In California, college graduates earn $1.3 million more over their lifetimes tha...


In California, college graduates earn $1.3 million more over their lifetimes than high school graduates. Failing to improve college completion consigns millions to an on-going cycle of poverty and spells economic disaster for our nation. More here: http://bit.ly/UnGc3R

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Romneys paid $1.94 million federal taxes for 2011

Republican presidential candidate and former Massachusetts Gov. Mitt Romney speaks at a campaign fundraising event at Red Rock Hotel and Casino in Las Vegas, Friday, Sept. 21, 2012. (AP Photo/Charles Dharapak)

Republican presidential candidate and former Massachusetts Gov. Mitt Romney speaks at a campaign fundraising event at Red Rock Hotel and Casino in Las Vegas, Friday, Sept. 21, 2012. (AP Photo/Charles Dharapak)

Republican presidential candidate and former Massachusetts Gov. Mitt Romney licks his fingers as he walks back to his seat after making himself a peanut butter and honey sandwich on his campaign plane en route to Las Vegas, Friday, Sept. 21, 2012. (AP Photo/Charles Dharapak)

This handout image provided by the Romney Campaign shows the front page of Republican presidential candidate and former Massachusetts Gov. Mitt Romney and Ann Romney's 2011 tax return. Mitt Romney and his wife, Ann, paid $1.94 million in federal taxes on last year's income of $13.7 million, for an effective tax rate of 14.1 percent, his campaign said. (AP Photo/Romney Campaign)

This handout image provided by the Romney Campaign shows the signature page of Republican presidential candidate and former Massachusetts Gov. Mitt Romney and Ann Romney's tax return. Mitt Romney and his wife, Ann, paid $1.94 million in federal taxes on last year's income of $13.7 million, for an effective tax rate of 14.1 percent, his campaign said. (AP Photo/Romney Campaign)

This handout image provided by the Romney Campaign shows the first of a two page healthcare statement from Republican presidential candidate and former Massachusetts Gov. Mitt Romney's doctor. Mitt Romney's presidential campaign has released a letter from his doctor saying he's healthy and physically fit to meet the rigorous demands of a presidency. (AP Photo/Romney Campaign)

WASHINGTON (AP) ? Mitt Romney, one of the wealthiest candidates ever to seek the presidency, paid nearly $2 million in federal taxes on $13.7 million in income that he and his wife reported last year, his U.S. returns showed Friday. That came to an effective tax rate of 14.1 percent, lower than millions of middle-income Americans but actually more than he had to pay.

Most of Romney's income was from investment returns. That is why his rate was lower than taxpayers whose income was mostly from wages, which can be taxed at higher rates.

Romney's taxes have emerged as a key issue during the 2012 presidential race with President Barack Obama. Romney released his 2010 returns in January, but he continues to decline to disclose returns from previous years ? including those while he worked at Bain Capital, the private equity firm he co-founded.

The Obama campaign and other Democrats have pushed for fuller disclosures, reminding the Republican candidate that his father, George Romney, released a dozen years of returns when he ran for president.

Overall, the Romneys' main tax return and separate forms for blind trusts totaled over 800 pages. The blind-trust income came from hedge funds and other complex investment vehicles. The couple also reported $3.5 million in income "from sources outside the United States," citing "various countries." Their forms included filings on holdings in Switzerland, Ireland, Germany and the Cayman Islands.

The Obama campaign accused Romney anew of profiting from millions invested overseas and "loopholes and tax shelters only available to those at the top."

Apparently hoping to resolve basic questions voters might have, the Romney campaign also released a letter from his accountants saying that in the 20 years prior to 2010 the Romneys paid an average annual effective rate of 20.2 percent, never lower than 13.66 percent. On average, middle-income families ? those making from $50,000 to $75,000 a year ? pay 12.8 percent of their income in federal taxes, according to Congress' Joint Committee on Taxation. But many pay a higher rate.

The former Massachusetts governor, whose wealth is estimated at perhaps $250 million, is aggressively competing with Obama for the support of middle class voters.

Obama's own tax return for last year showed that he and his wife, Michelle, paid $162,074 in federal taxes on $789,674 in adjusted gross income, an effective tax rate of 20.5 percent. Their income plunged from $1.7 million in 2010, with declining sales of the president's books. In 2009, the Obamas reported income of $5.5 million, fueled by the best-selling books.

The Romneys' tax bill could have been lower.

For the year, they claimed a deduction for $2.25 million of their $4.021 million in charitable contributions, said Brad Malt, trustee of the candidate's blind trust.

The Romneys gave $2.6 million in cash to the Church of Jesus Christ of Latter-day Saints, the documents show. They gave just over $2 million in non-cash charitable contributions ? including donations of stock holdings in Domino's Pizza, Dunkin Donuts and Warner Chilcott ? to a family trust.

They could have claimed more in deductions, Malt said, but the couple "limited their deductions of charitable contributions to conform to the governor's statement (n August, based on the January estimate of income, that he paid at least 13 percent in income taxes in each of the last 10 years."

Romney seemed to be painted into a corner by that statement, which came in reaction to Democratic Senate Majority Leader Harry Reid's claim to have heard that the Republican had paid no taxes in some years.

