Thursday, January 31, 2013

3 Things Your Business Should Spend On Before Social Media ...

Smart Business SpendingI have no doubt that you have already seen a dozen posts on the best Social Media tips and tricks for 2013, but before you start writing your must do list of Social Media I want to encourage you to spend money on three different things before you do.

Before I get into the three things you should spend on, I?m not saying that Social Media isn?t worth spending on, what I am saying is that it isn?t the priority that some Social Media ?guru?s? would have you believe.

Customer Service

This should be a no-brainer and yet for some reason here we are in 2013 and still companies think that a great Facebook page or a fun Twitter competition will some how make up for bad Customer Service. I think we can all agree the point of Social Marketing is to tap into the ?Word of Mouth? channel that already exists.

Businesses need to realize that the thing people talk about most is bad experiences and no where more than on Social channels. Investing in outstanding customer service will lead to happy and satisfied customers who are more than willing to recommend you. Zappo?s is often cited as a great example of a ?Social Business?. I call BS on that, what they are is a superbly customer focused business.? Investing in Customer Service is investing in your customers and they will show their appreciation with repeat business and repeat referrals.

Employees

How many times have you had a bad experience with a brand because of the point of human contact you had. Even the most patient of us (I should exclude myself from that statement because I have very little patience) who try to understand that the human being we are interacting with isn?t the company, they just work there and they are probably just following instructions.

The problem is that a lot of companies don?t see the connection between the point of contact and the point of sale. The person at the cash register isn?t just the operator and receiver of customer money. They are the face of your organization. Whether it is a can of beans or a sports car, people buy from people. Investing in employees makes great business sense, but it also makes for great customer experiences. As I pointed out above, providing great customer experiences leads to great customer commentary ? the same thing you are trying to achieve with that Facebook page, Twitter account, Instagram/Pinterest competition.

Education

A few years ago I was listening to Peter Shankman deliver a great session, he made one particular statement that has stuck with me ever since. He said that he was more than willing to pay for anyone who worked for him to take a writing course because communication is at the core of what we do.

He couldn?t be more right, but I would take it further. Invest in education for yourself, for your employees. Teach them skills that your business needs, give them the ability to do more for your business and you will retain them longer. Sure they will leave eventually and you will have to start again, but you?ll have to do that anyway. Investing in them will make them more invested in you. Don?t leave yourself out of the equation either. Many small business owners I have met have never held management positions, suddenly they have employees and beyond telling them what to do they have little or no knowledge about how to get the best from them. Taking a few personnel management/human resources courses at a local college will be an investment you won?t regret.

Those are the three things I would suggest you invest in before Social, what would you add to the list?

I'm glad you took the time to read this post. If you enjoyed it please do me a huge favor and use the share buttons to the left of your screen to spread the word, thank you.
If you enjoyed this post I'm sure you'll enjoy my once a week newsletter - Did You See..? - I'll send you a few stories from around the web that cover Social, Digital and Mobile Marketing that I found useful. It's a quick but informative read

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Source: http://www.theincslingers.com/2013/01/3-things-your-business-should-spend-on-before-social-media/

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Astro to offer Dead Space 3-themed A30 and A40 headsets on February 5th

DNP Astro Gaming releasing Dead Space 3 edition A30 and A40 headsets on February 5th

Just in time for the release of EA's ultra-creepy Dead Space 3, Skullcandy subsidiary Astro Gaming is introducing themed versions of its A30 and A40 gaming headsets. While the headgear remains virtually unchanged, the news here is the addition of six custom magnetic speaker tags that feature tricked-out artwork taken directly from the game. Available on February 5th for $210 (A30) and $260 (A40), both headsets feature Dolby 7.1 virtual surround, a swappable cable system and cross-platform support for Xbox 360, PS3 and PC. However, if you already own this eargear and are just looking to spruce up your cups, you can pick up the tags as a standalone purchase for $20 (A30) and $25 (A40) each.

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Source: Astro Gaming

Source: http://feeds.engadget.com/~r/weblogsinc/engadget/~3/jzjniY8xwvk/

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Stimulating the Brain with Microscopic Magnets

brain, deep brain stimulation, DBS, neurological diseases Image: GEORGE PAUL iStockphoto (brain); ANDREW DAVEY iStockphoto (spark)

  • Showcasing more than fifty of the most provocative, original, and significant online essays from 2011, The Best Science Writing Online 2012 will change the way...

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Imagine if your biggest health problem could be solved with the flip of a switch. Deep-brain stimulation (DBS) offers such a dramatic recovery for a range of neurological illnesses, including Parkinson's disease, epilepsy and major depression. Yet the metal electrodes implanted in the brain are too bulky to tap into intricate neural circuitry with precision and corrode in contact with tissue, so their performance degrades over time. Now neurophysiologists have developed a method of DBS that avoids these problems by using microscopic magnets to stimulate neurons.

In experiments published in June 2012 in Nature Communications, neurophysiologist John T. Gale of the Cleveland Clinic and his colleague Giorgio Bonmassar, a physicist at Harvard Medical School and an expert on brain imaging, tested whether micromagnets (which are half a millimeter in diameter) could induce neurons from rabbit retinas to fire. They found that when they electrically energized a micromagnet positioned next to a neuron, it fired.

In contrast to the electric currents induced by DBS, which excite neurons in all directions, magnetic fields follow organized pathways from pole to pole, like the magnetic field that surrounds the earth. The researchers found that they could direct the stimulus precisely to individual neurons, and even to particular areas of a neuron, by orienting the magnetic coil appropriately. ?That may help us avoid the side effects we see in DBS,? Gale says, referring to, for instance, the intense negative emotions that are sometimes accidentally triggered when DBS is used to relieve motor problems in Parkinson's.

The micromagnets also solve other problems associated with metal electrodes. The magnetic field easily penetrates the magnets' plastic coating, which prevents corrosion and the ensuing inflammation of brain tissue. ?I've been doing DBS research for 14 years now, and this is a totally different way of thinking about activating the brain for me, which is very exciting,? Gale says.

Although the study focused on stimulating neurons, micromagnets could be used to activate other excitable tissues, such as in the heart, inner ear or muscles in our extremities, as part of a pacemaker or prosthetic device. In humans, the micromagnets would be turned on and off by an external control pack, either wirelessly or by connecting to a wire implanted under the skin. A medical company has acquired the rights to manufacture the micromagnets, and if animal research continues to show them to be safe and effective, these devices could be tested in humans within five years, according to Gale.

This article was originally published with the title Stimulating the Brain with Microscopic Magnets.

Source: http://rss.sciam.com/click.phdo?i=4ab41374d3283ce09b6154d60a74d0eb

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Wednesday, January 30, 2013

Minnesota mirrors national trend of declining union membership

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Source: http://www.facebook.com/MinnPost/posts/114819772030748

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I Wish More Companies Had Simple Logos Like This

Inspired by the beautiful typography-centric logos of Japanese cameras in the 70's and 80's, design firm Antrepo re-imagined the logos of tech companies by stripping them down to their essence. What resulted were line-based logos that're clean, light and forever classic. More »


Source: http://feeds.gawker.com/~r/gizmodo/full/~3/UGNBFXm3DE8/i-wish-more-companies-had-simple-logos-like-this

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Government mistrust deters older adults from HIV testing

Jan. 29, 2013 ? One out of every four people living with HIV/AIDS is 50 or older, yet these older individuals are far more likely to be diagnosed when they are already in the later stages of infection. Such late diagnoses put their health, and the health of others, at greater risk than would have been the case with earlier detection.

