Many celebrities have had a little work done, but some drastically changed their appearance! A rhinoplasty, or more commonly known as a nose job, can make a huge difference in a person’s looks and we have the photos to prove it. Let’s check out some Hollywood stars that went under the knife to either make ...
The iPad is a great tablet for many things, whether you're getting your game on or getting serious work done. Just because it's a tablet doesn't mean you have to give up the flexibility of using it like a laptop, after all, the beauty of buying a tablet is that you can have one device capable of doing multiple things well. To that end, last week we asked you which iPad keyboards and cases you thought were the best available. You responded, and we took a look at the five best iPad keyboards and put them to an all-out vote. Now we're back to highlight the winner.
The Logitech Ultrathin Keyboard Cover for iPad took the top spot far and away with over 44% of the total vote. Those of you who voted for it praised its flexibility, battery life, super-thin profile, and the fact that the keys are comfortable to work with but the cover doesn't add a ton of bulk to your tablet.
Behind it in second place, with 17% of the votes cast, was the Zagg Folio, a thicker but more protective option with deeper keys and a full-body case and stand to go with it. In third place was the Logitech Tablet Keyboard, a tiny and portable Bluetooth keyboard in a case that doubles as a tablet stand, with over 15% of the vote. stand, with over 15% of the vote. With close to 12% of the vote, The Brydge took fourth place, shaking off its price point and winning over many of you with its aluminum body, built-in speakers, and tons of useful features. Behind it in fifth though, short by only nine votes, was the full-body ClamCase, coming in with 11% of the votes cast.
The Hive Five is based on reader nominations. As with most Hive Five posts, if your favorite was left out, it's not because we hate it?it's because it didn't get the nominations required in the call for contenders post to make the top five. We understand it's a bit of a popularity contest, but if you have a favorite, we want to hear about it. Have a suggestion for the Hive Five? Send us an email at tips+hivefive@lifehacker.com!
Of all the performers whose diaries we'd love to read, Amy Poehler is way up there. Lucky for us, she's decided to share them. The Parks and Recreation star has signed a deal for what the publisher describes as "her original twist on the conventional memoir."
The space mining buzzing is increasing lately. "Everyone on Earth would be a billionaire if we use the resources in the asteroid belt" claims R. Branson.
Well Richard, are you going to tell me that if we assimilate the resources the result won't be a handful of gazzilionares that will order planets at Magratea and the rest of us would slave it "Blade runner style". You wanna tell me that magically, incredibly our socioeconomic system will disappear overnight? Provided that by definition the people who can change the system are the greatest benefactors of it, so why will they want to change it?
A billion dollars will be pocket change? How much of it will "trickle down" to my "middle class, ever decreasing buying power because of financial frauds by greedy people" pocket, Richard? It does not matter at all how much resources we can lay our hands on. We will grow, expand, waste them even more recklessly as we do now and eventually finish them off....while all the evils of the socioeconomic system will be with us all the time. Don't fool yourself Richard. Don't try to fool me too!!
But you know, Richard, actually your lie is the way to go from purely egoistic, survival point of view. If we want to make it to the Star Trek era [in one piece] we have to change and I don't mean Obama's change here. I mean paradigm change. I mean the simplest idea of all time - limited growth in an practically infinite Universe. Everyone has their human needs fulfilled. That's just the starting point.
All the above is why I stopped being excited about technology news whatsoever. We made an engine that uses half the fuel? Well, we will just buy twice as many engines because they will be cheaper and besides the whole fraking world including politics, business and religion (but not art and science mind you) constantly, relentlessly screams "more people, more money, only infinite growth is possible, if we stop wasting ever more the economy will collapse, the world would burn and we will be back to the caves, we need more growth, more children or our pensions will be gone, we need more believers in the true faith, we need more, more, more, more, more.....).
Our civilization has no redundancy, no back-up, no long-term planning at all. It is the sloppiest piece of engineering of all time.....no decent geek would ever dream of putting his/her signature on such a piece of crap! And we all live by it, die by it, are run by it! It's horrifying that we first waste the most accessible and the least replaceable resources. That is the way of our system; nothing in it that contradicts this behavior survives. We are re-active not pro-active. Our leaders never lead, they follow, adapt and mimicry.
I will finish this rant by respectfully altering the last sentence from Richard Feinman's "addendum" to the NASA report about the Challenger disaster:
"For a successful civilization reality must take precedence over politics, business and religion *, for Nature cannot be fooled"
* politics, business and religion all operate without any regard of reality [they are all ideologies] and are therefore in the form they are, highly dangerous for the survival of Homo Sapiens
CARACAS, Venezuela (AP) ? Venezuelan authorities on Sunday finished evacuating inmates from a prison where 61 were reported killed in one of the deadliest prison clashes in the nation's history.
Penitentiary Service Minister Iris Varela said in a message on Twitter that the evacuation of Uribana prison in the city of Barquisimeto was completed on Sunday morning. Inmates were loaded aboard buses and driven to other prisons.
Varela posted photos of inmates filing out led by authorities, and said that what will come next for the prison is "now the reconstruction!"
Two days after the violence, government officials had yet to provide an official death toll from the fierce gunbattles, which pitted armed inmates against National Guard troops.
Dr. Ruy Medina, director of Central Hospital in the city, told The Associated Press on Saturday that the death toll had risen to 61, while about 120 were wounded in the violence.
Medina said that nearly all of the injuries were from gunshots and that 45 of the estimated 120 people who were wounded remained hospitalized.
Relatives wept outside the prison during the violence, and cried at the morgue as they waited to identify bodies.