Romney will surely be reminded by the Democrats that he also said in August, defending his right to pay no more taxes than he owed: "I don't pay more than are legally due, and frankly if I had paid more than are legally due I don't think I'd be qualified to become president."

He appears to be physically qualified by any measure.

The campaign released a separate report Friday ? by Romney's longtime physician, Dr. Randall Gaz of Massachusetts General Hospital ? that said he is healthy and ready to meet the rigorous demands of the presidency.

The report said Romney's heart appears healthy, and he takes a baby aspirin and medicine to treat high cholesterol to help keep it that way. He doesn't smoke or drink. And his resting heart rate is a low 40 beats per minute, in the range of well-trained athletes and reminiscent of President George W. Bush, who also had a low resting rate.

Romney is 6 feet 1? inches tall and weighs 184 pounds.

As for his taxes, the Romneys' 2011 rate was slightly above the 13.9 percent effective rate they paid for 2010 when their federal tax bill was about $3 million.

They paid federal taxes of $1,935,708 on income of $13,696.951 for last year, according to the returns filed Friday with the Internal Revenue Service. They had obtained a filing extension beyond the usual April 15 tax deadline. His campaign earlier estimated that he would pay about $3.2 million in taxes for the year, well above the $1.9 million actually paid.

Most of Romney's income is from investments held in a blind trust, and campaign aides have stressed that he makes no decisions on how his money is invested.

Most of the income for the year came from investments, which are now generally taxed at 15 percent whereas the top marginal rate for income from wages is 35 percent.

The Romneys reported $6.8 million in capital gains, such as from the sale of stocks and other securities, and $6.37 million from dividends and taxable interest.

Romney's vast fortune and his long association with Bain Capital have been much discussed this year.

Several tax law experts said Friday that his newly released tax returns would not be much help in resolving critics' questions about his sprawling finances ? whether he used aggressive tax-deferral strategies, what might be the specifics and tax advantages of his numerous offshore investments, what was the source of his massive retirement account and what are the details behind his now-closed $3 million Swiss bank account.

Analysts said details about his investments could emerge only if Romney provided far more of his tax returns ? including files dating back to his years at Bain, the private firm he left in 2001. Romney, who initially refused to disclose any tax returns, has drawn the line at providing those from the past two years.

"All the important compliance and policy questions relating to Romney's personal tax matters relate to the past," said Edward D. Kleinbard, a law professor at the University of Southern California and former chief of staff of Congress' Joint Committee on Taxation. "The issue has never been Romney's 2011 tax return ? in fact, it is a distraction to the real issues."

Only multiple returns would provide details about Romney's $100 million retirement account and how it grew, Kleinbard said. He also earlier returns would be crucial in knowing how often he paid gift tax on family trusts.

Joseph Bankman, a Stanford University law school professor and expert on tax law, said, "It's the Bain years we'd really need to know to have a full assessment of his tax strategies." Bankman said that the 2010 and 2011 returns "only raised these questions, but they can't provide real answers."

The Romneys applied a $1.5 million tax refund to their 2012 estimated tax payments.

The couple reported $190,350 in book royalties and speaking fees. And Romney also reported $260,390 in income last year from serving on various boards of directors.

Republican vice presidential nominee Rep. Paul Ryan of Wisconsin and his wife Janna, whose returns were also released Friday by the Romney campaign, paid $64,764 in taxes on $323,416 of adjusted gross income in 2011, for an effective rate of 20 percent.

Just over half of their income came from Ryan's congressional salary. Other income flowed from rental real estate and other investments, including a trust inherited by Janna Ryan. They donated $12,991 to charity, including to the Boy Scouts of America

___

Associated Press writers Stephen Braun, Stephen Ohlemacher, Kasie Hunt and Philip Elliott contributed.

___

Follow Tom Raum on Twitter: http://www.twitter.com/tomraum. For more AP political coverage, look for the 2012 Presidential Race in AP Mobile's Big Stories section. Also follow https://twitter.com/APcampaign and AP journalists covering the campaign: https://twitter.com/AP/ap-campaign-2012

Associated Press

Source: http://hosted2.ap.org/APDEFAULT/89ae8247abe8493fae24405546e9a1aa/Article_2012-09-21-Romney-Taxes/id-829a1f9750724af0bb1fd252b9ca04ed

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Crittenton Home Care Offers New Hope for those with Parkinson's ...

Parkinson?s disease affects an average of 1.5 million Americans each year making it difficult for patients to walk, talk and perform daily tasks. Imagine a world where loved ones with Parkinson?s disease could enhance their quality of life through a new therapy program that retrains the brain and patient?s body to promote movements that may have been lost due to the disease including tremors, stiffness and muscle weakness. LSVT Global has developed this therapy, and Crittenton Home Care has several certified Physical, Occupational and Speech Therapists offering LSVT LOUD and LSVT BIG.

LSVT BIG Physical and Occupational Therapists focus on ?BIG? body movements and movement patterns where patients are encouraged to follow a specific structure of exercises created for them by their therapist. These exercises focus on expansive movements in an attempt to re-engage neuro-pathways for everyday tasks. These skills help with long-term management of their Parkinson?s.

Amy Kurrle, OTR/L, LSVT-BIG, ?states that ?therapists work to emphasize large, repetitive motions to correct posture and walking as well as improve speed and balance for improved functionality in the ADLs.?