According to the Centers for Disease Control and Prevention, 43 percent of HIV-positive people between the ages of 50 and 55, and 51 percent of those 65 or older, develop full-blown AIDS within a year of their diagnosis, and these older adults account for 35 percent of all AIDS-related deaths. And since many of them are not aware that they have HIV, they could be unknowingly infecting others.

Various psychological barriers may be keeping this older at-risk population from getting tested. Among them are a general mistrust of the government -- for example, the belief that the government is run by a few big interests looking out for themselves -- and AIDS-related conspiracy theories, including, for example, the belief that the virus is human-made and was created to kill certain groups of people.

Now, a team of UCLA-led researchers has demonstrated that government mistrust and conspiracy fears are deeply ingrained in this vulnerable group and that these concerns often -- but in one surprising twist, not always -- deter these individuals from getting tested for HIV. The findings are published Jan. 29 in the peer-reviewed journal The Gerontologist.

"Our work suggests that general mistrust of the government may adversely impact peoples' willingness to get tested for HIV/AIDS," said Chandra Ford, an assistant professor of community health sciences at the UCLA Fielding School of Public Health and the study's primary investigator. "HIV/AIDS is increasing among people 50 and older, but there's not a lot of attention being paid to the HIV-prevention needs of these folks. Older adults are more likely to be diagnosed only after they've been sick, and as a result, they have worse prognoses than younger HIV-positive people do.

"Also, the CDC recommends that anyone who's in a high-risk category should be tested every single year," she said. "These findings mean that the CDC recommendations are not being followed."

The researchers sought to test the association between mistrust of the government, belief in AIDS conspiracy theories and having been tested for HIV in the previous year. For the cross-sectional study, they worked with data from 226 participants ranging in age from 50 to 85. Participants were recruited from three types of public health venues that serve at-risk populations: STD clinics, needle-exchange sites and Latino health clinics.

Of the participants, 46.5 percent were Hispanic, 25.2 percent were non-Hispanic blacks, 18.1 percent were non-Hispanic whites and 10.2 percent were of other races or ethnicities. The data were collected between August 2006 and May 2007.

The researchers found that 72 percent of the participants did not trust the government, 30 percent reported a belief in AIDS conspiracy theories and 45 percent had not taken an HIV test in the prior 12 months. The more strongly participants mistrusted the government, the less likely they were to have been tested for HIV in the prior 12 months.

Several of the findings surprised the researchers -- for example, the fact that HIV testing rates among this population were not higher at the locations where the participants were recruited, given that these locations attract large numbers of people with HIV.

"This finding is concerning because the venues all provide HIV testing and care right there," Ford said.

And there was an even bigger, perhaps counterintuitive surprise. The more strongly participants believed in AIDS conspiracy theories, the more likely they were to have been tested in the previous 12 months.

"We believe they might be proactively testing because they believe it can help them avoid the threats to personal safety that are described in many AIDS conspiracies," Ford said. "For instance, if I hold these conspiracy beliefs and a doctor tells me I tested negative, I might get tested again just to confirm that the result really is negative."

By contrast, individuals who reported mistrusting the government may not have been tested because the venues where they were recruited were, in fact, government entities, Ford said.

The study has some weaknesses. For instance, the study design did not allow the researchers to determine whether the participants held their beliefs before or after being tested; thus, the researchers couldn't tell what prompted their mistrust of the government or conspiracy beliefs. Also, it's possible that the prevalence of these theories is higher in this group than it is in the general public and that some participants may have been afraid to tell the truth.

The next step in the research is to study other groups of older adults to determine if these views are more widely held than just among the at-risk population the researchers studied.

Steven P. Wallace, Sung-Jae Lee and William Cunningham, all of UCLA, and Peter A. Newman of the University of Toronto co-authored the study.

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The above story is reprinted from materials provided by University of California, Los Angeles (UCLA), Health Sciences.

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


Journal Reference:

  1. C. L. Ford, S. P. Wallace, P. A. Newman, S.-J. Lee, W. E. Cunningham. Belief in AIDS-Related Conspiracy Theories and Mistrust in the Government: Relationship with HIV Testing Among At-Risk Older Adults. The Gerontologist, 2013; DOI: 10.1093/geront/gns192

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

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

Source: http://feeds.sciencedaily.com/~r/sciencedaily/top_news/~3/5R2fZxkn8Ew/130129171343.htm

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Tuesday, January 29, 2013

Cat Refuses Affection, Overtures of Love From Owner

Source: http://www.thehollywoodgossip.com/2013/01/cat-refuses-affection-overtures-of-love-from-owner/

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First ever UK based language tool to decode baby talk under development

Jan. 29, 2013 ? A tool which could radically improve the diagnosis of language delays in infants in the UK is being developed by psychologists.

A ?358,000 grant to develop the first standardised UK speech and language development tool means that for the first time, researchers will be able to establish language development norms for UK children aged eight months to 18 months.

The tool will plug an important gap which has left UK researchers, education and health professionals at a disadvantage.

Until now, UK language experts have been forced to rely upon more complicated methods of testing child language development, or on methods designed for American English speakers which can lead to UK babies being misdiagnosed as being delayed in language development.

The two-and-a-half year project funded by the ESRC will also look into the impact of family income and education on UK children's language development, as well as examining differences between children learning UK English, and other languages and English dialects.

The project is expected to make a major contribution to language development research as well as to the effectiveness of speech and language therapy and improved policy making.

Researchers are keen to hear from parents with children under 18 months to take part in the study.

They are also particularly interested in hearing from English dialect speakers such as families from Scotland and Northern Ireland, and from parents who left school early.

The research team is led by Dr Katie Alcock of Lancaster University's Centre for Research in Human Development and Learning, who will be working alongside fellow language development specialists Professor Caroline Rowland of the University of Liverpool and Dr Kerstin Meints of the University of Lincoln.

They will develop a UK Communicative Development Inventory (UK-CDI) which will consist of a checklist of a wide variety of children's communication abilities in using and understanding speech and gesture, which can be quickly and easily filled in by parents.

Once the tool is developed researchers will use it to carry out large scale studies of babies and toddlers in the UK. This wealth of new UK-specific data will enable parents and professionals to pick up on problems more easily by comparing a child's progress against national averages.

Dr Alcock said: "When we study children's language development, it is crucial to know what a 'typical' child can do, in order to ensure that teachers, doctors, speech and language therapists, and policy makers are properly informed.

"Parents are the very best people to tell us what their child can do and say -- they know the most about their child.

"Most language milestones occur in the first few years of life, so it is vital that we find out what these typical levels are for very young children. However, this is extremely difficult because most language tests cannot be used with very young children.

"Effective tools have been developed abroad but they are not appropriate for UK English speakers. Tools developed in the US, for example, have been shown to give inaccurate results for UK children. One research group for example found that using US scores with UK children would lead to high numbers of UK children being misdiagnosed as language delayed."

"When complete, this new research will directly improve the UK research on child speech and language development and make a substantial contribution to the wellbeing of children and families in the UK."

