the effort. President Barack Obama was meeting at the White House with gun violence victims.
Moderate Senate Democrats like Mark Pryor of Arkansas and Heidi Heitkamp of North Dakota are shunning Bloomberg as a meddling outsider while stressing their allegiance to their own voters' views and to gun rights. While saying they're keeping an open mind and support keeping guns from criminals and people with mental disorders, many Democrats are avoiding specific commitments they might regret later.
"I do not need someone from New York City to tell me how to handle crime in our state. I know that we can go after and prosecute criminals without the need to infringe upon the Second Amendment rights of law-abiding North Dakotans," Heitkamp said this week, citing the constitutional right to bear arms.
Heitkamp does not face re-election next year, but Pryor and five other Senate Democrats from Republican-leaning or closely divided states do. All six, from Southern and Western states, will face voters whose deep attachment to guns is unshakeable ? not to mention opposition from the still potent National Rifle Association should they vote for restrictions the NRA opposes.
"We have a politically savvy and a loyal voting bloc, and the politicians know that," said Andrew Arulanandam, spokesman for the NRA, which claims nearly 5 million paying members.
The heart of the Senate gun bill will be expanded requirements for federal background checks for gun buyers, the remaining primary proposal pushed by Obama and many Democrats since 20 first-graders and six women were shot to death in December at an elementary school in Newtown, Conn. Senate Democratic leader Harry Reid of Nevada already has given up any hope of winning majority support for reimposing a ban on assault weapons and large-capacity magazines for ammunition.
Today, the background checks apply only to sales by the nation's roughly 55,000 federally licensed gun dealers. Not covered are private transactions like those at gun shows and online. The Senate measure is still evolving as Sens. Chuck Schumer, D-N.Y., Joe Manchin, D-W.Va., and Mark Kirk, R-Ill., use Congress' two-week recess to negotiate for additional support in both parties.
Expanding background checks to include gun show sales got 84 percent support in an Associated Press-GfK poll earlier this year. Near universal background checks have received similar or stronger support in other national polls.
Polls in some Southern states have been comparable. March surveys by the Quinnipiac University Polling Institute found more than 9 in 10 people in Florida and Virginia backing expanded background checks, the same margin found by an Elon University Poll in North Carolina in February.
Analysts say people support more background checks because they consider it an extension of the existing system. That doesn't translate to unvarnished support from lawmakers, in part because the small but vocal minorities who oppose broader background checks and other gun restrictions tend to be driven voters that politicians are reluctant to alienate.
"It's probably true that intense, single-issue gun voters have been more likely to turn out than folks who want common-sense gun laws," said Mark Glaze, director of Mayors Against Illegal Guns, the group that Bloomberg helps lead. Glaze, however, said he believes that has changed somewhat since Newtown and other recent mass shootings.
Several moderate Democrats are holding back as they assess the political landscape. They're also waiting to see exactly what the Senate will consider.
Sen. Mark Begich, D-Alaska, said Wednesday his state's voters tell him, "Don't take away our rights, our individual rights, our guns." Begich said he opposes a strict proposal requiring background checks for nearly all gun sales but will wait to see whether there is a bipartisan compromise he can support.
The problems faced by gun control supporters go beyond the challenge of winning moderate Democrats. GOP opponents are sure to force Democrats to get 60 of the Senate's 100 votes to win, and there are only 53 Democrats plus two independents who generally support them.
Also targeted by Bloomberg's ads are 10 Republicans, including Sen. Jeff Flake of Arizona, home of ex-Rep. Gabrielle Giffords, who was severely wounded in a mass shooting; the retiring Saxby Chambliss of Georgia; and moderate Susan Collins of Maine.
In another indicator of hurdles facing gun control forces, the Senate voted 50-49 last week to require 60 votes for any legislation narrowing gun rights. The proposal lost because 60 votes in favor were required, but six Democrats voted for the proposal, offered by conservative Sen. Mike Lee, R-Utah.
"It confirms there's no such thing as an easy gun vote," said Jim Kessler, a senior vice president of the centrist Democratic group Third Way.
Underscoring the uncertainty about moderate Democrats:
?Sen. Mark Warner, D-Va., is "still holding conversations with Virginia stakeholders and sorting through issues on background checks" and proposals to ban assault weapons and high capacity ammunition magazines, spokesman Kevin Hal said.
?Pryor said of Bloomberg's ads: "I don't take gun advice from the mayor of New York City. I listen to Arkansans." Spokesman Michael Teague said Pryor opposes universal background checks but could favor expanding the requirement to gun show sales.
?Sen. Kay Hagan, D-N.C., told the Greensboro News & Record she favors expanded background checks, but said her vote would depend on the measure's details. Sen. Joe Donnelly, D-Ind., answered, "Yes," when the Fort Wayne Journal Gazette asked whether he supports gun show background checks.
The gun bill also increases penalties for illegal gun sales and slightly boosts aid for school safety.
More abrupt changes like an assault weapons ban generally get slight majorities in polls. Democratic leaders decided to omit it from the Senate bill because such a provision lacks enough votes.
TORONTO (Reuters) - BlackBerry co-founder Mike Lazaridis said on Thursday he has no plans to sell his stake in the smartphone maker even as he steps down from the board to focus on a new quantum computing investment fund.