In addition, Crittenton Home Care?s certified LSVT LOUD Speech Therapists focus on increasing loudness and voice quality for speaking. This increases oral and motor control to improve each patient?s vocal clarity. ?I?ve worked in Speech Therapy for more than 20 years and was so excited to see a new therapy offered for Parkinson?s patients,? said Leslie Shablin, Crittenton Home Care LSVT-LOUD Speech Therapist. ?Therapies for Parkinson?s were limited in the past and we?ve see amazing results with this new tool.?

Medication management remains an important tool to living successfully with Parkinson?s but now those affected by the disease can optimize better movement into everyday life. According to a recent survey, at the time of diagnosis patients should begin seeking lifestyle changes and seek education about conventional and alternative treatments to manage their Parkinson?s. LSVT LOUD and LSVT BIG have become ?foundational tools in improving the lives of those with Parkinson?s.

Crittenton Home Care has been providing Certified and Private Duty home care services for more than 25 years in Oakland, Macomb and surrounding counties. Providing a continuity of care approach is the focus of Crittenton Home Care. The organization strives to stand out above other agencies by providing an elite staff of qualified professionals to aid patients in their recovery process.

Both Private Duty and Certified services are provided in the privacy of each patients' home for individuals recovering from an accident, illness or those that may be entering challenging stages of life. Some of the many services Crittenton Home Care provides are: Skilled Nursing, High Tech Services, Physical, Occupational and Speech Therapies, Supportive Personal and Companion care. With the variety of health care issues that clients face, Crittenton Home Care?s goal is to provide a comprehensive care plan to match each unique case. Crittenton Home Care?s commitment is to provide cost effective, quality home care services that are individualized for the client and family.

For more information about Crittenton Home Care, visit www.crittentonhc.com or call 248-656-6757.

LSVT? Global pioneered the Lee Silverman Voice Treatment (LSVT), an innovative and clinically-proven method for improving voice and speech in individuals with Parkinson disease. Today, LSVT Global specializes in the development of innovative and effective treatments for the speech communication (LSVT LOUD) and physical/occupational therapy (LSVT BIG) needs of individuals with Parkinson disease as well as aging and other conditions including stroke, multiple sclerosis, cerebral palsy, Down syndrome. Their mission is to use technology to provide unlimited access to proven treatments for all who can benefit

Source: http://rochester.patch.com/announcements/crittenton-home-care-offers-new-hope-for-those-with-parkinsons-disease-from-advanced-therapy

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Squeeze light 'till it hurts' on a quantum scale: Researchers push the boundaries on ultra-precise measurement

ScienceDaily (Sep. 21, 2012) ? An international team of physicists has pushed the boundaries on ultra-precise measurement by harnessing quantum light waves in a new way.

It is one thing to be able to measure spectacularly small distances using "squeezed" light, but it is now possible to do this even while the target is moving around.

An Australian-Japanese research collaboration made the breakthrough in an experiment conducted at the University of Tokyo, the results of which have been published in an article, "Quantum-enhanced optical phase tracking" in the journal Science.

Leader of the international theoretical team Professor Howard Wiseman, from Griffith University's Centre for Quantum Dynamics (pictured), said this more precise technique for motion tracking will have many applications in a world which is constantly seeking smaller, better and faster technology.

"At the heart of all scientific endeavour is the necessity to be able to measure things precisely," Professor Wiseman said.

"Because the phase of a light beam changes whenever it passes through or bounces off an object, being able to measure that change is a very powerful tool."

"By using squeezed light we have broken the standard limits for precision phase tracking, making a fundamental contribution to science," he said. "But we have also shown that too much squeezing can actually hurt."

Dr Dominic Berry from Macquarie University has been collaborating with Professor Wiseman on the theory of this problem for many years.

"The key to this experiment has been to combine "phase squeezing" of light waves with feedback control to track a moving phase better than previously possible," Dr Berry said.

"Ultra-precise quantum-enhanced measurement has been done before, but only with very small phase changes. Now we have shown we can track large phase changes as well," he said.

Professor Elanor Huntington from UNSW Canberra, who directed the Australian experimental contribution, is a colleague of Professor Wiseman in the Centre for Quantum Computation and Communication Technology.

"By using quantum states of light we made a more precise measurement than is possible through the conventional techniques using laser beams of the same intensity," Professor Huntington said.

"Curiously, we found that it is possible to have too much of a good thing. Squeezing beyond a certain point actually degrades the performance of the measurement, making it less precise than if we had used light with no squeezing."

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Story Source:

The above story is reprinted from materials provided by Griffith University.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.


Journal Reference:

  1. H. Yonezawa, D. Nakane, T. A. Wheatley, K. Iwasawa, S. Takeda, H. Arao, K. Ohki, K. Tsumura, D. W. Berry, T. C. Ralph, H. M. Wiseman, E. H. Huntington, A. Furusawa. Quantum-Enhanced Optical-Phase Tracking. Science, 2012; 337 (6101): 1514 DOI: 10.1126/science.1225258

Note: If no author is given, the source is cited instead.