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

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

Source: http://feeds.sciencedaily.com/~r/sciencedaily/mind_brain/child_development/~3/C7lX8O21ORw/130129130907.htm

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Real angry birds 'flip the bird' before a fight: Biologists use robots to study attacks of male swamp sparrows

Jan. 28, 2013 ? Male sparrows are capable of fighting to the death. But a new study shows that they often wave their wings wildly first in an attempt to avoid a dangerous brawl.

"For birds, wing waves are like flipping the bird or saying 'put up your dukes. I'm ready to fight,'" said Duke biologist Rindy Anderson.

Male swamp sparrows use wing waves as an aggressive signal to defend their territories and mates from intruding males, Anderson said. The findings also are a first step toward understanding how the birds use a combination of visual displays and songs to communicate with other males.

Anderson and her colleagues published the results online Jan. 28 in the journal Behavioral Ecology and Sociobiology.

Scientists had assumed the sparrows' wing-waving behavior was a signal intended for other males, but testing the observations was difficult, Anderson said. So she and her co-author, former Duke engineering undergraduate student David Piech ('12), built a miniature computer and some robotics, which the team then stuffed into the body cavity of a deceased bird. The result was a 'robosparrow' that looked just like a male swamp sparrow, which could flip its wings just like a live male.

Anderson took the wing-waving robosparrow to a swamp sparrow breeding ground in Pennsylvania and placed it in the territories of live males. The robotic bird "sang" swamp sparrow songs using a nearby sound system to let the birds know he was intruding, while Anderson and her colleagues crouched in the swampy grasses and watched the live birds' responses. She also performed the tests with a stuffed sparrow that stayed stationary and one that twisted from side to side. These tests showed that wing waves combined with song are more potent than song on its own, and that wing waves in particular, not just any movement, evoked aggression from live birds.

The live birds responded most aggressively to the invading, wing-waving robotic sparrow, which Anderson said she expected. "What I didn???t expect to see was that the birds would give strikingly similar aggressive wing-wave signals to the three types of invaders," she said. That means that if a bird wing-waved five times to the stationary stuffed bird, he would also wing-wave five times to the wing-waving robot.

Anderson had hypothesized that the defending birds would match the signals of the intruding robots, but her team's results suggest that the males are more individualistic and consistent in the level of aggressiveness that they want to signal, she said.

"That response makes sense, in retrospect, since attacks can be devastating," Anderson said. Because of the risk, the real males may only want to signal a certain level of aggression to see if they could scare off an intruder without the conflict coming to a fight and possible death.

Still, the risk of severe injury or death didn't keep the studly males from swooping in and clawing at the robotic intruder, whether it wing-waved or not. "It's high stakes for these little birds. They only live a couple of years, and most only breed once a year, so owning a territory and having a female is high currency," Anderson said.

She and her team had planned to test how the sparrows use wing waves combined with a characteristic twitter called soft-song to show aggression and fend off competition. But the experiment may be on hold indefinitely because robosparrow's motor seems to be burned out, and its head was ripped off in an attack, a true fight to the death.

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The above story is reprinted from materials provided by Duke University. The original article was written by Ashley Yeager.

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


Journal Reference:

  1. R. C. Anderson, A. L. DuBois, D. K. Piech, W. A. Searcy, S. Nowicki. Male response to an aggressive visual signal, the wing wave display, in swamp sparrows. Behavioral Ecology and Sociobiology, 2013; DOI: 10.1007/s00265-013-1478-9

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/top_news/~3/ojdyQhq8B7c/130129100253.htm

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Monday, January 28, 2013

Purported death threat throws Nevada assembly into uncertainty (reuters)

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Best friends influence when teenagers have first drink

Jan. 28, 2013 ? Chances are the only thing you remember about your first swig of alcohol is how bad the stuff tasted. What you didn't know is the person who gave you that first drink and when you had it says a lot about your predisposition to imbibe later in life.

A national study by a University of Iowa-led team has found that adolescents who get their first drink from a friend are more likely to drink sooner in life, which past studies show makes them more prone to abusing alcohol when they get older. The finding is intended to help specialists predict when adolescents are likely to first consume alcohol, with the aim of heading off problem drinking at the pass.

"When you start drinking, even with kids who come from alcoholic families, they don't get their first drinks from their family," says Samuel Kuperman, a child and adolescent psychiatrist at the UI. "They get their first drinks from their friends. They have to be able to get it. If they have friends who have alcohol, then it's easier for them to have that first drink."

The basis for the study, published this month in the journal Pediatrics, is compelling: One-third of eighth graders in the United States report they've tried alcohol, according to a 2011 study of 20,000 teenagers conducted by the University of Michigan and funded by the National Institutes of Health. By 10th grade, more than half say they've had a first drink, and that percentage shoots to 70 percent by their senior year.

"There's something driving kids to drink," explains Kuperman, corresponding author on the paper. "Maybe it's the coolness factor or some mystique about it. So, we're trying to educate kids about the risks associated with drinking and give them alternatives."

Kuperman and his team built their formula from two longstanding measures of adolescent drinking behavior -- the Semi-Structured Assessment for the Genetics and Alcoholism and the Achenbach Youth Self Report. From those measures of nearly two-dozen variables and a review of the literature, the UI-led team found five to be the most important predictors: two separate measures of disruptive behavior, a family history of alcohol dependence, a measure of poor social skills, and whether most best friends drink alcohol.

The researchers then looked at how the five variables worked in concert. Surprisingly, a best friend who drank and had access to alcohol was the most important predictor. In fact, adolescents whose best friend used alcohol were twice as likely to have a first drink, the researchers found. Moreover, if considered independently of the other variables, teenagers whose best friends drank are three times as likely to begin drinking themselves, the study found, underscoring the sway that friends have in adolescents' drinking behavior.

"Family history doesn't necessarily drive the age of first drink," notes Kuperman, who has studied teen drinking for more than a decade. "It's access. At that age (14 or 15), access trumps all. As they get older, then family history plays a larger role."

The current study drew from a pool of 820 adolescents at six sites across the country. The participants were 14 to 17 years old, with a median age of 15.5, nearly identical to the typical age of an adolescent's first drink found in previous studies. More than eight in 10 respondents came from what the researchers deemed high-risk families, but more than half of the teenagers had no alcohol-dependent parents. Tellingly, among those adolescents who reported having had drunk alcohol, nearly four in ten said their best friends also drank.

The result underscores previous findings that teenagers who have their first drink before 15 years of age are more likely to abuse alcohol or become dependent. It also supports the screening questions selected in the National Institute on Alcohol Abuse and Alcoholism and the American Academy of Pediatrics initiative to identify and help youth at risk for alcohol use, the researchers write.

Kuperman, whose faculty appointment is in the Carver College of Medicine, says he hopes to use the study to delve into the genetics underpinning alcoholism, chiefly tracking adolescents who use alcohol and see whether they have genes that match up with their parents if they also are problem drinkers.

"We're trying to separate out those who experiment with alcohol to those who go on to problematic drinking," he says.

Contributing authors include John Kramer from the UI; Grace Chan and Victor Hesselbrock, University of Connecticut Health Center; Leah Wetherill, Indiana University School of Medicine; Kathleen Bucholz, Washington University School of Medicine in St. Louis; Danielle Dick, Virginia Commonwealth University; Bernice Porjesz and Madhavi Rangaswamy, State University of New York Downstate Medical Center, Brooklyn; and Marc Schuckit (principal investigator on the grant), University of California San Diego School of Medicine.