BlackBerry, formerly Research In Motion, announced the former co-CEO's departure from the board on Thursday as it reported its first quarterly earnings since launching its make-or-break new BlackBerry 10 smartphones.
"I'm really proud of what we built together at RIM, and I believe I'm leaving it in good hands, and remain one of its largest shareholders," said Lazaridis in an interview.
Asked whether he will hold on to that investment, Lazaridis said he has no plans to do otherwise. He owns 5.7 percent of the Waterloo, Ontario-based company, according to Thomson Reuters data from December 31, 2012.
Lazaridis, a silver-haired engineer who was born in Turkey, immigrated to Canada with his Greek parents as a child, and attended university in Waterloo, where he co-founded RIM in 1984.
Lazaridis also offered new details on his exit from the executive suite - he and co-CEO Jim Balsillie stepped down in January 2012, as the company bled market share to Apple Inc's iPhone and phones based on Google Inc's Android operating system, and its BlackBerry 10 ran behind schedule.
Lazaridis said he went to the board that month and asked them to make Thorsten Heins chief executive.
"I was asked to reconsider my decision to give up the CEO post, but I promised the board that I would assist Thorsten and his team in the completion of the development of BB10," he said. "I believe I've now fulfilled my commitment to the board."
Lazaridis and Doug Fregin, RIM's co-founder, announced their new $100 million Quantum Valley Investments fund earlier this month.
Those who do time-consuming calculations have for years longed for quantum computers, which could theoretically complete tasks many orders of magnitude faster than a conventional machine by tapping some peculiar properties of matter to do many calculations simultaneously.
Lazaridis, a physics buff who used some of his fortune to found the Perimeter Institute for Theoretical Physics in Waterloo, said he sees the quantum computing field "producing opportunities in the near-term." He said the fund has started making investments, but gave no details.
"This is ground-breaking work," he said. "We have the resources to put us in a position to help them fulfill the potential of these breakthroughs."
(Writing by Allison Martell; Additional reporting by Alastair Sharp; Editing by Janet Guttsman and Gunna Dickson)
Mar. 28, 2013 ? Teenagers' struggles to connect with their peers in the early adolescent years while not getting swept along by negative peer influences predict their capacity to form strong friendships and avoid serious problems even ten years later. Those are the conclusions of a new longitudinal study by researchers at the University of Virginia that appears in the journal Child Development.
"Overall, we found that teens face a high-wire act with their peers," explains Joseph P. Allen, Hugh P. Kelly Distinguished Professor at the University of Virginia, who led the study. "They need to establish strong, positive connections with them while at the same time establishing independence in resisting deviant peer influences. Those who don't manage this have significant problems as much as a decade later."
Researchers followed about 150 teens over a 10-year period (starting at age 13 and continuing to 23) to learn about the long-term effects of their peer struggles early in adolescence. They gathered information from multiple sources -- the teens themselves, their parents and peers, and by observing teens' later interactions with romantic partners. The teens comprised a racially, ethnically, and socioeconomically diverse group.
Teens who had trouble connecting well with their peers in early adolescence had difficulty establishing close friendships in young adulthood. Teens who didn't connect well at 13 also had more difficulty managing disagreements in romantic relationships as adults.
Teens who had trouble establishing some autonomy and independence with peers (especially with respect to minor forms of deviance such as shoplifting and vandalism) were found to be at higher risk for problems with alcohol and substance use, and for illegal behavior, almost a decade later.
Conversely, teens who were seen as desirable companions -- those deemed empathetic, able to see things from different perspectives and control their impulses, and having a good sense of humor -- were more likely to have positive relationships in young adulthood.
Teens who were able to establish some autonomy vis a vis peers' influences were more likely to avoid problematic behavior in young adulthood, with teens who showed they were able to think for themselves in the face of negative peer influences using less alcohol as early adults and having fewer problems with alcohol and substance abuse as young adults. But teens who were seen as desirable companions were more likely to have higher levels of alcohol use in early adulthood and future problems associated with alcohol and substance use.
"The findings make it clear that establishing social competence in adolescence and early adulthood is not a straightforward process, but involves negotiating challenging and at times conflicting goals between peer acceptance and autonomy with regard to negative peer influences," Allen notes.
"Teaching teens how to stand up for themselves in ways that preserve and deepen relationships -- to become their own persons while still connecting to others -- is a core task of social development that parents, teachers, and others can all work to promote," adds Allen.
Teens who managed both of these goals simultaneously -- connecting with peers while retaining their autonomy -- were rated by their parents as being most competent overall by age 23. "There is a positive pathway through the peer jungle of early adolescence," says Allen, "but it is a tricky one for many teens to find and traverse."
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The above story is reprinted from materials provided by Society for Research in Child Development, via EurekAlert!, a service of AAAS.
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Journal Reference:
Joseph P. Allen, Joanna Chango, David Szwedo. The Adolescent Relational Dialectic and the Peer Roots of Adult Social Functioning. Child Development, 2013; DOI: 10.1111/cdev.12106
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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.