The riot was the latest in a series of deadly clashes in Venezuela's overcrowded and often anarchical prisons, where inmates typically obtain weapons and drugs with the help of corrupt guards. Critics called it proof that the government is failing to get a grip on a worsening national crisis in its penitentiaries.
The gunbattles seized attention amid uncertainty about President Hugo Chavez's future, while he remained in Cuba recovering and undergoing treatment more than six weeks after his latest cancer surgery.
Government officials pledged a thorough investigation, while some critics said there should have been ways for the authorities to prevent such bloodshed.
The riot was the deadliest in nearly two decades. In January 1994, more than 100 inmates died in the country's bloodiest prison violence on record when a riot and fire set by inmates tore through a prison in the western city of Maracaibo. In 1992, about 60 inmates were killed in a riot in a Caracas prison.
Varela said that the violence erupted on Friday when groups of inmates attacked National Guard troops who were attempting to carry out an inspection. She said the government decided to send troops to search the prison after reports of clashes between groups of inmates during the past two days.
"No one doubts that inspections are necessary procedures to guarantee prison conditions in line with international standards, but they can't be carried out with the warlike attitude as (authorities) have done it," said Humberto Prado, an activist who leads the Venezuelan Prisons Observatory, a watchdog group.
"It's clear that the inspection wasn't coordinated or put into practice as it should have been. It was evidently a disproportionate use of force," Prado said.
In 2011, when Chavez had been in office for 12 years, he created a Cabinet ministry to focus on prisons and appointed Varela to lead it. The president made that decision following a deadly, weekslong armed uprising at the prisons El Rodeo I and El Rodeo II outside Caracas.
Chavez at the time acknowledged that his government's previous initiatives to improve the prisons hadn't worked, and he pledged changes including building new prisons, improving conditions and speeding trials. Since then, Chavez has approved funds to repair and renovate prisons. But opponents and activists say the government hasn't made real progress at penitentiaries where hundreds continue to die each year.
Venezuela has 33 prisons built to hold about 12,000 inmates. Officials have said the prisons' population is currently about 47,000.
___
Associated Press writers Vivian Sequera in Bogota, Colombia, and Jorge Rueda in Caracas contributed to this report.
Hugh Mitchell can still see it ? 7,000 people on their feet, leaning out against the rail, and the wall of sound as they cheered.
?It was almost deafening. I was a kid, and the horses were running to the wire. It was so exciting There was an energy,? said the chief executive of Western Fair Raceway.
?My mom and dad would drag me to Western Fair when I was about 10 years old. I remember it like it was yesterday, the horses grunting down the track. It was the soaring ?60s and sizzling ?70s, the only form of true gaming then. It had a monopoly and it prospered.?
Today, it?s different. Crowds are sparse, and the industry is on the cusp of change that will forever alter the sport, and perhaps the agricultural and rural culture.
Mitchell compares the atmosphere at the track then to Budweiser Gardens today when everyone cheers a London Knights goal ? another thing he knows a little about, as he captained the Windsor Spitfires in the mid-1970s and played college hockey for the Guelph Gryphons.
He finished his university career with a degree in agricultural business. ?You learn the financial management side of the business, you learn about the agricultural sector,? he said.
That comes in handy at Western Fair, which has not just the track and agricultural shows, but also four pads of ice for hockey, combining his passions, he adds.
After graduating from Guelph, Mitchell?s first job was with Purina in Woodstock, selling animal feed in surrounding counties.
He moved on to become agricultural manager of Western Fair, beginning a back-and-forth experience during which he returned to Purina as marketing manager, then back to Western Fair to be raceway manager before becoming assistant general manager.
In 1998, Toronto?s Woodbine Raceway made him vice-president of standardbred racing.
?My love of racing drew me to work at the premiere racetrack in Canada and it was a huge responsibility. I am always looking to take on more responsibilities and workloads,? he said.
Western Fair again called Mitchell and he returned in 2005 as chief operating officer, becoming chief executive in 2009.
But if there?s been one constant in his life, it?s been horses. He grew up in Lambeth, son of a veterinarian who worked at Western Fair Raceway; that?s how, at the tender age of 10, he first experienced screaming racing fans.
The horse influence runs deep in the family ? his brother is a veterinarian in New Jersey.
Mitchell also has two horses, Nash and Mattie, on his eight-?hectare Delaware-area hobby farm.
?I was hooked on horses. I loved them even at a young age.?
Mitchell, who had a front-row seat for the sport?s heyday, has one for what may be its decline.
?It became very competitive and racetracks are very expensive,? he said of the decline that began in the 1980s, when greater competition arose for the gambling dollar. ?It takes a huge piece of land, a lot of bricks and mortar, and it is very labour-intensive.?
In the 1990s, the Slots at Racetrack Program was implemented. Tracks were given money for slot machines the province installed at tracks. Knowing slots would hurt racing?s bottom line, the province doled out part of slot profits to the horse industry as compensation.
At Western Fair, the track has received $10.5 million and the horse industry and purses another $10.5 million, while the province has taken in $75 million and the city about $4 million.
Ontario will announce a new funding plan in which it will give less to tracks and the industry. Many fear it may kill what?s left of horse racing in Ontario, a $2-billion?-a-year industry, with about half the tracks shut down.
But Mitchell, remains optimistic, saying the changes are painful, but necessary.
?Once we get our industry right-sized and refocused on the customer, we may have a chance to prosper,? he said.