The National Institutes of Health (grant number: 5 U10 AA008401), the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse funded the study.

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The above story is reprinted from materials provided by University of Iowa. The original article was written by Richard C. Lewis.

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Journal Reference:

  1. S. Kuperman, G. Chan, J. R. Kramer, L. Wetherill, K. K. Bucholz, D. Dick, V. Hesselbrock, B. Porjesz, M. Rangaswamy, M. Schuckit. A Model to Determine the Likely Age of an Adolescent's First Drink of Alcohol. PEDIATRICS, 2013; DOI: 10.1542/peds.2012-0880

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

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

Source: http://feeds.sciencedaily.com/~r/sciencedaily/top_news/~3/BlqvBqU0MNw/130128133136.htm

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Team flag waves as 49ers arrive for Super Bowl

San Francisco 49ers head coach Jim Harbaugh talks with reporters during a news conference on Sunday, Jan. 27, 2013, in New Orleans. The 49ers will face the Baltimore Ravens in the NFL Super Bowl XLVII football game on Feb. 3. (AP Photo/Mark Humphrey)

San Francisco 49ers head coach Jim Harbaugh talks with reporters during a news conference on Sunday, Jan. 27, 2013, in New Orleans. The 49ers will face the Baltimore Ravens in the NFL Super Bowl XLVII football game on Feb. 3. (AP Photo/Mark Humphrey)

A flag is seen outside the plane carrying the San Francisco 49ers as they arrive at the Louis Armstrong International Airport for the NFL Super Bowl XLVII football game Sunday, Jan. 27, 2013, in New Orleans. (AP Photo/David J. Phillip)

San Francisco 49ers head coach Jim Harbaugh makes a face on the team bus after arriving at the Louis Armstrong International Airport for the NFL Super Bowl XLVII football game Sunday, Jan. 27, 2013, in New Orleans. (AP Photo/Pat Semansky)

The San Francisco 49ers arrive at the Louis Armstrong International Airport for the NFL Super Bowl XLVII football game Sunday, Jan. 27, 2013, in New Orleans. (AP Photo/Morry Gash)

Street performer Ruben Moten, a San Francisco native, wears a San Francisco 49ers visor as he performs as a robot on Sunday, Jan. 27, 2013, in New Orleans. The 49ers and the Baltimore Ravens are scheduled to play in the NFL Super Bowl XLVII football game on Feb. 3. (AP Photo/Mark Humphrey)

(AP) ? Jim Harbaugh stepped to the podium, smirked a bit, and greeted his first news conference as a Super Bowl coach.

"We're super happy to be here," he said Sunday night as his NFC champion San Francisco 49ers arrived in the Big Easy for the big game.

"I think this team has the best focus on unity and winning I've ever been a part of."

Considering that Harbaugh was an NFL quarterback for 14 seasons and a successful college coach before joining the 49ers, he knows something about winning.

Under Harbaugh, San Francisco has been to two NFC title games and, now, to its first Super Bowl in 18 years. The Niners (13-4-1) will play Baltimore (13-6), coached by Harbaugh's older brother, John, in next Sunday's Super Bowl.

He is certain his team is ready for the task as the 49ers seek their sixth Vince Lombardi Trophy; they are 5-0 in Super Bowls.

"These are uncharted waters for a rookie Super Bowl coach," Harbaugh said. "But that's exciting. It's a great thrill, and we have a desire to be in uncharted waters. We always strive for that kind of challenge."

Earlier in the evening, with a team flag waving from an open window of their chartered plane, the 49ers arrived in a businesslike manner. The players calmly walked off the airplane ? no video recorders or cameras, no waves to onlookers.

Most of the team's veteran players disembarked first, including center Jonathan Goodwin, who won a Super Bowl three years ago with the Saints.

"You get to go to the Super Bowl with your childhood team, so that's something special to me," he said. "So hopefully I can find a way to win the Super Bowl with my childhood team."

Quarterback Colin Kaepernick, wearing a red wool cap sporting "49ers" on it, mouthed the words to a song on his headphones as he walked on the tarmac.

He seemed just as relaxed 90 minutes later as he met the media.

"Pressure comes from a lack of preparation," said Kaepernick, who took over as the starter when Alex Smith got a concussion in November and has been sensational in keeping the job. "This is not a pressure situation. It's a matter of going out and performing."

Harbaugh said the 49ers came to New Orleans on Sunday to simulate a normal week. He likened their trip to his strategy the last two seasons when the 49ers spent a week in Youngstown, Ohio, between Eastern games rather than return to the Bay Area.

He liked the way the players and coaches bonded during that experience.

"Same approach," Harbaugh said. "Enjoy the moment and the preparation. I think our team enjoys that the most: the meetings, the preparation and then, especially, the competition."

Associated Press

Source: http://hosted2.ap.org/APDEFAULT/347875155d53465d95cec892aeb06419/Article_2013-01-28-FBN-Super-Bowl-49ers-Arrive/id-486b9847e0234a6f9455d1a1a13ec361

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Sunday, January 27, 2013

Australia Day message from the Samuel Griffith Society - Michael ...

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President?s Australia Day Message
Hon Ian Callinan AC

26th January, 2013

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It seems as if each year the Constitution and the cohesion of our Australian community are put at some new and entirely unnecessary risk.? The dangers of the current one, of the introduction of a new law to criminalize speech which might cause offence to anyone, should not be underestimated.? Even the imaginative powers of George Orwell would not have conceived of an administration that would dare to try to forbid every member of society from passing adverse comment upon any other member of it.? The proposed law is such a silly one that it will turn everyone into offenders.? A law of this kind fails the elementary test of rational, consistent, and worse,?undiscriminating application.? In consequence, the cases selected for prosecution will be exactly that, ?selected?, that is to say, carefully chosen, under the influence or pressure of the most vociferous pressure groups.? Every Australian with an ideal of democracy - and I hope that means most Australians - should do everything they lawfully can to oppose the introduction of this outrageous law.? I remain optimistic however that if good political sense does not prevail, and the law is enacted, it will not survive the scrutiny of the courts.

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I wish all Australians a happy and prosperous 2013, after the difficult years that we have experienced, since the GFC.

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The Hon I D F Callinan AC

President

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The Samuel Griffith society website is here.

Source: http://www.michaelsmithnews.com/2013/01/australia-day-message-from-the-samuel-griffith-society.html

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Pilates Health and fitness & TRX Suspension Pertaining to ...

The very good news is: you can fit exercise inside your schedule, and you also DO NOT have to have a fancy gym membership to complete it. Doctors are now said to be urging people to possess gastric bypass procedures to loose weight so they can prevent the complications of diabetes, instead of save the surgery being a last measure it is affordable, an easy task to use and yes it really benefits our health in various ways. Trying to lose weight always offers you an automated trapdoor for escape should you feel it gets to hard.

The calories burned depend for the distance you cover and excess fat greater than another factors. Seek medical health advice when you see blood within your stool buy phen375 discuss why due to the fact are healthy and how they're going to enhance your teen's quality lifestyle, including calcium for strong bones and protein for a good amount of energy. This will aid fat loss during and after your walk.