Sidney Crosby, left, and Jarome Iginla, chat during a practice at the Men's National Olympic Hockey Team orientation camp in Calgary, Tuesday, Aug. 25, 2009. The Calgary Flames Hockey Club have traded team captain Jarome Iginla in exchange for forwards Kenneth Agostino and Ben Hanowski and the Pittsburgh Penguins 2013 first round pick. (AP Photo/The Canadian Press, Fred Chartrand, file)
Sidney Crosby, left, and Jarome Iginla, chat during a practice at the Men's National Olympic Hockey Team orientation camp in Calgary, Tuesday, Aug. 25, 2009. The Calgary Flames Hockey Club have traded team captain Jarome Iginla in exchange for forwards Kenneth Agostino and Ben Hanowski and the Pittsburgh Penguins 2013 first round pick. (AP Photo/The Canadian Press, Fred Chartrand, file)
PITTSBURGH (AP) ? Jarome Iginla had his choice of destinations when the Calgary Flames star was given freedom to explore a trade.
Only one of those destinations allowed Iginla to play with Sidney Crosby on hockey's hottest team.
Iginla called the opportunity to chase a Stanley Cup with the player he called "the best in the world" as the biggest reason the six-time All-Star agreed to a trade to Pittsburgh Wednesday night.
The 35-year-old Iginla says he's looking forward to joining the Penguins, who have ripped off 13 straight games heading into Thursday night's matchup with Winnipeg.
The move makes the Penguins the prohibitive Cup favorite, and Crosby says he's not worried about the sky-high expectations. Crosby says he always feels pressure to win the Cup no matter who is on the roster.
It was a fight-packed episode of "The Ultimate Fighter" as Tuesday night's episode had two fights and visits from two different champs.
Ronda Rousey stops by -- Kelvin won his first match, so he was rewarded with a visit with UFC women's bantamweight champion Ronda Rousey. It wasn't just for show, either, as Rousey showed Team Sonnen several judo techniques. She also pumped them up with some of her favorite "Momisms," including the choice line, "No one has the right to beat you."
Collin Hart (Team Jones) vs. Kelvin Gastellum (Team Sonnen)
Gastellum said in his pre-fight interviews that no one respects his boxing. Uh, they will now. Gastellum struck Hart quickly with a left hook that sent him down to the ground. Hart hit his head on the canvas, rolled over, and took a few more punches before the fight was stopped. It was a vicious, vicious knockout.
Mike Tyson! Oh, hey, no big deal. Mike Tyson showed up at the training center. He stopped in the locker rooms to say hello to the fighters.
Dylan Andrews (Team Jones) vs. Luke Barnatt (Team Sonnen)
A fight for the Queen as Australian Andrews takes on Brit Barnatt. Andrews got the takedown early in the first round, and Barnatt had no answer on the ground for much of the round. Andrews tried for a few chokes, but was unsuccessful.
Barnatt did a much better job in the second, creating offense from the bottom. This led to a third round, where Andrews took over. He knocked a clearly tired Barnatt around until he finally knocked him out in the third round.
Everyone was impressed with how Andrews fought through the third round, including the man signing the checks.
"I'm blown away and impressed with Dylan. That's how it's done here." ? Dana White
The next two quarterfinals are next week, and they'll have a tough act to follow.
March 28 (Reuters) - Rory McIlroy, playing for the first time since losing his world number one ranking earlier this week, got off to a shaky start at the Houston Open on Thursday where he dropped three shots over his opening eight holes. The 23-year-old Northern Irishman, who was replaced atop the world rankings by Tiger Woods this week, struggled to find his rhythm on an ideal day for low scoring at the Redstone Golf Club in Humble, Texas. He bogeyed the par-four second hole and made a double-bogey seven on the eighth hole to limp to the turn at three-over. ...
A few minutes after the Supreme Court issued its landmark decision upholding President Obama?s health care law last summer, a senior adviser to Mitch McConnell walked into the Senate Republican leader?s office to gauge his reaction.
McConnell was clearly disappointed, and for good reason. For many conservatives, the decision was the death knell in a three-year fight to defeat reforms that epitomized everything they thought was wrong with Obama?s governing philosophy. But where some saw finality, McConnell saw opportunity ? and still does.
Sitting at his desk a stone?s throw from the Senate chamber, McConnell turned to the aide and, with characteristic directness, said: ?This decision is too cute. But I think we got something with this tax issue.?
He was referring to the court?s ruling that the heart of the 2010 Affordable Care Act, the so-called individual mandate that requires everyone in the country to buy health insurance or pay a penalty, was a tax. And while McConnell thought calling the mandate a tax was ?a rather creative way? to uphold the law, it also opened a new front in his battle to repeal it.
McConnell, a master of byzantine Senate procedure, immediately realized that, as a tax, the individual mandate would be subject to the budget reconciliation process, which exempted it from the filibuster. In other words, McConnell had just struck upon how to repeal Obamacare with a simple majority vote.
The Kentucky Republican called a handful of top aides into his office and told them, ?Figure out how to repeal this through reconciliation. I want to do this.? McConnell ordered a repeal plan ready in the event the GOP took back control of the Senate in November ? ironic considering Democrats used the same process more than two years earlier in a successful, last-shot effort to muscle the reforms into law.
In the months that followed, top GOP Senate aides held regular strategy meetings to plot a path forward. Using the reconciliation process would be complicated and contentious. Senate rules would require Republicans to demonstrate to the parliamentarian that their repeal provisions would affect spending or revenue and Democrats were sure to challenge them every step of the way. So the meetings were small and secret.