--- --- ---
Hugh Mitchell
58 years old
Chief executive, Western Fair Raceway
Raised in Lambeth
Sir Wilfrid Laurier secondary school
University of Guelph, degree in agricultural business
Earlier today Facebook ecommerce platform Payvment announced it was shutting down and transitioning its 200,000 merchants to competitor Ecwid, but we've just discovered that's because Intuit is acquiring Payvment's team, technology, and patents. Several Payvment employees have already changed their LinkedIn profiles to show Intuit as their new home.
Streaming video is the future. Well, it's the present, but the future too. And as resolutions increase, it's going to be a tougher and tougher proposition to pipe all that data to your screen of choice in a timely fashion. Fortunately, the new H.265 standard has been approved by the ITU and it's here to help. More »
KONNA, Mali (Reuters) - French special forces in Mali with air support on Saturday seized the airport and a key bridge over the Niger River at the Islamist rebel-held stronghold of Gao as France accelerated its ground offensive against al Qaeda-allied fighters.
"The rebels have melted in to the local population. There is harassment. The operation is still under way. It is a bit complicated," a French officer in Mali, who asked not to be named, told Reuters, referring to the assault on Gao.
France's Defence Minister Jean-Yves Le Drian announced the seizure of the airport and bridge at Gao, the largest town in Mali's Saharan north which was occupied last year by a coalition of Islamist groups including al Qaeda's North African wing AQIM.
France's defense ministry initially gave few details of the operation at Gao, but there were unconfirmed reports from Malian sources that it involved French paratroops.
The French officer said the attacking French forces were facing "harassment" attacks but no solid line of resistance.
The speed of the French action at Gao suggested French and Malian government troops intended to drive aggressively into the north of Mali in the next few days against other Islamist rebel-held towns, such as Timbuktu and Kidal.
For two weeks, French jets and helicopter gunships have been harrying the retreating Islamists, destroying their vehicles, command posts and weapons depots. The French action had already halted a sudden Islamist offensive launched in early January that had threatened Mali's southern capital Bamako.
A French defense ministry statement quoted minister Le Drian as saying that many of the Islamist fighters' vehicles and logistics bases had been destroyed.
News that the French forces were at Gao came as African states struggled to deploy a planned 6,000-strong African intervention force in Mali, known as AFISMA, under a U.N. mandate.
African Union leaders meeting at a summit in Addis Ababa were calling on the United Nations to provide emergency logistics and funding to allow the AFISMA force to deploy.
AU officials say AFISMA is severely hampered by logistical shortages and needs airlift support, ammunition, telecoms equipment, field hospitals, food and water. It also required training to operate in Mali's desert and arid mountains.
So far, only around 1,200 soldiers of the African force, to be mostly comprised of troops from neighboring West African nations, have arrived in Mali.
In contrast, France has 2,500 soldiers already on the ground in its former colony, taking the lead in the offensive against the Islamist groups.
The United States and Europe strongly back the U.N.-mandated Mali operation as a counterstrike against the threat of radical Islamist jihadists using the country's inhospitable Saharan north as a launch pad for international terrorist attacks.
But Washington and European governments, while providing airlift and intelligence support to the operation, are not planning to send in any combat troops.
(Reporting by James Regan in Paris, Richard Valdmanis in Konna, Mali and David Lewis in Dakar; Writing by Pascal Fletcher)
In Business Finance Store?s latest blog post, author Brentt Taylor discusses how small businesses can use home equity loans for small business growth.
Santa Ana, CA (PRWEB) January 22, 2013
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Tim Berners-Lee, the inventor of the hyperlinked World Wide Web, isn?t entirely happy with what he has helped create ? and has thrown down the gauntlet to web developers to come up with more disruptive forms of online communication that can break down cultural not just geographical barriers.
Talking about the web as it is today, rather than the ?collaborative tool? he originally designed, he said:??World peace has not miraculously occurred. People still mainly talk to their neighbours, people still mainly talk to the people who have the same religion, and the same culture, so for all its breaking down geographical boundaries in principle it hasn?t really broken down cultural boundaries.?Can we develop systems on the web which will actually help solve that sort of ?challenge??
Berners-Lee was speaking in an interview at the World Economic Forum today,?entitled ?what?s wrong with social networking?? but he joked the title had been cooked up merely to draw in the crowds.
?As a universal platform the web wasn?t supposed to dictate what you did with it,? he told his audience in Davos. ?The world wide web is a platform and humanity does what it can with it??There?s lots of people who think we could do more. What do we really want to get out of this web thing? What do we really want to get out of human communication??
While it began as a collaborative tool, the web subsequently took off as a publishing medium ? or it did to a ?certain extent?, said Berners-Lee, pointing to the fact that publishing online remains a relatively elite activity and therefore, again, does not live up to his original collaborative vision for a truly global web.
?We?ve got wikis, we?ve got blogs, but still most people? aren?t publishing on the web. And actually when you go to most places you?re not in a position where you can take place in the conversation very much. Sometimes you can comment but actually the comment tends to be at a second level,? he said.
Asked about the erosion of online openness threatened by walled garden social networks, Berners-Lee said the networks both help humanity by providing the data that enables computers to help people but also highlighted how there is ?a lot of frustration, from a lot of people? that they can?t connect up the personal data they have entered into different services in all the ways they might like to.
?Each of these social network systems is a silo so there is a frustration that I?ve told it all my data but I don?t have access to that,? he said.
Despite yearning for more openness and fewer shackles stifling the free flow of online data, Berners-Lee was careful to say he was not calling for an online data free-for-all. There do need to be ?reasonable boundaries?, he accepted ? whether it?s sensitive personal or government or military data. ?The web isn?t about just sharing everything, destroying privacy? [but] if I want to share something with you it shouldn?t be the technology that gets in the way.?