Medicinal ingredients used to the preparation of this herbal supplement are already employed for centuries to the treatment of reproductive disorders. Without a prescription, it is possible to purchase Tylenol or even a nonsteroidal anti-inflammatory drug Aleve, Advil, Motrin, among others to take care of your symptoms you can still boost the dosage about the third day to 3 capsules two tmes a day, then around the most of 4 capsules twice a day around the fourth day. Obesity is a from the factors responsible for hiatal hernia and acid reflux disorder, so because of this controlling your weight can help manage the symptoms.

Source: http://texacity.com/blog/3587/pilates-health-and-fitness-trx-suspension-pertaining-to-functional-cross-tr/

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Operational Risk Management...: C?: Continuous Continuity in the ...

Many enterprises today understand the myriad of potential threats to its people, processes, systems and structures. It stands to be better equipped for sustained continuity. Business Crisis and Continuity Management (BCCM) is a dynamic change management initiative that requires dedicated resources, funding and auditing.

Certainly the largest organizations realize that the risks are taking on different forms than the standard fire, flood, earthquake and hurricane/twister scenarios. These large catastrophic external loss events have been insured against and the premiums are substantial. What it is less easy to analyze from a threat perspective are the constantly changing landscapes and continuity postures of the many facets of the organization having to do with people, processes and systems.

The many sources of significant loss events are changing as we speak. Here are a few that should not be overlooked:

? Public perception

? Unethical dealings

? Regulatory or civil action

? Failure to respond to market changes

? Failure to control industrial espionage

? Failure to take account of widespread disease or illness among the workforce

? Fraud

? Exploitation of the 3rd party suppliers

? Failure to establish a positive culture

? Failure in post employment process to quarantine information assets upon termination of employees

Frankly, corporate directors have their hands full helping executives managing risk and continuity on behalf of the shareholders.?The risk management process will someday have as big an impact on the enterprise as other key functions because shareholders will be asking more questions about the changing landscape of managing risk for corporate governance.

Since effective BCCM analysis is a 24/7 operation, it takes a combination of factors across the organization to provide what one might call C?, or ?Continuous Continuity?. A one-time threat or risk assessment or even an annual look at what has changed across the enterprise is opening the door for a Board of Directors worst nightmare. These nightmares are ?Loss Events? that could have been prevented or mitigated all together.

Most of the best practices talk about a BCCM plan that will be periodically updated. Periodic is not continuous. Change is the key factor here. What changes take place in your organization between these periodic updates? How could any organization accurately account for all the changes to the organization in between BCCM updates? The fact is that they can?t.

This will change over time as organizations figure out that this is now as vital a business component as Accounts Receivable. The BCCM will become a core process of the organization if it is not already, dynamically evolving by the minute as new change-based factors take place in the enterprise. As new or terminated employees, suppliers and partners come and go into the BCCM process, the threat profile is updated in real-time. This takes the operational management that much closer to C?, or ?Continuous Continuity?.

So what? Boards of Directors have the responsibility to insure the resiliency of the organization. The people, processes, systems and external events that are constantly changing the operational risk landscape become the greatest threat to an enterprise. It?s the shareholders duty to scrutinize which organizations are most adept at ?Continuous Continuity? before they invest in their future.

operational risk

Source: http://operationalrisk.blogspot.com/2013/01/c-continuous-continuity-in-enterprise.html

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Saturday, January 26, 2013

'American Pie' singer fined for speeding in Maine

ROCKLAND, Maine (AP) ? "American Pie" singer Don McLean has been fined $400 for driving his Chrysler too fast through a Maine school zone.

McLean's lawyer says he was driving 43 mph in an area that has a limit of 15 mph when school zone warning lights are flashing and 45 mph when they're not. He argued that the lights were off, but police said in Rockland District Court on Thursday that they were on.

A judge lowered the fine from $515 to $400, and McLean immediately paid up.

McLean lives in nearby Camden, along Maine's coast. He burst into popularity in 1971 with his hit "American Pie," about the deaths of Buddy Holly, Ritchie Valens and the Big Bopper in a plane crash on Feb. 3, 1959 ? The Day the Music Died.

Source: http://news.yahoo.com/american-pie-singer-fined-speeding-maine-222409830.html

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FCC tweaks Broadband Acceleration Initiative to expedite network expansion, temporary cell tower deployment

FCC tweaks Broadband Acceleration Initiative for accelerated deployment, makes erecting temporary cell towers easier

Waiting for LTE to roll out to your neighborhood? FCC Chairman Julius Genachowski understands, and he's trying to speed up the process. The commission's head honcho recently announced new actions to the Broadband Acceleration Initiative, clarifying technical provisions within the Middle Class Tax Relief and Job Creation Act of 2012 that should make mobile broadband deployment a little easier. The crux of the change focuses on how requests to modify existing base stations and wireless towers are reviewed, and is designed to give providers less pause when investing in building out their infrastructure.

"Just as is the case for our nation's roads and bridges, we must continue to invest in improvements to cell towers and transmission equipment, in order to ensure ubiquitous, high-speed Internet for all Americans," Genachowski said in an official statement. "To keep pace with technological advances, such as the advent of small cells, and to lay the groundwork for new developments, our policies must continue to adapt." Speaking of adaptation, the Chairman's announcement also noted FCC efforts to expedite the installation of temporary cell towers, used to bolster network capacity for events like the Super Bowl or Olympics. You wouldn't want to miss tweeting about the half time show, would you? Read on for the Chairman's official announcement.

Show full PR text

FCC CHAIRMAN JULIUS GENACHOWSKI ANNOUNCES NEW BROADBAND ACCELERATION INITIATIVE ACTIONS; CLARIFIES RULES TO SPEED WIRELESS INFRASTRUCTURE DEPLOYMENT; MOVES TO EXPEDITE TEMPORARY CELL TOWERS

Actions would provide more certainty to providers and spur private investment and deployment of critical high-speed Internet equipment

(Washington, D.C.) - FCC Chairman Julius Genachowski today announced new actions as part of the Broadband Acceleration Initiative, a comprehensive effort to remove barriers to broadband build-out, including streamlining the deployment of mobile broadband infrastructure, such as towers, distributed antenna systems (DAS) and small cells.

The Commission defined and clarified a technical provision in the Middle Class Tax Relief and Job Creation Act of 2012 regarding local review of requests to modify an existing wireless tower or base station. This provision will accelerate deployment and delivery of high-speed mobile broadband to communities across the nation. This action will create greater certainty and predictability for providers that today invest more than $25 billion per year in mobile infrastructure, one of the largest U.S. sectors for private investment.

The Commission today also launched a proceeding to expedite placement of temporary cell towers - cells on wheels (COWs) and cells on light trucks (COLTs) - that are used to expand capacity during special events, such as the Inauguration or the Super Bowl.

Chairman Genachowski also announced actions in the coming months to further streamline DAS and small cell deployment; examine whether current application of the tower siting shot clock offers sufficient clarity to industry and municipalities; and begin developing model facility siting rules for localities. Each of these actions would contribute to faster, more efficient deployment of wireless infrastructure.

Chairman Genachowski said, "Providing more certainty to industry and municipalities, and more flexibility to carriers to meet extraordinary, short-term service needs will accelerate private and public investment to strengthen our nation's communications networks. Just as is the case for our nation's roads and bridges, we must continue to invest in improvements to cell towers and transmission equipment, in order to ensure ubiquitous, high-speed Internet for all Americans. To keep pace with technological advances, such as the advent of small cells, and to lay the groundwork for new developments, our policies must continue to adapt."