?You?re going in to make an argument. You don?t want to preview your entire argument to the other side ahead of time,? said a McConnell aide who participated in the planning. ?There was concern that all of this would leak out.?
By Election Day, Senate Republicans were ready to, as McConnell put it, ?take this monstrosity down.?
?We were prepared to do that had we had the votes to do it after the election. Well, the election didn?t turn out the way we wanted it to,? McConnell told National Journal in an interview. ?The monstrosity has ... begun to be implemented and we?re not giving up the fight.?
Indeed, when it comes to legislative strategy, McConnell plays long ball. Beginning in 2009, the Republican leader led the push to unify his colleagues against Democrats? health care plans, an effort that almost derailed Obamacare. In 2010, Republicans, helped in part by public opposition to the law, won back the House and picked up seats in the Senate. Last year, GOP presidential nominee Mitt Romney?s embrace of the individual mandate while Massachusetts governor largely neutralized what had been a potent political issue.
But, in the next two years, Republicans are looking to bring the issue back in a big way. And they?ll start by trying to brand the law as one that costs too much and is not working as promised.
Democrats will be tempted to continue to write off the incoming fire as the empty rhetoric of a party fighting old battles. But that would be a mistake. During the health care debate, the GOP?s coordinated attacks helped turn public opinion against reform. And in the past two years, no more than 45 percent of the public has viewed Obamacare favorably, according to the Kaiser Family Foundation?s tracking polls. Perhaps even more dangerous for Democrats, now-debunked myths spread by Republicans and conservative media remain lodged in the public consciousness. For instance, 40 percent of the public still believes the law includes ?death panels.?
During the legislative debate over the law, Democrats promised Obamacare would create jobs, lower health care costs, and allow people to keep their current plans if they chose to. Those vows, Republicans argue, are already being broken.
The Congressional Budget Office, the Hill?s nonpartisan scorekeeper, estimated that the health care law would reduce employment by about 800,000 workers and result in about 7 million people losing their employer-sponsored health care over a decade. The CBO also estimated that Obamacare during that period would raise health care spending by roughly $580 billion.
McConnell?s office has assembled the law?s 19,842 new regulations into a stack that is 7 feet high and wheeled around on a dolly. The prop even has it?s own Twitter account, @TheRedTapeTower.
?All you got to do is look at that high stack of regulation and you think, ?How in the world is anybody going to be able to comply with all this stuff?? ? GOP Sen. Orrin Hatch, told National Journal. ?And I?m confident that the more the American people know of the costs, the consequences, the problems with this law, then someday there are going to be some Democrats who are going to join us in taking apart some of its most egregious parts.?
In fact, just a few hours after that interview last week, 34 Democrats joined Hatch on the Senate floor to support repealing Obamacare?s medical-device tax. Though the provision passed overwhelmingly, it doesn?t have a shot at becoming law because the budget bill it was attached to is nonbinding. Still, Republicans see it as a harbinger of things to come.
?Constituent pressure is overriding the view that virtually all Democrats have had that Obamacare is sort of like the Ten Commandments, handed down and every piece of it is sacred and you can?t possibly change any of it ever,? McConnell said. ?When you see that begin to crack then you know the facade is breaking up.?
Of course, Republicans are doing their best to highlight and stoke the kind of constituent anger that would force Democrats to tweak the law. In fact, if Democrats come under enough pressure, Republicans believe they might be able to inject Obamacare into the broader entitlement-reform discussion they are planning to tie to the debt-limit debate this summer.
But that is a long shot. If Republicans hope to completely repeal the health care law, they have to start by taking back the Senate in 2014 and would likely need to win the White House two years later. Still, some Republicans think the politics are on their side.
?I?m not one of those folks who ... because I didn?t support something, I want it to be bad. I want good things for Americans. But I do think this is going to create a lot of issues and ? affect things throughout 2014 as it relates to politics,? Republican Sen. Bob Corker said. ?The outcome likely will create a better atmosphere for us.?
Republicans will need to win half a dozen seats to retake the chamber. So, what are the chances??
?There are six really good opportunities in really red states: West Virginia, North Carolina, Louisiana, Arkansas, South Dakota, and Alaska,? McConnell said last week. ?And some other places where you have open seats like Michigan and Iowa. And other states that frequently vote Republican, an example of that would be New Hampshire. So, we?re hopeful.?
And earlier this week, Democratic Sen. Tim Johnson put his home state of South Dakota in play when he announced he will not be running for reelection in 2014.
In addition to trying to win back the Senate, McConnell will have to protect his own seat in two years. McConnell has made moves to shore up his right flank to fend off conservative challengers. He?s hired fellow Kentucky Republican Sen. Rand Paul?s campaign manager, who helped Paul defeat the establishment candidate McConnell backed in the primary. ?
In the meantime, Republicans will continue to, as GOP Sen. John Barrasso put it, ?try to tear (Obamacare) apart.? And the GOP suspects it might get some help from moderate Democrats less concerned about protecting Obama?s legacy than winning reelection.