Turning to the economic argument, Berners-Lee conceded there is a problem with current online business models ? especially when it comes to finding ways to pay musicians. The web should be ?about spreading culture, music and getting payment back to musicians?, he said. ? We?ve got to find new ways of doing that.?
Specifically he called for new protocols to be developed to support online payments. ?We need to find a whole lot of new business models ? I think we should develop new payment protocols so that when you?re using a web browser it?s a lot easier to pay for things.?
He also argued for the economic value in opening up data that is unnecessarily locked away, pointing to a U.K. initiative to open up government data so that the citizens who have paid for the data to be created in the first place can have the benefit of using it ? and use it to create new businesses. ?You?re making a great common good, that?s making the world run more efficiently,? he argued.
Likewise, he argued that the benefit to humanity of opening up scientific data ? to ?scientists everywhere? ? would be ?huge?.??It?s a?question of unlocking this potential that we really already have ? it?s getting huge benefit for very little cost,? he said.
Berners-Lee was also asked about Internet activist?Aaron Swartz, who was arrested for downloading academic journals and subsequently committed suicide ? and argued that Swartz?s tragedy is an example of what can happen when ?legislation gets too strong?.
?He was an incredibly ethical person. He thought a huge amount about what was right and how the world should be? but because [the FBI] saw that what he was doing was accessing a computer system there seems to be a deep suspicion of that,? he said.
?He used his programming to try to make a point, in a way as a protest. But they ended up using a very unfair law which had been changed from its original form which said that if you break into a computer system in any way then you are guilty of a felony? ?People are thinking now about that law, and there already proposals to change it.?
?To be a hacker ? when I use the term ? is somebody who is creative and does wonderful things,? Berners-Lee added. ?We need more coders, we need more people who understand how to put data online.?
A graduate of Oxford University, England, in 1989, Tim Berners-Lee invented the World Wide Web, an internet-based hypermedia initiative for global information sharing while at CERN, the European Particle Physics Laboratory. He wrote the first web client and server in 1990. His specifications of URIs, HTTP and HTML were refined as Web technology spread. He is the 3COM Founders Professor of Engineering in the School of Engineering with a joint appointment in the Department of Electrical Engineering and Computer Science...
Republican National Committee Chairman Reince Priebus. (Scott Olson/Getty Images)
CHARLOTTE, N.C. -- Republican National Committee members gathered here to re-elect Chairman Reince Priebus for a second term. But by week's end, that vote seemed secondary to the question of the party's long term survival.
After three months of denial, anger, despair and depression over the results of a bruising national election that gave Democrats an edge in Congress and kept President Barack Obama in the White House, Republicans know they must adapt if they are to move forward.
They acknowledge that it's time for a serious gut check. (Or as Haley Barbour put it in November, a "proctology exam.")
Whatever bodily metaphor you choose, the fact remains that the election so jolted and shocked the party that it is taking real steps to change.
And change they will! As soon as they figure out how.
While Republicans in Virginia and other battleground states launched an effort this week to alter electoral college rules so that votes are doled out proportionately--which would likely give the GOP at least a short term edge--GOP leaders here discussed their party's own shortcomings and sought areas of internal improvement.
Almost every conversation in the bar of the Charlotte Westin Hotel this week involved a discussion about what the party must do to win the next elections. Floating through the air is a desire to re-capture glorious days of the past, a challenge made difficult by a country that refuses to stand still. Demographics are changing, minorities are growing in political influence and views on social issues like gay marriage are drifting rapidly leftward. Something's got to give.
Bring in The Bobs
Enter the RNC's five-person "Growth and Opportunity" committee, an ethnically diverse cadre of political veterans and RNC members analyzing what the party must to do avoid another 2012-like drubbing. (Think of them as "The Bobs" from Office Space, but with American flag lapel pins.)
The group includes Henry Barbour, a Mississippi committeeman and Haley Barbour's nephew; former George W. Bush White House spokesman Ari Fleischer; Florida strategist Sally Bradshaw; South Carolina committeeman Glenn McCall and Puerto Rico committeewoman Zori Fonalledas. They will submit a detailed report in March that looks back on the 2012 election and forward to 2014 and 2016.
"You're going to see a very renewed aggressive effort by this party to put on a different face," Bradshaw said Thursday. "We've got to find a way to take our message to more people and get more votes. It's not a particularly complicated formula. We got beat; we have to change what we're doing."
The report is a work in progress, and only part of it will be made public, but The Bobs delivered an update on their findings Thursday to the RNC members.
First, they said Republicans must work on improving their tone when taking their ideas to the American people. For example, when discussing immigration, maybe presidential candidates should avoid phrases like "self-deportation" (Mitt Romney) and "anchor babies" (Michele Bachmann.)
Henry Barbour said some in the party can appear "hostile" to certain constituencies with the rhetoric they use. The party must increase communication training for candidates, he said.
"There are certainly too many times when we've had candidates who have come across as hostile and that's not really helpful when you're trying to win elections," Barbour said.
Robert Bennett, chairman of the Ohio Republican Party, was even more blunt.
"We need to understand that we can't come off as a bunch of angry white men," he said.
Minority 'engagement' a top priority
Making an honest effort to engage minorities was above anything else the main, yet unofficial, focus of party leaders this week.
On Thursday, committee members took part in a closed-door panel discussion on minority engagement. Edward Cousar, a black committeeman from South Carolina who sat on the panel, said white Republicans struggle in part because they spend too much time with other white Republicans. They have little idea how to speak or interact in a way that appears welcoming to outsiders who come from different ethnic and social backgrounds.