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

Source: http://feeds.sciencedaily.com/~r/sciencedaily/~3/lJZAZH5YN5I/120921083542.htm

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Arnold Schwarzenegger Will 'Transform' For 'Ten'

'We're going to reinvent the guy. It's going to be a new Arnold,' director David Ayer tells MTV News about his upcoming Schwarzenegger thriller.
By Josh Wigler, with reporting by Josh Horowitz


Arnold Schwarzenegger
Photo: Getty Images

Source: http://www.mtv.com/news/articles/1694139/arnold-schwarzenegger-ten.jhtml

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Intrinsically disordered proteins: A conversation with Rohit Pappu

[ Back to EurekAlert! ] Public release date: 20-Sep-2012
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Contact: Diana Lutz
dlutz@wustl.edu
314-935-5272
Washington University in St. Louis

Students are taught that a protein's 3-dimensional shape is critical to its function, but it turns out that many proteins exist in a state of 'disorder' and yet are functional

If you open any biology textbook to the section on proteins, you will learn that a protein is made up of a sequence of amino acids, that the sequence determines how the chain of amino acids folds into a compact structure, and that the folded protein's structure determines its function. In other words sequence encodes structure and function derives from structure.

But the textbooks may have to be rewritten. As Rohit Pappu and two colleagues explain in a perspective published Sept. 20 in Science, a large class of proteins doesn't adhere to the structure-function paradigm. Called intrinsically disordered proteins, these proteins fail fold either in whole or in part and yet they are functional.

We sat down recently with Pappu, PhD, professor of biomedical engineering and director of the Center for Biological Systems Engineering at Washington University in St. Louis to catch up on the latest science.

When did people realize some proteins violate the rules?

It's been about 20 years. The earliest clue was that some protein segments didn't show up in X-ray crystallography or NMR studies, the standard ways of studying protein structure.

By the 1990s people who studied how proteins interact with DNA had noticed the proteins often change shape when they interact with DNA. In the absence of DNA all the standard probes for protein structure reported back that the proteins were floppy, and yet when the protein formed a complex with DNA it had a well-defined three-dimensional structure.

How did you first come to hear about them?

By serendipity. When I was leaving Johns Hopkins University to come to Washington University in 2001 I had a meeting with Keith Dunker of the Indiana University Schools of Medicine and Informatics, one of the founding fathers of this field. It was pure chance. The meeting started awkwardly because Keith was wondering who I was and I had never heard of him. I was working on a polymer physics description of unfolded proteins, and it turned out he had just written an 80-page review paper on intrinsically disordered proteins.

"Every time you talk to people in the back alleys of protein science," he said, "they tell you their proteins are very flexible or highly dynamic, and this dynamism is important for function."

So Keith did two things. He synthesized all of the information then known about these flexible, highly disordered proteins. And, together with his colleague Vladimir Uversky, he asked if it was possible to predict which sequences would be incapable of folding autonomously. With the help of computer scientists who taught him how to look for patterns in high-dimensional spaces, he learned that 11 out of the 20 amino acids predispose sequences toward being disordered. Today there are about 20 predictors of disorder.

So when I heard this story I thought, "OK, either this is absolutely crackers or it is going to be transformative. I'm going to take a bet on transformative because I find what he's saying compelling."

So during my first two years at Washington University I started to devour the literature. I think I scared a lot of people here who weren't sure they had hired the person they thought they were hiring.

What percentage of proteins are intrinsically disordered?

It goes by kingdoms. So in bacteria and prokaryotic organisms these numbers are pretty small. They're about 5 percent of the proteome, the entire set of proteins made by an organism. But if you go to eukaryotes or multicellular organisms then the numbers get to 30 or 40 percent of the entire proteome.

But if you ask what percentage of sequences that make up the signaling proteome proteins that are busy passing messages to other proteins are intrinsically disordered, then the numbers jump up to 60 to 70 percent.

There seems to be a division of responsibilities. Structured proteins take part in catalysis and transport. Intrinsically disordered proteins are important for signaling and regulation.

Why are disordered proteins involved in signaling and regulation?

I think there are two logical reasons. One is that complexes involving intrinsically disordered proteins are short-lived and the other is that they typically bind many rather than just one molecule.

If a molecule cannot fold except in the context of a complex, then some of the energy used for folding must come from intermolecular interactions. And if the molecule has taken out an energy loan, the complex that forms is not going to be very stable or long-lived.

You're combining high specificity (because the protein will only fold when it recognizes the molecule with which it forms a complex) with low overall affinity (because the complex is not very stable).

The many-to-one interactions arise because disordered proteins typically function through short amino acid stretches instead of large protein-protein interfaces. So a single polypeptide stretch can interact with multiple targets. One motif talks to one protein, and a second motif talks to another protein, but through the chain they can communicate with each other.

That's why these molecules happen to be at hubs within networks. They're trafficking information through networks like the air traffic control tower in an airport hub. Because most of their functions are carried out by these very short motifs, they are capable of coordinating large amounts of information that are disparate in nature. You get many things happening at the same time.

What was remarkable to me about your perspective is that you emphasized functionality of these proteins. Isn't the name a bit misleading?

You're right. As we get to know them better we've thought we should have called disordered proteins, molecular rheostats. But to a physicist disorder just means thermal fluctuations are dominant, so for physicists it's an accurate description. The problem is that in the biomedical field the word disorder has been coopted for disease.