Comments

Source: http://www.engadget.com/2013/01/26/fcc-broadband-acceleration-initiative/

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Italy's Monti calls for investigation of Monte Paschi scandal

SIENA, Italy (Reuters) - Italian Prime Minister Mario Monti called on Friday for an immediate investigation of a widening scandal at Monte dei Paschi di Siena over the historic bank's losses of nearly $1 billion in a series of complex derivatives deals.

Monti defended the Bank of Italy, whose governor at the time of the losses was Mario Draghi, the European Central Bank chief now facing criticism for failing to spot the trouble brewing at Monte Paschi.

"This episode has to be dealt with the maximum clarity and those responsible have to be dealt with rigorously," Monti told RAI radio.

Monti has promised to address parliament on the matter but he denied the government shared responsibility and said the problems did not affect the Italian banking system as a whole. He expressed "full and total confidence" in the Bank of Italy.

"Italian savers should know, and I think they know, that Italian banks have been among the most solid during the crisis," he said, adding that Monte Paschi was the only bank to be required to boost its capital by European authorities.

The Tuscan bank, Europe's oldest, which is already seeking a 3.9 billion euro ($5.22 billion) government bailout, this week revealed derivatives and structured finance trades that could cost it as much as 720 million euros.

The case has already become a major political issue ahead of national elections on February 24-25 because of historic links between the bank and the centre-left Democratic Party, which is leading in opinion polls.

Bank of Italy Governor Ignazio Visco, under pressure for the central bank's supervision of the case, rejected criticism, saying it had nothing to hide.

"It's wrong to insinuate that there was a lack of supervision by the Bank of Italy," he told CNBC television at the sidelines of the World Economic Forum in Davos.

He said there was no threat to the stability of Monte dei Paschi, which is already under investigation for the expensive acquisition of smaller rival Antonveneta in 2007.

"There is no question that the bank is stable," he said.

However doubts were raised about the Bank of Italy's assertion that it was unaware of the trades at the centre of the scandal by reports in the Corriere della Sera daily.

It quoted central bank documents saying said inspectors had expressed concerns about the monitoring of derivatives as long ago as 2010. No immediate comment on the report was available from the Bank of Italy.

"HIDDEN TRADES"

Monte Paschi shares, which had fallen 20 percent this week, recovered strongly on Friday, rising almost 9 percent as prices rebounded after the recent losses.

In Siena, where Monte Paschi was holding a special shareholder meeting to discuss the scandal on Friday, Chairman Alessandro Profumo said the bank was still evaluating the impact of the derivatives trades on its finances.

But the bank management faced criticism from shareholders enraged by a scandal that has raised the spectre of nationalisation of a bank whose origins go back to the Renaissance and which is synonymous with the beautiful Tuscan city.

"What they did to Monte dei Paschi is worse than Bribesville and Parmalat put together," said Beppe Grillo, head of the anti-establishment 5 Star Movement, who attended the meeting. He was referring to the two biggest scandals in recent Italian history.

"That's the scale of the damage they've done. They've turned the party into a bank and the bank into a party," he said in reference to the Democratic Party's links with the bank.

The case has already forced former chairman Giuseppe Mussari, who left the bank in April, to step down as head of the Italian banking association this week.

The Bank of Italy has said the former management of Monte Paschi hid details of the trades while Visco said the central was working with judicial authorities investigating the case.

"There is no immediate action from the Bank of Italy. We are actively collaborating with the judiciary," he told Reuters.

The latest deals to be revealed are the so-called "Alexandria" trade with Japanese bank Nomura, the "Santorini" trade with Deutsche Bank and a derivative called "Nota Italia", which several sources said was structured by JP Morgan. JP Morgan declined to comment.

The Corriere della Sera said central bank inspectors had expressed misgivings about the supervision of both the Alexandria and Santorini deals.

Findings of a review on the trades are expected to be submitted to the bank's board by mid-February.

($1 = 0.7477 euros)

(Additional reporting by Lisa Jucca in Davos; writing by James Mackenzie; editing by Barry Moody and Giles Elgood)

Source: http://news.yahoo.com/italys-monti-calls-investigation-monte-paschi-scandal-110932712--finance.html

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Friday, January 25, 2013

Super Stocks?Great Companies for Any Stock Market Portfolio

Friday, January 25th, 2013
By Mitchell Clark, B.Comm. for Profit Confidential

Great Companies for Any Stock MarketOver the years, I?ve seen a lot of wacky things in the stock market, from spectacular capital gains to equally spectacular wealth destruction (often from the same companies). Even the best companies on the stock market that offer rising dividends can crash. Remember the dot-coms? Those stocks shot straight upward in value for no other reason than they were just going up. Most became ?dot-bombs.? Then there were the outright frauds?a lot of them, from gold miners to big-name companies to Chinese stocks (most with a big seal of approval from auditors). I know a person that was so scared, so outright certain that the financial world was going to end in 2008, that she just couldn?t take it anymore. She sold every security she owned for cash. She still won?t touch the stock market.

My grandmother also hated the stock market. She thought it was too risky. Of course, living through World War II and the Great Depression influenced her views. For her, nothing counted as much as cash. After the war, times were tough, but they slowly got better. She and my grandfather worked hard, and they saved their money?or rather they didn?t spend. Even in retirement, with no mortgage, she wouldn?t buy fresh bread?too expensive. She just didn?t spend; she saved, because that was her investment philosophy.

Nowadays, cash is still king, but it doesn?t pay any returns. I?m sure there are plenty of seniors who would love to have more of their savings allocated to cash, but artificially low interest rates can?t even beat inflation. A lot of people who are either saving for retirement or are already retired need to have some exposure to the stock market, even if it?s just for the dividends.

I have no idea what?s going to happen to the stock market this year. Looking at recent trading action, there?s probably more upside in the near term. Because corporations are in great shape, we?re likely going to keep seeing increased dividends. This year, there could be another war. There?s the sovereign debt crisis in Europe and the U.S., the potential for currency wars (central banks are now repatriating their gold), and our not knowing how exposed we are to global financial derivatives. Investment risk is high?but life must go on.

There are companies out there that are very good at making money for shareholders. And they pay increasing dividends, which can be reinvested, used for income, or both. Here are some of them: Colgate-Palmolive Company (NYSE/CL), Oracle Corporation (NASDAQ/ORCL), Pepsico, Inc. (NYSE/PEP), International Business Machines Corporation (NYSE/IBM), Canadian National Railway Company (NYSE/CNI), Johnson & Johnson (NYSE/JNJ), Bunge Limited (NYSE/BG), 3M Company (NYSE/MMM), Bank of Montreal (NYSE/BMO), The Procter & Gamble Company (NYSE/PG), Wells Fargo & Company (NYSE/WFC), and The Walt Disney Company (NYSE/DIS). These are the kind of businesses that have proven themselves over time, and I think are worth considering when they?re down in price on the stock market. (See ?Dividends from Blue Chips the Only Game in Town This Year.?) They are great brands that are professionally managed, pay good dividends, and represent underlying businesses with real staying power.

Of course, not every investor looks to the stock market for dividends, and that?s fine. Speculators just want short-term capital gains, so dividends aren?t necessary. All I know is that the business cycle is going to play itself out regardless. In every correction or crash in the stock market, we still need to brush our teeth, eat, and use more essential products and services, such as financial services?and a computer keeps track of it all. But to add to this, corporations need to keep investors interested?that?s what dividends are really for.