"People get set in their ways, and maybe they don't have a diverse set of friends and they say things," Cousar told Yahoo News in an interview before the panel. "It's not that they're being racist, they just don't know."
Cousar, who leads the Black Republican Political Action Committee, pointed to past Republican efforts to suppress early voting--"shameful," he said-- and Mitt Romney's writing off of 47 percent of the country as un-winnable.
"I always thought Romney had better policies," Cousar, who is the only Republican in his family, said, comparing Romney and Obama. "But he was a horrible messenger."
In November, Obama won more than 70 percent of the Hispanic vote and more than 95 percent of black voters supported him. Single women also fled the Republican party on Election Day, with about two-thirds supporting the Democrat. It's a serious problem for Republicans, one they admit will take a lot of time to overcome.
"It's not going to happen overnight," said McNall, a black member of the study group. "But it can be done and we're going to make that effort."
No more witches
Part of that effort relies heavily on recruiting quality candidates, many attendees said.
For the past four years, Republicans have faced a series of disappointing setbacks after mediocre candidates-- often tea party favorites--have gone on to lose very winnable elections.
They include Todd "Legitimate Rape" Akin, who lost a Missouri Senate race last year and forced Romney and other Republicans on the defensive over women's issues.
In 2010, Nevada's Sharron "Second Amendment Remedies" Angle and Delaware's Christine "I'm Not A Witch" O'Donnell lost Senate races Republicans had been expected to win.
The party hopes to take steps to avoid such catastrophes.
Republicans say that if that means supporting a moderate candidate who can actually win, over a hardline conservative who doesn't stand a chance, so be it. (You may have noticed that among the names that make up The Bobs, there isn't anyone who might be considered a "tea party leader.")
"If we're not nominating candidates that can win in the general election, what business are we in?" Barbour said. "We are in the business of winning elections."
There is one thing, however, that no one--not the committee members, elected officials or even The Bobs--seem interested in addressing, and that's whether core Republican ideas need to change.
Most here said they don't.
"The conservative message sells," said Saul Anuzis, the former chairman of the Michigan Republican Party. "I think we're on the right side of history, on the right side of the issues. We just haven't done a very good job on articulating the issues."
Anuzis's analysis is pretty universal in Republican circles. They see the true cause of their problems as merely poor presentations of otherwise good ideas.
That mans a tricky rhetorical sleight of hand.
Don't believe women should have access to an abortion if they are raped or victims of incest? Try not to talk about it. Think the 47 percent of Americans who don't pay federal income taxes are "takers"? Please don't quote Ayn Rand in your stump speech. Support laws banning gay couples from legal rights guaranteed to straight couples? Keep it in the closet. And remember, when in doubt, pivot, and talk about economic growth.
Barbour admitted his committee wasn't brought in to debate or change those policy ideas. Their task, he said, is to put Republicans on a path to win election -- not a squishy exercise in lazy pontificating or a dorm room bull session about the proper role of government.
It's data driven.
It's going to hurt some feelings.
And most of all, it's damn serious.
"We did get whipped in the presidential election," Barbour said. "That's not something we take lightly."
Mistakes Are Costing You! Learn To Stop?Making ALL 189 Of Them!
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Even novice PC users have created flourishing businesses, and you could be next. The following article will give you the information you need to become a successful Internet marketer.
Every email you send out should ask your customers to take a specific action right away. The action may be to visit a particular place online or to make a certain purchase. This also gives you valuable insight on your email campaign?s effectiveness since you can track each of these actions.
TIP! Use tech tools to help measure how many visitors become customers to help improve your marketing strategy. The most successful sites use customizable applications that track site statistics like sales and traffic.
Use social media sites such as Twitter and Facebook as a part of your Online marketing campaign. You can communicate quickly on social media websites, giving your customers messages about sales and promotions. However, it is important that your comments or tweets are not overly promotional in nature. Try to keep your posts valuable and insightful, and only include marketing in a portion of them.
Allow customers to post reviews on your site. User reviews can help boost sales as well as increase your online presence.
The appearance and performance of your website is just as important as the in-store buying experience. Make sure you always test your links and ads to ensure that they work for your visitors. Costumers will leave if your site is not working properly.
TIP! It is a good idea to keep contact information for your customers. Give your clients the opportunity to opt-in to signing up with a subscribe link or making their email address part of the ordering process.
Make a game if you want to attract others to your website. Customers love to play free games online, and that can keep people coming back for more after they play once. Use the game for subtle product advertising. If you are a purveyor of pet supplies, for example, you might design a canine companion game that incorporates specific products and services you offer.
You should guarantee your products and say so in each of your advertisements. Customers want to know that your product is a sure bet before they part with their hard-earned cash. The only limit to what you can guarantee is what you decide it to be. Two options are 90 day guarantees and lifetime guarantees. Tailor your guarantee to your product.
Ask for opinions from people who don?t choose to buy from you by adding a simple feedback form after your sales pitch. If they decided not to purchase because of a problem with your website, you can improve it.
TIP! Contemplate the various methods you are interested in using in your web design efforts. For example, you may find that some of the best ways to go about marketing your site won?t cost you a single penny.
It is important to know what audience you want to reach and what sort of content will make them want to visit your site. Knowing who you want to reach makes it easier to produce content that will bring visitors back to your site again and again.
When it comes to Web marketing, be sure customers are aware that your site?s checkout process is secure. Many online users are reluctant to provide personal or financial details over the Internet, so it is important to assuage them with guarantees that this information is truly safe.
You could give a part of your profit to a charity if you believe your audience will be interested in helping out a good cause. This should be clearly advertised, though not too excessively, on your website. You do not give a large percentage of your profits to a charity for this to be a good marketing strategy.