You mention several tricks these proteins have up their sleeves. One I thought was clever was modulating the local chemical environment to encourage a particular reaction.

This is a very important idea. If you're doing chemistry in a test tube, and you want to make a reaction go, you increase the concentration of the reactants: A needs to bump into B and do so often. But this is a matter of probability so you might need a gazillion molecules of A and bazillion of B to get some statistics.

But if there's a tether between A and B, they're guaranteed to bump into each other quite often. You might be able to get away with a handful of molecules instead of gazillion.

The loose tether, in effect, increases the concentration of A around B, and the tether is often a disordered region.

Another thing you mentioned was cryptic disorder: the idea that structured proteins can become disordered. That's such a backward flip.

Richard Kriwacki of St. Jude Children's Research Hospital, a co-author of this perspective, is the person who made the clearest discovery in that regard. He shows that two structured domains can come together this is part of the whole p53 tumor suppressor apparatus and in trying to commingle, they undergo an unfolding transition that exposes sites that otherwise were buried.

This is the idea of cryptic disorder: that domains, by promoting disorder in one another, reveal hidden, or cryptic, motifs or sites that now are available for function.

You mention that in the biomedical community disorder is associated with disease. Your co-author M. Madan Babu of the MRC Laboratory of Molecular Biology in Cambridge has written about this connection.

Yes. Cells make many decisions. They decide to differentiate, to die, to regenerate, or to go quiet ,and these decisions are controlled by regulatory networks. The integrators in the networks are predominantly disordered regions.

So the question is: Will mutations in those regions give rise to unwarranted cellular phenotypes and hence diseases, such as cardiovascular disorders, cancer and neurodegeneration? The answer is absolutely yes.

But what we are learning is that mutations in disordered regions don't necessarily generate a deleterious phenotype because disordered regions are fairly unconstrained compared to structured regions. So these regions are also engines of robustness.

They're more robust to mutation?

At least the one study that looked at cancer mutation would suggest that. It showed that cancer-associated mutations partition toward structured regions of proteins, not toward disordered regions.

Do you think the new awareness of disordered proteins will lead to medical breakthroughs?

Maybe. If I tell you that a disordered protein is at the hub of a network, then it stands to reason that targeting the hub with a drug gives you a ready-made way of controlling a cellular decision.

The only problem is that we don't quite know what it means to target a hub. If a protein has a very precise shape we know how to target it: it's like designing a key for a lock. But if a protein is disordered we have to understand what that means for that particular hub. We also have to be aware that anything that changes the hub will change a range of downstream processes, pathways and cellular decisions.

Nonetheless many people now are talking about these disordered proteins as druggable targets.

Together with Peter Tompa, another of the field's founders, you organized a Gordon Research Conference on disordered proteins this summer. This was a chance for the leading scientists in the field to explore their thoughts off the record. What was the consensus?

It was evident that the more you know the harder it is to draw the order/disorder demarcation. There is a continuum. In fact, many disordered regions do end up adopting structure; they just defer the adoption of structure to the appropriate context.

We wrote the Science perspective because we thought this was the opportune moment to make the point that there is probably evolutionary synergy between the structured domains and the disordered regions, and that synergy is what we really need to wrap our heads around if we are really going to get at how biology integrates signals to control processes and generate responses.

So at the end of the day what you end up with is molecular integrators and it appears that these disordered regions are the molecular integrators.

###


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[ Back to EurekAlert! ] Public release date: 20-Sep-2012
[ | E-mail | Share Share ]

Contact: Diana Lutz
dlutz@wustl.edu
314-935-5272
Washington University in St. Louis

Students are taught that a protein's 3-dimensional shape is critical to its function, but it turns out that many proteins exist in a state of 'disorder' and yet are functional

If you open any biology textbook to the section on proteins, you will learn that a protein is made up of a sequence of amino acids, that the sequence determines how the chain of amino acids folds into a compact structure, and that the folded protein's structure determines its function. In other words sequence encodes structure and function derives from structure.

But the textbooks may have to be rewritten. As Rohit Pappu and two colleagues explain in a perspective published Sept. 20 in Science, a large class of proteins doesn't adhere to the structure-function paradigm. Called intrinsically disordered proteins, these proteins fail fold either in whole or in part and yet they are functional.

We sat down recently with Pappu, PhD, professor of biomedical engineering and director of the Center for Biological Systems Engineering at Washington University in St. Louis to catch up on the latest science.

When did people realize some proteins violate the rules?

It's been about 20 years. The earliest clue was that some protein segments didn't show up in X-ray crystallography or NMR studies, the standard ways of studying protein structure.

By the 1990s people who studied how proteins interact with DNA had noticed the proteins often change shape when they interact with DNA. In the absence of DNA all the standard probes for protein structure reported back that the proteins were floppy, and yet when the protein formed a complex with DNA it had a well-defined three-dimensional structure.

How did you first come to hear about them?

By serendipity. When I was leaving Johns Hopkins University to come to Washington University in 2001 I had a meeting with Keith Dunker of the Indiana University Schools of Medicine and Informatics, one of the founding fathers of this field. It was pure chance. The meeting started awkwardly because Keith was wondering who I was and I had never heard of him. I was working on a polymer physics description of unfolded proteins, and it turned out he had just written an 80-page review paper on intrinsically disordered proteins.