It?s just the latest act in a play that saw McConnell give more than 100 floor speeches critical of Democratic reforms and paper Capitol Hill with more 225 messaging documents in the 10 months before Obamacare?s passage. Away from the public spotlight, McConnell worked his caucus hard to convince them to unite against the law, holding a health care meeting every Wednesday afternoon. GOP aides said they could not remember a time before, or since, when a Republican leader held a weekly meeting with members that focused solely on one subject.
?What I tried to do is just guide the discussion to the point where everybody realized there wasn?t any part of this we wanted to have any ownership of,? McConnell recounted. ?That was a nine-month long discussion that finally culminated with Olympia Snowe?s decision in the fall not to support it. She was the last one they had a shot at.?
Indeed, some Republicans remember opposition forming organically as it became clearer where Democrats were headed, crediting McConnell for crystallizing the issue. Asked who unified Senate Republicans against Obamacare, Corker recalled, ?I think it happened over time.? As time moved on, it just seemed that this train was going to a place that was going to be hard to support.?
McConnell had finally won his long-fought battle to unite the conference against Obamcare. And some Republicans credit McConnell with being first to that fight.
?He had the Obama administration?s number before almost anyone else,? Hatch recalled. ?He began laying the groundwork for this fight very early, in private meetings and so forth, and really was the first one on our side in the ring, throwing punches just about how bad it was for families, businesses, and our economy.?
?There?s been no stronger fighter against this disastrous law than Mitch McConnell,? he added.
And as McConnell?s war continues, Democrats have begun positioning themselves for the next battle. Leading up to last week?s three-year anniversary of the law?s passage, Democrats held press events touting its benefits, claiming more than 100 million people have received free preventive services; 17 million children with preexisting conditions have been protected from being denied coverage; and 6.6 million young adults under 26 have been covered by their parents' plan.
Democrats wisely rolled out many of the easiest, most-popular Obamacare benefits first. The next few years will see the implementation of provisions that are both more complicated and controversial, like creating state-based insurance exchanges where people can buy coverage. Asked about the political ramifications of possible implementation problems, Democratic Sen. Max Baucus, a chief architect of Obamacare, sidestepped the question saying, "My job is to do my best to make sure this statute works to help provide health care for people at the lowest possible cost."
Far from a full-throated assurance that everything will run smoothly, Baucus?s answer hints at the dangers Democrats face as Obamacare comes online.
And with the law moving from the largely theoretical to the demonstrable, the health care debate is poised to return to intensity levels not seen since before the law passed.
For congressional Republicans, it?s probably their last, best chance to turn opposition into political gain.
And much of that job falls to McConnell, a brilliant defensive coordinator who will have to play flawless offense if he hopes to take control of the Senate next year.
Pediatric researchers, investigating the biology of brain tumors in children, are finding that crucial differences in how the same gene is mutated may call for different treatments. A new study offers glimpses into how scientists will be using the ongoing flood of gene-sequencing data to customize treatments based on very specific mutations in a child's tumor.
"By better understanding the basic biology of these tumors, such as how particular mutations in the same gene may respond differently to targeted drugs, we are moving closer to personalized medicine for children with cancer," said the study's first author, Angela J. Sievert, M.D., M.P.H., an oncologist in the Cancer Center at The Children's Hospital of Philadelphia.
Sievert, working with co-first author Shih-Shan Lang, M.D., in the translational laboratory of neurosurgeon Phillip Storm, M.D., and Adam Resnick, Ph.D., published a study ahead of print today in the Proceedings of the National Academy of Sciences.
The study, performed in cell cultures and animals, focused on a type of astrocytoma, the most common type of brain tumor in children. When surgeons can fully remove an astrocytoma (also called a low-grade glioma), a child can be cured. However, many astrocytomas are too widespread or in too delicate a site to be safely removed. Others may recur. So pediatric oncologists have been seeking better options---ideally, a drug that can selectively and definitively kill the tumor with low toxicity to healthy tissue.
The current study focuses on mutations in the BRAF gene, one of the most commonly mutated genes in human cancers. Because the same gene is also mutated in certain adult cancers, such as melanoma, the pediatric researchers were able to make use of recently developed drugs, BRAF inhibitors, which were already being tested with some success against melanoma in adults.
The current study provides another example of the complexity of cancer: in the same gene, different mutations behave differently. Sievert and her colleagues at Children's Hospital were among several research groups who reported almost simultaneously in 2008 and 2009 that mutations in the BRAF gene were highly prevalent in astrocytomas in children. "These were landmark discoveries, because they suggested that if we could block the action of that mutation, we could develop a new, more effective treatment for these tumors," said Sievert.
However, follow-up studies in animal models were initially disappointing. BRAF inhibitors that were effective in BRAF-driven adult melanomas made brain tumors worse?via an effect called paradoxical activation.
Further investigation revealed how tumor behavior depended on which type of BRAF mutation was involved. The first-generation drug that was effective in adult melanoma acted against point mutations in BRAF called V600E alterations. However, in most astrocytomas the mutation in the BRAF gene was different; it produced a fusion gene, designated KIAA1549-BRAF. When used against the fusion gene, the first-generation drug activated a cancer-driving biological pathway, the MAPK signaling cascade, and accelerated tumor growth.
By examining the molecular mechanisms behind drug resistance and working with the pharmaceutical industry, the current study's investigators identified a new, experimental second-generation BRAF inhibitor that disrupted the cancer-promoting signals from the fusion gene, and did not cause the paradoxical activation in the cell cultures and animal models.