TIP! Sell your products by motivating your customers in a positive way. Let customers know which of their problems your product will solve, and how it will solve them.
It is always best to handle customer complaints personally. Outsourcing your customer service might seem to be a good solution, but the resolutions offered by these companies can often seem impersonal and may infuriate an already angry customer even more. If an unhappy customer sends you an irate email, respond yourself to that email, offer a resolution, and let the customer know that you value him or her and his or her business.
Don?t be afraid to get started. You can learn from your experience as you go along. Use this advice to reach your ultimate goal.
Are you ready to have success in the home based business industry and build it on autopilot? Click below to register for free today. See how it works here. Also check out our team benefits here
NEW YORK (Reuters) - A systems error at U.S. stock market operator BATS Global Markets that led to a number of trades not being executed at the best possible price over a four-year period, was not as wide-spread as originally thought, BATS said on Friday.
The coding problem led to around 12,000 transactions being executed at prices that were not the best available, in violation of U.S. Securities and Exchange Commission rules, not the more than 440,000 transactions that BATS had originally disclosed earlier this month, a spokesman said.
The actual cost to BATS customers was around $17,000, not the around $420,000 originally thought, spokesman Randy Williams added.
BATS, which is the third-largest U.S. stock exchange by volume, behind NYSE Euronext and Nasdaq OMX Group , also said it successfully deployed a fix for the problem on Friday.
The problem had existed from the time BATS became an exchange in 2008, and was difficult to detect because the transactions in question were a small fraction of the 12.1 billion trades on BATS options and equities markets during the time frame, BATS said earlier in January.
BATS discovered the problem in a routine self-audit of its data and self reported it.
(Reporting By John McCrank; Editing by Nick Zieminski)
NEW DELHI/MUMBAI: India should consider the argument for higher taxes on the ?very rich?, Finance Minister P Chidambaram said in comments likely to fuel speculation about steps he may take in next month?s budget to boost tax flows and narrow a yawning fiscal gap.
In an offthe- record pre-budget meeting with Chidambaram and Finance Ministry officials on Jan. 7, some economists pressed for higher taxes on the rich to make sure they are paying their fair share, alarming business lobby groups that warn such a move would stifle growth.
The Indian finance minister?s comments come against the backdrop of a global debate, from the United States to France, about whether the very wealthy pay enough taxes. The growth rate of Asia?s third-largest economy is widely expected to slip to a decade-low in fiscal 2012/13 as the government grapples with ballooning budget and current account deficits and high inflation. Chidambaram wants to plug holes in the nation?s finances by cutting expenditure and increasing revenues through improved tax collection. ?I think we should have stability in tax rates but we should consider the argument that very rich should be asked to pay a little more on some occasions, but that is not the view I am expressing. That is simply the argument I have heard and I am repeating,? Chidambaram said in a TV interview aired yesterday.
Chidambaram offered no definition of the ?very rich?, but his comments are likely to please many in his centre-left Congress party who feel recent reforms to further liberalize the economy favor corporate India at the expense of the common man. The Congress party is facing a tough fight to hold on to power in a series of state elections this year and general elections due by May 2014. ?It is good electoral politics but economically doesn?t make sense,? said Venugopal Dhoot, who controls India?s diversified Videocon Group and ranks 38th in Forbes? India rich list with a net worth of $1.5 billion. It was not immediately clear if Chidambaram was referring to higher taxes on income, assets or capital gains in a regime that currently makes India a good place for the rich to live.
At present the top income tax rate is 30 percent, which applies to earnings above 1.0 million rupees ($18,500) a year. There are just 35 million taxpayers in a country of 1.2 billion people, and of them about 1.5 million declare annual earnings of more than 1.0 million rupees, according to the Finance Ministry. There is no inheritance tax, an issue Chidambaram raised as a concern after being appointed finance minister last August.
In 2009, his predecessor withdrew a 10 percent surcharge on the 30-percent rate paid on earnings above 1.0 million rupees. A government official with direct knowledge of the debate in the Finance Ministry said the focus is on plugging loopholes in the collection of income tax paid by individuals and companies. ?There are options of revisiting the inheritance tax and surcharge on income tax paid by the individuals,? the official said, declining to say if these were firm proposals on the table for the budget to be unveiled around the end of February. ?Even if they bring (back) the surcharge that will only add about 15-20 billion rupees, which is a drop in the ocean and will be lost in the decline of tax revenues that will arise due to lower compliance if tax rates are raised,? said Surjit Bhalla, chairman of advisory firm Oxus Investments.
India?s richest people tend to own businesses and other assets and thus have comparatively little exposure to salaries tax. Billionaire Mukesh Ambani, for example, was paid salary and perks of 150 million rupees ($2.8 million) in the last fiscal year by Reliance Industries, which he controls. According to Forbes, Ambani is worth $21 billion. Similarly, Azim Premji, founder of India?s No 3 software exporter, Wipro Ltd, and India?s third-richest person with a net worth of $1.2 billion, took home a salary and allowances of $84,696 in the last financial year, less than half of what the company?s chief financial officer was paid.
Premji said at a gathering of business leaders in Davos, Switzerland, on Wednesday that in principle he was not against higher taxes for the wealthy.? Reuters
Much of the United States has been suffering through a deep freeze for several days, and farmers are starting to express concern about damage to crops. Citrus growers in the West say damage to the fruit has already occurred, although not enough to impact prices. All this damaged fruit has one Explainer reader wondering: Is there anything wrong with eating visibly bruised produce?