"Every time you talk to people in the back alleys of protein science," he said, "they tell you their proteins are very flexible or highly dynamic, and this dynamism is important for function."

So Keith did two things. He synthesized all of the information then known about these flexible, highly disordered proteins. And, together with his colleague Vladimir Uversky, he asked if it was possible to predict which sequences would be incapable of folding autonomously. With the help of computer scientists who taught him how to look for patterns in high-dimensional spaces, he learned that 11 out of the 20 amino acids predispose sequences toward being disordered. Today there are about 20 predictors of disorder.

So when I heard this story I thought, "OK, either this is absolutely crackers or it is going to be transformative. I'm going to take a bet on transformative because I find what he's saying compelling."

So during my first two years at Washington University I started to devour the literature. I think I scared a lot of people here who weren't sure they had hired the person they thought they were hiring.

What percentage of proteins are intrinsically disordered?

It goes by kingdoms. So in bacteria and prokaryotic organisms these numbers are pretty small. They're about 5 percent of the proteome, the entire set of proteins made by an organism. But if you go to eukaryotes or multicellular organisms then the numbers get to 30 or 40 percent of the entire proteome.

But if you ask what percentage of sequences that make up the signaling proteome proteins that are busy passing messages to other proteins are intrinsically disordered, then the numbers jump up to 60 to 70 percent.

There seems to be a division of responsibilities. Structured proteins take part in catalysis and transport. Intrinsically disordered proteins are important for signaling and regulation.

Why are disordered proteins involved in signaling and regulation?

I think there are two logical reasons. One is that complexes involving intrinsically disordered proteins are short-lived and the other is that they typically bind many rather than just one molecule.

If a molecule cannot fold except in the context of a complex, then some of the energy used for folding must come from intermolecular interactions. And if the molecule has taken out an energy loan, the complex that forms is not going to be very stable or long-lived.

You're combining high specificity (because the protein will only fold when it recognizes the molecule with which it forms a complex) with low overall affinity (because the complex is not very stable).

The many-to-one interactions arise because disordered proteins typically function through short amino acid stretches instead of large protein-protein interfaces. So a single polypeptide stretch can interact with multiple targets. One motif talks to one protein, and a second motif talks to another protein, but through the chain they can communicate with each other.

That's why these molecules happen to be at hubs within networks. They're trafficking information through networks like the air traffic control tower in an airport hub. Because most of their functions are carried out by these very short motifs, they are capable of coordinating large amounts of information that are disparate in nature. You get many things happening at the same time.

What was remarkable to me about your perspective is that you emphasized functionality of these proteins. Isn't the name a bit misleading?

You're right. As we get to know them better we've thought we should have called disordered proteins, molecular rheostats. But to a physicist disorder just means thermal fluctuations are dominant, so for physicists it's an accurate description. The problem is that in the biomedical field the word disorder has been coopted for disease.

You mention several tricks these proteins have up their sleeves. One I thought was clever was modulating the local chemical environment to encourage a particular reaction.

This is a very important idea. If you're doing chemistry in a test tube, and you want to make a reaction go, you increase the concentration of the reactants: A needs to bump into B and do so often. But this is a matter of probability so you might need a gazillion molecules of A and bazillion of B to get some statistics.

But if there's a tether between A and B, they're guaranteed to bump into each other quite often. You might be able to get away with a handful of molecules instead of gazillion.

The loose tether, in effect, increases the concentration of A around B, and the tether is often a disordered region.

Another thing you mentioned was cryptic disorder: the idea that structured proteins can become disordered. That's such a backward flip.

Richard Kriwacki of St. Jude Children's Research Hospital, a co-author of this perspective, is the person who made the clearest discovery in that regard. He shows that two structured domains can come together this is part of the whole p53 tumor suppressor apparatus and in trying to commingle, they undergo an unfolding transition that exposes sites that otherwise were buried.

This is the idea of cryptic disorder: that domains, by promoting disorder in one another, reveal hidden, or cryptic, motifs or sites that now are available for function.

You mention that in the biomedical community disorder is associated with disease. Your co-author M. Madan Babu of the MRC Laboratory of Molecular Biology in Cambridge has written about this connection.

Yes. Cells make many decisions. They decide to differentiate, to die, to regenerate, or to go quiet ,and these decisions are controlled by regulatory networks. The integrators in the networks are predominantly disordered regions.

So the question is: Will mutations in those regions give rise to unwarranted cellular phenotypes and hence diseases, such as cardiovascular disorders, cancer and neurodegeneration? The answer is absolutely yes.

But what we are learning is that mutations in disordered regions don't necessarily generate a deleterious phenotype because disordered regions are fairly unconstrained compared to structured regions. So these regions are also engines of robustness.

They're more robust to mutation?

At least the one study that looked at cancer mutation would suggest that. It showed that cancer-associated mutations partition toward structured regions of proteins, not toward disordered regions.

Do you think the new awareness of disordered proteins will lead to medical breakthroughs?

Maybe. If I tell you that a disordered protein is at the hub of a network, then it stands to reason that targeting the hub with a drug gives you a ready-made way of controlling a cellular decision.