This preclinical work result lays a foundation for multicenter clinical trials to test the mutation-specific targeting of tumors by this class of drugs in children with astrocytomas, said Sievert. As this effort progresses, it will benefit from CHOP's commitment to resources and collaborations that support data-intense research efforts.
The direction of brain tumor research over the past several years reflects some of those data-driven advances, says Adam C. Resnick, Ph.D., the senior author of the current paper and principal investigator of the astrocytoma research team in the Division of Neurosurgery at Children's Hospital. "For years, astrocytomas have been lumped together based on similar appearance to pathologists studying their structure, cell shape and other factors," said Resnick. "But our current discoveries show that the genetic and molecular structure of tumors provides more specific information in guiding oncologists toward customized treatments."
Earlier this year, Children's Hospital announced its collaboration with the gene-sequencing organization BGI-Shenzhen in performing next-generation sequencing of pediatric brain tumors at the Joint Genome Center, BGI@CHOP. The center's sophisticated, high-throughput sequencing technology will greatly speed the discovery of specific gene alterations involved in childhood brain cancers.
This genomic discovery program dovetails with the work of the Childhood Brain Tumor Tissue Consortium, a multi-institutional collaboration recently launched by CHOP, with support from the Children's Brain Tissue Foundation. Because even large research centers may not hold enough tumor tissue specimens to power certain research, the consortium pools samples from a group of institutions, providing an important scientific resource for cooperative studies.
"The better we understand the mutational landscape of tumors, the closer we'll be to defining therapies tailored to a patient's specific subtype of cancer," added Resnick.
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Children's Hospital of Philadelphia: http://www.chop.edu
Thanks to Children's Hospital of Philadelphia for this article.
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New vaccine-design approach targets HIV and other fast-mutating virusesPublic release date: 28-Mar-2013 [ | E-mail | Share ]
Contact: Mika Ono mikaono@scripps.edu 858-784-2052 Scripps Research Institute
LA JOLLA, CA March 28, 2013 A team led by scientists from The Scripps Research Institute (TSRI) and the International AIDS Vaccine Initiative (IAVI) has unveiled a new technique for vaccine design that could be particularly useful against HIV and other fast-changing viruses.
The report, which appears March 28, 2013, in Science Express, the early online edition of the journal Science, offers a step toward solving what has been one of the central problems of modern vaccine design: how to stimulate the immune system to produce the right kind of antibody response to protect against a wide range of viral strains. The researchers demonstrated their new technique by engineering an immunogen (substance that induces immunity) that has promise to reliably initiate an otherwise rare response effective against many types of HIV.
"We're hoping to test this immunogen soon in mice engineered to produce human antibodies, and eventually in humans," said team leader William R. Schief, who is an associate professor of immunology and member of the IAVI Neutralizing Antibody Center at TSRI.
Seeking a Better Way
For highly variable viruses such as HIV and influenza, vaccine researchers want to elicit antibodies that protect against most or all viral strainsnot just a few strains, as seasonal flu vaccines currently on the market. Vaccine researchers have identified several of these broadly neutralizing antibodies from long-term HIV-positive survivors, harvesting antibody-producing B cells from blood samples and then sifting through them to identify those that produce antibodies capable of neutralizing multiple strains of HIV. Such broadly neutralizing antibodies typically work by blocking crucial functional sites on a virus that are conserved among different strains despite high mutation elsewhere.
However, even with these powerful broadly neutralizing antibodies in hand, scientists need to find a way to elicit their production in the body through a vaccine. "For example, to elicit broadly neutralizing antibodies called VRC01-class antibodies that neutralize 90 percent of known HIV strains, you could try using the HIV envelope protein as your immunogen," said Schief, "but you run into the problem that the envelope protein doesn't bind with any detectable affinity to the B cells needed to launch a broadly neutralizing antibody response."
To reliably initiate that VRC01-class antibody response, Schief and his colleagues therefore sought to develop a new method for designing vaccine immunogens.
From Weak to Strong
Joseph Jardine, a TSRI graduate student in the Schief laboratory, evaluated the genes of VRC01-producing B cells in order to deduce the identities of the less mature B cellsknown as germline B cellsfrom which they originate. Germline B cells are major targets of modern viral vaccines, because it is the initial stimulation of these B cells and their antibodies that leads to a long-term antibody response.
In response to vaccination, germline B cells could, in principle, mature into the desired VRC01-producing B cellsbut natural HIV proteins fail to bind or stimulate these germline B cells so they cannot get the process started. The team thus set out to design an artificial immunogen that would be successful at achieving this.
Jardine used a protein modeling software suite called Rosetta to improve the binding of VRC01 germline B cell antibodies to HIV's envelope protein. "We asked Rosetta to look for mutations on the side of the HIV envelope protein that would help it bind tightly to our germline antibodies," he said.
Rosetta identified dozens of mutations that could help improve binding to germline antibodies. Jardine then generated libraries that contained all possible combinations of beneficial mutations, resulting in millions of mutants, and screened them using techniques called yeast surface display and FACS. This combination of computational prediction and directed evolution successfully produced a few mutant envelope proteins with high affinity for germline VRC01-class antibodies.