Not necessarily. A bruise is an indicator of cellular damage. When you ding an apple or a banana, it can compromise the ability of the skin or the peel to keep oxygen away from the fruit, and oxygen breaks down the cellular walls and membranes. When the chemicals within the fruit become oxidized by enzymes like polyphenoloxidase, the reaction causes an unappealing brown color. There?s no evidence, however, that oxidized fruit is bad for you. Nor is a bruise necessarily indicative of an infection. If you want to cut the bruised portion of your fruit away for aesthetic reasons, by all means do so. There are also plenty of ways to cover up the mushy consistency of bruised fruit?homesteaders turn their bruised fruits into pies, juice, jams, or fruit leathers. But if you can?t be bothered to trim your bruised banana or bake it into bread, there?s little risk to your health in just eating it.
There is a caveat: Bruising makes a piece of fruit more susceptible to infection. As the cell walls break down, nutrients leak into the open, inviting colonization by microbes already present on the surface of the fruit or in the air. As they feed on the fruit?s exposed innards, the cells multiply rapidly. It?s possible for damaged fruit to grow some of the more notorious varieties of food-borne pathogens, such as salmonella or E. coli, but garden-variety yeasts and molds are far more common. Yeasts are of minimal concern?inoculating fruit with yeasts gives us such delights as wine and cider?but molds can be dangerous. Some species of mold release mycotoxins, which can cause a variety of human illnesses. (The most notorious mycotoxin, known as aflatoxin, is a potent carcinogen that grows on milk, cheese, nuts, and grains.) If your bruised fruit has so much fungal activity that you can see or smell it, don?t eat it. In addition to bruised areas, you should check the area around the fruit?s stem for mold, which is an entry point for opportunistic microbes. Food safety experts have a saying: If in doubt, throw it out. Healthy adults often take their chances and get away with it, but this advice is especially important for small children or the elderly.
If your bruised fruit has visible microbial growth, is it still safe to eat the nondamaged portion? It depends on the fruit. The question is whether the roots of the mold have penetrated the food. It?s difficult for mold to grow deep into firm fruits. So feel free to cut away the moldy portion of a bell pepper?yes, bell peppers are a fruit?and eat the remainder. Bananas, on the other hand, are too soft to repel a mold invasion, so a banana with a bruised, moldy spot should be tossed.
Got a question about today?s news? Ask the Explainer.
Explainer thanks Doug Gubler of UC-Davis and Lynne McLandsborough of the University of Massachusetts, Amherst.
So, we were out playing with some friends the other night, listening to Gogostar and Who Who at Club FF (we totally love Club FF in Hongdae, by the way), and we had a bit to drink as well. Now, we?re usually very responsible drinkers. We don?t binge drink, we don?t black out, we don?t lose all of our inhibitions and go nuts, we just enjoy to drink while we dance to live music, you know?
Side note: I never understood how people ?lost their inhibitions? when they?re drunk. How does someone drink to the point that they want to make out with strangers, or pick fights with people, or drive a car, or ? as is the defence for some cases ? even rape someone? This makes NO SENSE TO US WHATSOEVER. When we?re drunk, the first thing that we think to ourselves is ?holy crap: we?re getting too drunk. Stop drinking! Rehydrate! Get some food in your belly. Get the hell out of here!? We don?t get stupid when we?re drunk. We get less eloquent, and our motor skills might waver a bit, but we never do something that we wouldn?t want to do while sober. It?s just so bizarre that people change when they drink. We don?t understand it whatsoever.
Ok, side note over. Point is, we got to the point the other night that we realized, yep, we should pack it in and go home. Martina didn?t fare so well the next day, though, and had a bit of a hangover. We could have laid in bed all day and whined about it like babies, OR WE COULD MAKE A MOVIE ABOUT IT! WOOHOO! Uhhm. Not really the thing that most people would think about doing while hungover, right? Are we just weird? We?re weird, aren?t we? *cough*
So we wanted to make the best out of a bad situation and make a video of us trying something we never tried before: hangover soup! We know next to nothing about it, apart from the fact that old people FREAKING LOVE THIS. Hey! Are you an old Korean person reading this? Do you like Hangover soup? We never see young people eating hangover soup, for some reason. Only old people. Maybe it?s not cool to eat it. Young Korean people: what do you eat when you?re hungover? Tell us your secrets!
Also, my bad for thinking this was Gamja-Tang, when it clearly wasn?t. We didn?t order the soup ourselves, but I heard Gamja-Tang being mentioned in the conversation, so I thought it was Gamja-Tang. It clearly wasn?t, and I knew that after looking at it, but?yeah! That?s why I messed up so bad in the video.
Lastly, for this week?s bloopers we reveal a secret that we?re kind of scared to say in Korea?but, umm. WE HATE MAKGEOLLI! It?s delicious, yes, but we had the worst hangover of our lives because of it in our first year in Korea, and now whenever we smell it we recall the crushing pain of that night. So?no more Makgeolli!
This is likely not the biggest change SkyDrive will ever see, but Microsoft's still confident that Windows 8 and RT users of its cloud service are going to benefit from the latest tweak. And why wouldn't they, right? Earlier today, the Redmond-based company announced it's brought support for Live Tiles to the SkyDrive application on both Windows 8 and RT, with its main purpose being to show notifications rather than only being useful for launching the app. Naturally, this means folks will now be able to see relevant messages within the tiles when they make certain account modifications, including things like adding new files and quick previews of recently uploaded pictures. According to Microsoft, the novel feature will be available today, but it is rolling out gradually, so fret not if you're not seeing it pop up just yet.
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Until Elwood?s modelling career takes off, this is all I have.