The only problem is that we don't quite know what it means to target a hub. If a protein has a very precise shape we know how to target it: it's like designing a key for a lock. But if a protein is disordered we have to understand what that means for that particular hub. We also have to be aware that anything that changes the hub will change a range of downstream processes, pathways and cellular decisions.

Nonetheless many people now are talking about these disordered proteins as druggable targets.

Together with Peter Tompa, another of the field's founders, you organized a Gordon Research Conference on disordered proteins this summer. This was a chance for the leading scientists in the field to explore their thoughts off the record. What was the consensus?

It was evident that the more you know the harder it is to draw the order/disorder demarcation. There is a continuum. In fact, many disordered regions do end up adopting structure; they just defer the adoption of structure to the appropriate context.

We wrote the Science perspective because we thought this was the opportune moment to make the point that there is probably evolutionary synergy between the structured domains and the disordered regions, and that synergy is what we really need to wrap our heads around if we are really going to get at how biology integrates signals to control processes and generate responses.

So at the end of the day what you end up with is molecular integrators and it appears that these disordered regions are the molecular integrators.

###


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Source: http://www.eurekalert.org/pub_releases/2012-09/wuis-idp091912.php

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Actress in anti-Muslim film to ask for injunction

(AP) ? An actress who appears in the anti-Muslim film trailer that has been blamed for causing riots in the Middle East wants a judge to order YouTube to take down the clip.

Attorneys for Cindy Lee Garcia plan to seek the injunction Thursday against the 14-minute YouTube trailer for "Innocence of Muslims" in a Los Angeles court.

On Wednesday Garcia filed a lawsuit against the filmmaker for fraud and slander, claiming she was duped by Nakoula Basseley Nakoula, the man behind "Innocence of Muslims" who has gone into hiding since the trailer rose to prominence last week.

She said she was unaware of the film's anti-Muslim content and the pages of the script she received had no mention of the prophet Muhammad, religion or sexual content, according to her complaint.

YouTube has refused Garcia's requests to remove the film, according to the lawsuit. The complaint contends that keeping it online violates her right of publicity, invades her privacy rights and the post-filming dialogue changes cast her in a false light. "(Garcia) had a legally protected interest in her privacy and the right to be free from having hateful words put in her mouth or being depicted as a bigot," the lawsuit states.

YouTube said it is reviewing the complaint and its lawyers will be in court on Thursday. The site is owned by search giant Google and has blocked users in Saudi Arabia, Libya and Egypt from viewing the "Innocence of Muslims" trailer. It has also blocked the video from being viewed in Indonesia and India because it violates laws in those countries.

The lawsuit states Garcia responded to an ad and thought she was appearing in an ancient Egyptian adventure film called "Desert Warriors." Dialogue in the amateurish film was later dubbed to include anti-Islamic messages and to portray Muhammad as a fraud, a womanizer and a child molester, and it was also translated into Arabic.

"The film is vile and reprehensible," Garcia's attorney, M. Cris Armenta, wrote in the document. Her client has received death threats since the film's trailer began drawing attention, and she is no longer able to care for her grandchildren, the lawsuit states.

"This lawsuit is not an attack on the First Amendment nor on the right of Americans to say what they think, but does request that the offending content be removed from the Internet," the complaint states.

Garcia, who lives in Bakersfield, Calif., claims her association with the film has harmed her reputation and caused "shame, mortification, and hurt feelings" and will impact her ability to get future acting roles, according to the lawsuit.

A man who answered the phone at the law offices of Steven Seiden, who represents Nakoula on any criminal repercussions he may face, declined comment. He said Seiden does not represent Nakoula, who is on probation for a bank fraud case in which he opened 600 fraudulent credit accounts, in civil matters.

According to the terms of his probation, Nakoula was allowed to only access websites with the permission of probation officials and for work purposes. It is unclear who uploaded the film to the site.

The lawsuit also names Sam Bacile, an alias that Nakoula gave to The Associated Press after the trailer was linked to protests that have since killed at least 30 people in seven countries, including the U.S. ambassador to Libya.

___

Anthony McCartney can be reached at http://twitter.com/mccartneyAP

Associated Press

Source: http://hosted2.ap.org/APDEFAULT/386c25518f464186bf7a2ac026580ce7/Article_2012-09-20-Anti-Muslim%20Film-Lawsuit/id-921bb268282a4757af44c37bd1e17d82

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Tokyo Game Show focuses on social, smartphones

CHIBA, Japan (AP) ? It's not quite game over at the annual Tokyo Game Show opening Thursday, but with smartphones, tablets and other computer-like devices luring people away from the once-dominant consoles devoted to video games, the rules have changed.

Adding to the uncertainty is the long wait for the possible successors to such game consoles as Sony Corp.'s PlayStation 3 and Microsoft Corp.'s Xbox 360 ? perhaps a PlayStation 4 or Xbox 720. Nintendo's Wii U home console goes on sale in November in the U.S. and Europe, and on Dec. 8 in Japan.

"The game industry in general is still very much in a state of flux," said game veteran Mark MacDonald, executive director at Tokyo-based 8-4, which localizes and consults about games, including "Monster Hunter 4," one of the blockbusters displayed at the show.

"Mobile and social games continue to grow, and although some business models have emerged, everyone still seems uncertain of their future. Will they keep growing? Will they be looked back on as a fad? Or are they the future?" MacDonald said.