Jardine then focused on making a minimal immunogenmuch smaller than HIV envelopeand so continued development using the "engineered outer domain (eOD)" previously developed by Po-Ssu Huang in the Schief lab while Schief was at the University of Washington. Several iterative rounds of design and selection using a panel of germline antibodies produced a final, optimized immunogena construct they called eOD-GT6.
A Closer Look
To get a better look at eOD-GT6 and its interaction with germline antibodies, the team turned to the laboratory of Ian A. Wilson, chair of the Department of Integrative Structural and Computational Biology and a member of the IAVI Neutralizing Antibody Center at TSRI.
Jean-Philippe Julien, a senior research associate in the Wilson laboratory, determined the 3D atomic structure of the designed immunogen using X-ray crystallographyand, in an unusual feat, also determined the crystal structure of a germline VRC01 antibody, plus the structure of the immunogen and antibody bound together.
"We wanted to know whether eOD-GT6 looked the way we anticipated and whether it bound to the antibody in the way that we predictedand in both cases the answer was 'yes'," said Julien. "We also were able to identify the key mutations that conferred its reactivity with germline VRC01 antibodies."
Mimicking a Virus
Vaccine researchers know that such an immunogen typically does better at stimulating an antibody response when it is presented not as a single copy but in a closely spaced cluster of multiple copies, and with only its antibody-binding end exposed. "We wanted it to look like a virus," said Sergey Menis, a visiting graduate student in the Schief laboratory.
Menis therefore devised a tiny virus-mimicking particle made from 60 copies of an obscure bacterial enzyme and coated it with 60 copies of eOD-GT6. The particle worked well at activating VRC01 germline B cells and even mature B cells in the lab dish, whereas single-copy eOD-GT6 did not.
"Essentially it's a self-assembling nanoparticle that presents the immunogen in a properly oriented way," Menis said. "We're hoping that this approach can be used not just for an HIV vaccine but for many other vaccines, too."
The next step for the eOD-GT6 immunogen project, said Schief, is to test its ability to stimulate an antibody response in lab animals that are themselves engineered to produce human germline antibodies. The difficulty with testing immunogens that target human germline antibodies is that animals typically used for vaccine testing cannot make those same antibodies. So the team is collaborating with other researchers who are engineering mice to produce human germline antibodies. After that, he hopes to learn how to drive the response, from the activation of the germline B cells all the way to the production of mature, broadly neutralizing VRC01-class antibodies, using a series of designed immunogens.
Schief also hopes they will be able to test their germline-targeting approach in humans sooner rather than later, noting "it will be really important to find out if this works in a human being."
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The first authors of the paper, "Rational HIV immunogen design to target specific germline B cell receptors," were Jardine, Julien and Menis. Co-authors were Takayuki Ota and Devin Sok of the Nemazee and Burton laboratories at TSRI, respectively; Travis Nieusma of the Ward laboratory at TSRI; John Mathison of the Ulevitch laboratory at TSRI; Oleksandr Kalyuzhniy and Skye MacPherson, researchers in the Schief laboratory from IAVI and TSRI, respectively; Po-Ssu Huang and David Baker of the University of Washington, Seattle; Andrew McGuire and Leonidas Stamatatos of the Seattle Biomedical Research Institute; and TSRI principal investigators Andrew B. Ward, David Nemazee, Ian A. Wilson, and Dennis R. Burton, who is also head of the IAVI Neutralizing Center at TSRI.
The project was funded in part by IAVI; the National Institutes of Health (AI84817, AI081625 and AI33292); and the Ragon Institute.
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New vaccine-design approach targets HIV and other fast-mutating virusesPublic release date: 28-Mar-2013 [ | E-mail | Share ]
Contact: Mika Ono mikaono@scripps.edu 858-784-2052 Scripps Research Institute
LA JOLLA, CA March 28, 2013 A team led by scientists from The Scripps Research Institute (TSRI) and the International AIDS Vaccine Initiative (IAVI) has unveiled a new technique for vaccine design that could be particularly useful against HIV and other fast-changing viruses.
The report, which appears March 28, 2013, in Science Express, the early online edition of the journal Science, offers a step toward solving what has been one of the central problems of modern vaccine design: how to stimulate the immune system to produce the right kind of antibody response to protect against a wide range of viral strains. The researchers demonstrated their new technique by engineering an immunogen (substance that induces immunity) that has promise to reliably initiate an otherwise rare response effective against many types of HIV.
"We're hoping to test this immunogen soon in mice engineered to produce human antibodies, and eventually in humans," said team leader William R. Schief, who is an associate professor of immunology and member of the IAVI Neutralizing Antibody Center at TSRI.
Seeking a Better Way
For highly variable viruses such as HIV and influenza, vaccine researchers want to elicit antibodies that protect against most or all viral strainsnot just a few strains, as seasonal flu vaccines currently on the market. Vaccine researchers have identified several of these broadly neutralizing antibodies from long-term HIV-positive survivors, harvesting antibody-producing B cells from blood samples and then sifting through them to identify those that produce antibodies capable of neutralizing multiple strains of HIV. Such broadly neutralizing antibodies typically work by blocking crucial functional sites on a virus that are conserved among different strains despite high mutation elsewhere.