Warren Buffett is correct when he advocates that investors should build positions in the stock market over time in good companies that they understand. I like companies that pay increasing dividends, because there is a lot of security there. Plus, reinvested dividends compound wealth faster than you might think. Saving and investing doesn?t have to be complicated. The marketplace has proven that it will reward good, dividend-paying, well-managed businesses. That?s really all you can ask for as an investor.

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Source: http://www.profitconfidential.com/stock-market/super-stocks-great-companies-for-any-stock-market-portfolio/

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5 Staples of the Legal System That Statistics Say Don't Work ...

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Disorder at Work

Proteins without a definite shape can still take on important jobs

By Tanya Lewis

Web edition: January 24, 2013
Print edition: February 9, 2013; Vol.183 #3 (p. 26)

Enlarge

In its unbound state, some parts of the p53 protein take on a definite structure (gray model) while other regions remain flexible and disordered (other colors).

Credit: P. Tompa/Trends in Biochemical Sciences 2012

Richard Kriwacki refused to give up on his protein. He had tried again and again to determine its three-dimensional shape, but in every experiment, the protein looked no more structured than a piece of cooked spaghetti.

Normally, this lack of form would be a sign that the protein had been destroyed, yet Kriwacki knew for a fact it could still do its job in controlling cell division. While discussing the conundrum with his adviser in the atrium of their La Jolla, Calif., lab, insight dawned: Maybe the floppy protein didn?t take shape until it attached to another protein. Kriwacki raced off to do yet another experiment, this time combining his protein, p21, with a partner. Sure enough, Kriwacki got what he was looking for. Once joined, a seemingly ruined mess gave way to a neatly folded structure. The finding defied a foundational dogma of biology, that structure determines function.

Nearly everything the human body does, from shuttling oxygen through the bloodstream to digesting a meal, relies on proteins. These biological workhorses are composed of chains of molecules called amino acids. Whenever a chain is made, conventional scientific wisdom says, electrical forces cause it to immediately bend into helical ribbons and tight zigzags, which twist further into even more defined three-dimensional forms. The resulting shape determines what other molecular players the protein can bind to and thus what it can accomplish in a cell. Unfolded proteins were thought to result only from intolerable conditions that render a protein useless, such as extreme heat or acidity.

But since around the time of Kriwacki?s discovery more than 15 years ago, disorder has surfaced as a key player in the protein world. ?Intrinsically disordered proteins,? or IDPs, turn out to play vital parts in controlling cellular processes. More than one-third of all human proteins, in fact, may be partially or completely disordered in structure, floating around like strands of wet noodles. ?The roles that disordered regions can play are quite diverse,? says Kriwacki, now at St. Jude Children?s Research Hospital in Memphis, Tenn.

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Some disordered protein regions, such as the one below (in purple), take shape once they meet up with another protein (gray).

Credit: H.J. Dyson and P.E. Wright/Nature Reviews Molecular Cell Biology 2005

To better understand how something so flexible can be functional, researchers are now taking a closer look at how the disordered proteins interact with other proteins. The disordered dissidents can behave as switches, quickly turning cellular processes on or off in response to changing conditions, or as shape-shifting ensembles that integrate multiple signals before telling a cell to get a job done. Studying the interactions of intrinsically disordered proteins may even yield insight into certain diseases and lead to new treatments.

Floppiness exposed

Disordered proteins flew under the radar for so long because the standard technique for determining a protein?s structure, known as X-ray crystallography, requires that the protein retain a set shape long enough to be crystallized. Scientists had found a few examples of proteins that couldn?t be crystallized, but these were thought to be anomalies.

When Kriwacki encountered the troublesome p21 protein, he was working with molecular biologists Jane Dyson and Peter Wright at the Scripps Research Institute. Dyson and Wright were using a technique called nuclear magnetic resonance, or NMR, spectroscopy, which reveals a molecule?s form based on the magnetic properties of its atoms? nuclei as opposed to its crystal structure. ?Peter and Jane?s lab at the time was the world-leading protein NMR lab,? says Kriwacki. Advances in NMR were what allowed him to finally figure out what his protein looked like.

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STRUCTURE SPECTRUM

Choosing to label a protein as disordered or ordered is not always straightforward. Some proteins are as wiggly as cooked spaghetti, while others can be mostly structured with just a few regions that dabble in disorder.

Credit: H.J. Dyson and P.E. Wright/Nature Reviews Molecular Cell Biology 2005

After p21, examples of these proteins just kept turning up. You don?t need to go looking for them, Dyson says, ?they?ll come looking for you, believe me.? In 1999, Dyson and Wright published a landmark review paper in the Journal of Molecular Biology that set the stage for a new protein paradigm. There were too many examples to be mere outliers; it was clear that something bigger was going on. ?We were finding that these proteins were not only unstructured, but had to be,? Dyson says.

Meanwhile, other scientists were independently building a strong case for the existence of intrinsically disordered proteins. Keith Dunker, a bioinformatician at Indiana University School of Medicine in Indianapolis, and Peter Tompa, a protein chemist at the Free University of Brussels, were both leading efforts to predict disorder mathematically. ?The main thing we did was to determine that unstructured proteins have a fundamentally different amino acid composition compared to structured proteins,? Dunker says.

A protein?s mix of amino acids can create regions that are either hydrophilic (?water-loving?) or hydrophobic (?water-hating?). Structured proteins that exist in solution typically fold into spherical shapes with a hydrophilic shell enclosing a hydrophobic core. But disordered proteins contain few, if any, hydrophobic regions, so they don?t fold up. They also tend to have more electrically charged portions. ?If you look at these differences, you can anticipate that they?re not going to fold into a 3-D structure,? Dunker says. To help study the differences, he and his colleagues developed ?DisProt,? a database of proteins that experiments have shown to be disordered.

Though scientists often speak of ?structured proteins? and ?intrinsically disordered proteins? as if they are distinct classes, along the way it has become clear that any particular protein?s degree of disorder falls on a spectrum, from precise rigidity to complete disarray. Proteins can also migrate along that spectrum from one moment to another, shifting into different versions of themselves. Many disordered proteins, including p21, eschew their wiggly nature when binding to a partner protein ? like a string puppet snapping to attention. Others fold to a more limited extent upon binding, and some never shape up at all.

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PROTEIN POWER

View larger image | Because of its disorder, a protein known as I?B? can act as a switch that turns a host of cellular behaviors on and off. It?s I?B??s interaction with another disordered protein, NF?B, that makes this regulatory role possible. Source: H.J. Dyson and E.A. Komives/Iubmb Life 2012

Credit: S. Egts

Fold for a cause

How a protein?s degree of disorder enables its function is now a hot topic of research. Ongoing efforts suggest some disordered proteins act like switches, triggering or stopping an action in response to a signal. This makes them well-suited for controlling activities such as the production of other proteins, cell growth or division, and the sending of cellular signals.

Lately, Dyson has been working with Elizabeth Komives of the University of California, San Diego to study a duo of proteins, NF-kappaB and I-kappa-B-alpha. Together, the proteins control a host of vital phenomena in cells, from growth and development to immunity and stress response. The proteins, which both contain disordered regions, normally exist bound together as a complex within a cell. When the cell receives a signal, such as a hormone molecule binding to its surface, I?B? is tagged for destruction and degraded. NF?B is released and sent to the nucleus. There, NF?B binds to the DNA, turning on genes that hold the instructions for making specific proteins.