Some of the booths at Makuhari Messe hall in this Tokyo suburb looked familiar, with big screens running trailers of the latest versions of hit games like "Biohazard" from Capcom and "Final Fantasy" from Square Enix. But some booths also had games for smartphones.

Gree Inc., founded in 2004, has risen to stardom through social games, often played on smartphones, in which players can interact and cooperate with each other. Gree had the second biggest booth at the show after Capcom.

Yoshikazu Tanaka, founder and chief executive of Gree, was not only bullish about smartphones and social games, he said he was also looking to emerging markets for the next wave of growth.

He said game consoles will not catch on in some developing nations, but people there had mobile phones, presenting opportunities for Gree. In a decade, emerging nations will make up 80 percent to 90 percent of the game market, he predicted.

Gree is rapidly growing, tripling its employees to more than 1,800 over the last year. The startup now has overseas offices, including San Francisco, London, Beijing, Sao Paulo and Dubai ? determined to conquer emerging markets, he said.

"If we stop taking up challenges, there is no future. Globalization is a huge opportunity," he said in a keynote speech at the show.

The advent of faster mobile connections, known as LTE or 4G, already available in some parts of Japan as well as the U.S., could pave the way for new kinds of games. A new technology using the Internet called cloud computing also holds potential for games.

"It's not a lost cause. The market is still growing. There are still business opportunities," said Shin Unozawa, vice president of major Japanese game software maker Namco Bandai Games.

He said one of his company's blockbuster Gundam games was offered for free, but raked in 700 million yen ($8.9 million) in revenue by charging for additional playing after the first three free eight-minutes of play per day.

Andrew House, chief of Sony's game business, brushed off worries about losing out to smartphones.

He said the boundaries between game machines and other network-connecting devices were "artificial," and game machines were also enjoying growth because of digital downloads, connectivity and social games.

The introduction Wednesday of the slimmer PlayStation 3 home console with bigger memory storage, key for social games and downloads, was in response to such consumer needs, he said. The new PlayStation 3 goes on sale later this year.

"To equate packaged media's shift to digital to the disappearance of consoles is something maybe of a misnomer," House said. "The pace of change is very rapid. And I think that creates simultaneously a lot of excitement about new possibilities. But it also presents challenges."

___

Follow Yuri Kageyama on Twitter at http://twitter.com/yurikageyama

Source: http://news.yahoo.com/tokyo-game-show-focuses-social-smartphones-075932343--finance.html

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Baby Showers ? Simple but Effective Decorations | The Ultimate ...

I went to a baby shower recently, purely as a guest, whilst visiting?family?in the USA. I was both enchanted and shocked by the WOW! factor as I entered the room.

Enchanted because it was?endearing that somebody could put together so much for their dear friend and arrange so many decorations. Shocked because it didn?t work at all and almost shouted ?IT?S ALL ABOUT BABY!? as I walked through the door. There was so much to take in that it was quite overwhelming. There must have been selections from every theme available, all jumbled up in to a mass of hideousness. Sorry! None of it worked. It looked like a hasty shopping trip, purchasing everything baby-related and shoving it all in to one room. Not good at all.

So, thats how not to do it?. To create a beautiful room, which is as much about mum-to-be as it is about baby then it?s best to be subtle. Less is more. Choose your decorations carefully and select high quality over cheap quantity. I?d much rather see a room with a few thoughtful pieces than a mass of pastels.

Centrepieces always work well and make a table setting look attractive along with themed napkins and beautiful cupcakes and cookies. A table showing off all the favours for the guests to take home makes them feel special and intrigued although no touching until home-time!

Balloons really lift a room and bring a new dimension but don?t go overboard. Some themed baby shower balloons along with pinks, blues, silvers etc look better than lots of clashing colours. Vases of flowers look elegant and feminine, adding a soft touch. Never under-estimate white flowers, they look stunning!

Elegant non-alcoholic drinks

Cute Lamb Cookies

This entry was posted in Uncategorized by Ally Atkins. Bookmark the permalink.

Source: http://www.theultimatebabyshower.co.uk/blog/?p=422

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Free Small Business Consulting Services | Mine Your Biz

We posted on one free small business consulting service about two years ago ( SCORE) so when I ran across an article that mentioned SCORE and four other free small business consulting services I thought it would be helpful for start ups and small business owners who could use some assistance. 5 Resources for Free Business Consulting provides information on these sources.

  1. Small-Business Development Centers
  2. SCORE
  3. National Entrepreneurship Week
  4. MicroMentor
  5. Linkedln

I had heard of SCORE, National Entrepreneurship Week, and Linkedln but did not know anything about the other two resources so I clicked on the links to those sites. I was impressed with the concept behind MicroMentor and there were some great success storied posted on their site.

I also followed the link to Small-Business Development Centers (SBDC), put in my zip code on the home page and found out there were several centers in the St. Louis area with one only 11 miles from me. When I visited the Missouri SBDC website I was very impressed with all the online resources and many training events scheduled throughout Missouri in September.? If Missouri is typical of the resources available by state, I think it would be well worth a visit by any small business owner.

This entry was posted in General Business, Uncategorized. Bookmark the permalink.

Source: http://www.mineyourbiz.net/2012/09/free-small-business-consulting-services/

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