However, even with these powerful broadly neutralizing antibodies in hand, scientists need to find a way to elicit their production in the body through a vaccine. "For example, to elicit broadly neutralizing antibodies called VRC01-class antibodies that neutralize 90 percent of known HIV strains, you could try using the HIV envelope protein as your immunogen," said Schief, "but you run into the problem that the envelope protein doesn't bind with any detectable affinity to the B cells needed to launch a broadly neutralizing antibody response."
To reliably initiate that VRC01-class antibody response, Schief and his colleagues therefore sought to develop a new method for designing vaccine immunogens.
From Weak to Strong
Joseph Jardine, a TSRI graduate student in the Schief laboratory, evaluated the genes of VRC01-producing B cells in order to deduce the identities of the less mature B cellsknown as germline B cellsfrom which they originate. Germline B cells are major targets of modern viral vaccines, because it is the initial stimulation of these B cells and their antibodies that leads to a long-term antibody response.
In response to vaccination, germline B cells could, in principle, mature into the desired VRC01-producing B cellsbut natural HIV proteins fail to bind or stimulate these germline B cells so they cannot get the process started. The team thus set out to design an artificial immunogen that would be successful at achieving this.
Jardine used a protein modeling software suite called Rosetta to improve the binding of VRC01 germline B cell antibodies to HIV's envelope protein. "We asked Rosetta to look for mutations on the side of the HIV envelope protein that would help it bind tightly to our germline antibodies," he said.
Rosetta identified dozens of mutations that could help improve binding to germline antibodies. Jardine then generated libraries that contained all possible combinations of beneficial mutations, resulting in millions of mutants, and screened them using techniques called yeast surface display and FACS. This combination of computational prediction and directed evolution successfully produced a few mutant envelope proteins with high affinity for germline VRC01-class antibodies.
Jardine then focused on making a minimal immunogenmuch smaller than HIV envelopeand so continued development using the "engineered outer domain (eOD)" previously developed by Po-Ssu Huang in the Schief lab while Schief was at the University of Washington. Several iterative rounds of design and selection using a panel of germline antibodies produced a final, optimized immunogena construct they called eOD-GT6.
A Closer Look
To get a better look at eOD-GT6 and its interaction with germline antibodies, the team turned to the laboratory of Ian A. Wilson, chair of the Department of Integrative Structural and Computational Biology and a member of the IAVI Neutralizing Antibody Center at TSRI.
Jean-Philippe Julien, a senior research associate in the Wilson laboratory, determined the 3D atomic structure of the designed immunogen using X-ray crystallographyand, in an unusual feat, also determined the crystal structure of a germline VRC01 antibody, plus the structure of the immunogen and antibody bound together.
"We wanted to know whether eOD-GT6 looked the way we anticipated and whether it bound to the antibody in the way that we predictedand in both cases the answer was 'yes'," said Julien. "We also were able to identify the key mutations that conferred its reactivity with germline VRC01 antibodies."
Mimicking a Virus
Vaccine researchers know that such an immunogen typically does better at stimulating an antibody response when it is presented not as a single copy but in a closely spaced cluster of multiple copies, and with only its antibody-binding end exposed. "We wanted it to look like a virus," said Sergey Menis, a visiting graduate student in the Schief laboratory.
Menis therefore devised a tiny virus-mimicking particle made from 60 copies of an obscure bacterial enzyme and coated it with 60 copies of eOD-GT6. The particle worked well at activating VRC01 germline B cells and even mature B cells in the lab dish, whereas single-copy eOD-GT6 did not.
"Essentially it's a self-assembling nanoparticle that presents the immunogen in a properly oriented way," Menis said. "We're hoping that this approach can be used not just for an HIV vaccine but for many other vaccines, too."
The next step for the eOD-GT6 immunogen project, said Schief, is to test its ability to stimulate an antibody response in lab animals that are themselves engineered to produce human germline antibodies. The difficulty with testing immunogens that target human germline antibodies is that animals typically used for vaccine testing cannot make those same antibodies. So the team is collaborating with other researchers who are engineering mice to produce human germline antibodies. After that, he hopes to learn how to drive the response, from the activation of the germline B cells all the way to the production of mature, broadly neutralizing VRC01-class antibodies, using a series of designed immunogens.
Schief also hopes they will be able to test their germline-targeting approach in humans sooner rather than later, noting "it will be really important to find out if this works in a human being."
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The first authors of the paper, "Rational HIV immunogen design to target specific germline B cell receptors," were Jardine, Julien and Menis. Co-authors were Takayuki Ota and Devin Sok of the Nemazee and Burton laboratories at TSRI, respectively; Travis Nieusma of the Ward laboratory at TSRI; John Mathison of the Ulevitch laboratory at TSRI; Oleksandr Kalyuzhniy and Skye MacPherson, researchers in the Schief laboratory from IAVI and TSRI, respectively; Po-Ssu Huang and David Baker of the University of Washington, Seattle; Andrew McGuire and Leonidas Stamatatos of the Seattle Biomedical Research Institute; and TSRI principal investigators Andrew B. Ward, David Nemazee, Ian A. Wilson, and Dennis R. Burton, who is also head of the IAVI Neutralizing Center at TSRI.
The project was funded in part by IAVI; the National Institutes of Health (AI84817, AI081625 and AI33292); and the Ragon Institute.
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Public release date: 28-Mar-2013
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