One of the proteins produced is more I?B?, which allows the response to be switched off again when it is no longer needed. I?B? binds to NF?B and strips it from the DNA, Dyson and Komives reported last year in IUBMB Life. It?s not yet clear how the stripping process works, but the disordered regions of I?B? appear to cast around like a fishing line to find NF?B and peel it off the DNA. The new complex of NF?B and I?B? leaves the nucleus and returns to its resting state within the cell. Thanks in part to the disordered regions, the cell can respond flexibly and rapidly to external stimuli.

Enlarge

Alpha-synuclein, a protein implicated in Parkinson?s disease (spots show abnormal clumping in brain stem), may be disordered in its healthy state.

Credit: S. Rajan/WikiMedia Commons

While NF?B and I?B? become mostly structured upon binding, other IDPs remain highly dynamic. One example is Sic1, a disordered protein found in yeast that prevents DNA replication and thus keeps cells from dividing. A 2008 study led by Julie Forman-Kay of the University of Toronto and then-colleague Tanja Mittag revealed how proteins such as Sic1 function as ?dynamic ensembles? of disordered states. Sic1 contains six short disordered regions that take turns binding in a ?pocket? of a partner protein. At any given moment, only one of Sic1?s six regions sits inside the pocket, while the other regions remain disordered. Each of these six regions is susceptible to modifications that can deactivate it in a way that prevents it from binding. All six of them must be ready to bind for Sic1 to hold onto its protein partner and stave off cell division. Each segment?s activation is like a weight added to one side of a balance ? only with enough weights does the scale tip.

While some disordered regions play active roles in sensitive responses, others serve only to hold more structured areas together like beads on a string. The disordered protein complex CBP/p300 has several structured regions connected by long, floppy ?flexible linkers.? The linkers form a malleable scaffold for bringing together the structured parts of the protein complex, controlling how and when these other players interact.

In sickness and health

Historically, before IDPs took off, anything other than a properly structured protein was considered a disease risk. This was a reasonable conclusion, given that diseases often result when proteins take forms they aren?t meant to, a process called misfolding. Today, though, scientists know that a disordered protein is not the same as a misfolded one.

Still, IDPs, like any proteins, can misfold. And misfolded proteins known to play roles in some high-profile diseases have recently turned out to be disordered. The tau protein, for example, forms the characteristic protein tangles seen in Alzheimer?s disease. Same, it seems, for alpha-synuclein and Parkinson?s disease. Some scientists think disordered proteins may be more prone to misfolding than other types, but the relationship is not yet clear. By understanding the full range of protein folding behavior, scientists hope to gain insight into the causes of such diseases.

Homing in on interactions involving disordered proteins could also lead to new approaches to treatment. Drug developers have traditionally focused on creating molecules that bind to highly structured proteins that carry out reactions in a cell. That means binding to what?s called an ?active site.? But the new understanding of IDPs opens possibilities for designing drugs that instead interfere with protein-protein interactions, by binding to intrinsically disordered proteins or binding to a site on a partner protein where the IDP attaches.

?The idea of targeting disordered proteins themselves remains very challenging,? Kriwacki says. ?Much more feasible is to target binding sites on folded [partner] proteins.? If a short sequence of a disordered protein is known to bind to another protein that triggers a disease state, a small molecule could mimic that sequence, binding to the partner protein and deactivating it. An anticancer drug developed by the pharmaceutical company Roche is made from Nutlin-3a, a chemical that works in just this way. Nutlin-3a prevents an IDP commonly associated with cancer, p53, from interacting with its partner protein.

Of course, scientists? current understanding of disordered proteins assumes that the versions studied in lab dishes are in fact disordered in cells, a notion some researchers challenge.

Disorder doubters

As with any paradigm shift, the idea that proteins can be disordered but still functional has its skeptics. ?I think the majority of people accept disorder,? says Wright, ?but there are still a few critics.? Most studies of IDPs are conducted in lab dishes rather than in living cells, because today?s techniques, for the most part, aren?t sensitive enough to allow the study of proteins at the low amounts present in actual cells. Scientists commonly use bacterial cells to create many copies of a protein. The protein is then isolated and studied under artificial conditions. This has led some researchers to question whether the apparently disordered state of IDPs is merely an artifact of the lab environment. In the true setting of a cell, which is much more crowded with other molecules, the proteins might be folded, the critics argue.

Neuroscientist Dennis Selkoe of Harvard Medical School and colleagues published a controversial paper in 2011 suggesting that alpha-synuclein protein, widely believed to be disordered in its healthy form, actually exists in a structured state inside cells. Selkoe?s team studied alpha-synuclein obtained from human brain cells grown in a lab dish, reporting that the protein appears to occur naturally as a helix-shaped ?tetramer? of four proteins as opposed to a single, unstructured protein.

But the findings are highly contested, and others have failed to replicate them. Philipp Selenko, a biochemist at the Leibniz Institute of Molecular Pharmacology in Berlin, used NMR to show that alpha-synuclein was unstructured inside intact E. coli bacteria. Biologist Guy Lippens of Lille University of Science and Technology in France and colleagues have shown that tau protein, too, appears unstructured in immature frog egg cells. Still, says Lippens, the question of whether all lab-studied IDPs are truly disordered in cells remains open.

Assuming the proteins are unstructured, another mystery is how they evade degradation. Cells have machinery that recognizes proteins that haven?t folded properly and digests them. One theory posits that since IDPs lack regions of the type the degradation system recognizes, the disordered proteins appear to the cell as folded proteins. Another theory holds that ?chaperone? proteins bind to IDPs to stabilize them so they don?t get eaten up by the cell. A third theory suggests that IDPs are tightly regulated and kept at low levels in the cell, broken down when they are not needed. Studying proteins under natural conditions ? in cells ? will help provide the answer.

Despite a growing awareness of disorder in proteins, much more research remains to be done. In this chaotic new view of the protein world, scientists must reexamine everything they have assumed about structure and function. ?Just like in physics,? Tompa says, ?the protein universe seems to have this dark matter we have neglected, which now turns out to be important in cells.?


Loose jobs
Intrinsically disordered proteins, or IDPs, have important regulatory and signaling jobs in cells (some outlined below). Their disorder is thought to make them better at these tasks, by enabling quick and flexible responses to the changing conditions that cells face.

  • Cell cycle activities? Disordered proteins help control when and how a cell grows and divides.

  • Transcription? These proteins turn on and off the copying of genes (DNA) into protein-making instructions (RNA).

  • Translation ?IDPs are involved in the reading of RNA to make proteins.

  • Signal transduction? The flexibility of intrinsically disordered proteins allows them to convert a signal coming from outside the cell into a response that shows up within the cell.

  • Self-assembly of multiprotein complexes? IDPs help bring together different proteins to form larger structures ? such as the ribosome, a molecular machine that serves as the site of protein synthesis.

  • Cargo transport? These proteins play a role in moving large molecules around a cell along the fibers making up the cell?s skeleton.

  • Apoptosis ?Disordered proteins can mediate a cell suicide pathway.

Source: http://www.sciencenews.org/view/feature/id/347758/title/Disorder_at_Work

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