I took a hiatus from life to work a contract gig as a copywriter for a major corporation. With the exception of technical writing (or being a hugely famous author), copywriting is the most lucrative day job in the writing world. Travel writing appears to be the least lucrative so unless I want to be one of those hostel people (with dog? and husband? heck no), this is what I have to do.
There?s also video game writing, which I hear pays handsomely. I have no idea what that entails though.
If only I played Zelda more
I should stroll the bohemian stroll. I should be in Uruguay or something. I will be traveling again, once I figure out how to make travel journalism a fulltime job. That?s my goal this year and I am happy you?re aboard for the ride.
Thankfully, my current job is very creative and there?s free coffee. And because of all the stress and caffeine, I have an eye twitch. Maybe after my eye explodes, I?ll have to wear a patch and then I?ll become a super villainess ? a corporate crime fighter in a pencil skirt.
Passive voiceis like periodontal disease. It seeps into your writing, right up underneath the gums and weakens the bones. Floss it out.?(Get rid of am, is, are, were, be, being been).
Put the ?offer? up front. Restructure your sentences so the most important piece stays strong up front. Start off strong, then get into the nitty gritty. In copywriting, I write to a message hierarchy. I figure out the key takeaways ? every offer I craft goes back to the key takeaway, with the first of the message hierarchy on the top. This focus helped immensely.
Pay attention.?Typos don?t matter much on a blog (some of us don?t have editors, you know), but they matter when thousands of dollars have been spent on a campaign. I pay attention to everything I write to avoid a horrific embarrassment.
Don?t be weird for weird?s sake. We?re talking weird names, exotic pets, too many scarves, failure to meet deadlines. Weird is fine. But don?t reinvent yourself as a crazy kook. Creatives can be both the most brilliant and fun colleagues or the most obnoxious and pretentious. Be the former.
Hunt down inspiration.?I developed an incredible amount of discipline from my career in copywriting and journalism. All it takes is a fear of being fired, a diet coke, a few Swedish Fish and BLAMMO! the muse is standing in my cube. I no longer wait for inspiration; I hunt it down. My muse resembles Mr. T, circa 1980s.
Don?t jam gigantic words into everything.?Copywriters don?t have a ton of room, which is phenomenal because I avoid a big letter count in favor of a precise word. I don?t use the word cocophonus nearly enough. I don?t speak this way, why would I write this way? Maybe this is why I?ve always been drawn to tough guys, like Hemingway and Junot Diaz.
Criticism is necessary. My work is projected onto a screen where it?s critiqued by my boss and team.?I no longer freak out when someone tells me its not right.
Tell a story. I tend to focus on little details: how the sun looked like a lemon drop. I get lost there and forget the entire point ? there?s a story. Words that don?t work to tell that story are wasted. The limited space in copywriting keeps me focused and on point.
Tags: travel writing, Writers Resources, Arts, Copywriting, Swedish Fish
If you want to live like Houston Texans linebacker Brian Cushing, you'll have to be able to throw down more than a football: try $1.3 million. Cushing might have been taken out of the 2012 NFL season early with a torn ACL, but he's still going for a touchdown in real estate. He's thrown his 7,007-square-foot Missouri City, Texas, mansion on the market.
Now's the perfect time for him to sell, really. He's been recovering from surgery after his injury, and honestly, what else is he going to do with his time? Give us some house porn, of course!
Here's what being an All-Pro affords you (aside from these six NFL stars' homes that were recently up for sale): Tucked away behind the gates of a secluded community, Cushing's five-bedroom, six-bathroom home features a marble-lined grand foyer that extends into a spacious common room and dining room area. Perched above the foyer is a media room and game room with balcony views of a lake and the backyard pool. Our favorite part, though, is an in-house theater with a wet bar. (Movies + booze = best date night ever.) They say everything's bigger in Texas -- and Cushing sure is going big with this listing!
See the listing for more details.
Find other homes for sale in Missouri City, Texas, or search listings in your area.
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Got a tip for House of the Day? Know of an exceptional or unusual property currently listed for sale? Please email krisanne.alcantara@huffingtonpost.com with your suggestions and be sure to include links to listing details and photos. (Due to the volume of response, we unfortunately are unable to reply to each submission.)
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"...I think it will probably get smacked down. But it spike up first or maybe stay flat for awhile."
That pretty well covers all the possibilities.
I noticed this morning that Citigroup has changed their outlook for gold:
"...At Citigroup on Monday, analysts cut their gold forecasts for 2013 by 4.2% to $1,675 a troy ounce and 0.2% to $1,653 a troy ounce for 2014. Their silver price forecasts remained unchanged." I could not locate their current silver forecast, but seem to recall it's around a 5% gain for 2013.
I see evidence, even among CT members, that expenses of daily living are causing some folks to liquidate their stacks. I think that trend will accelerate later in the year, especially in Europe, and that will create downward price pressure, more so if the world's central banks sell off their silver (don't think they have very much) in order to buy gold.
Immune cells engineered in lab to resist HIV infection, Stanford study showsPublic release date: 22-Jan-2013 [ | E-mail | Share ]
Contact: Ruthann Richter richter1@stanford.edu 650-725-8047 Stanford University Medical Center
STANFORD, Calif. Researchers at the Stanford University School of Medicine have found a novel way to engineer key cells of the immune system so they remain resistant to infection with HIV, the virus that causes AIDS.
A new study describes the use of a kind of molecular scissors to cut and paste a series of HIV-resistant genes into T cells, specialized immune cells targeted by the AIDS virus. The genome editing was made in a gene that the virus uses to gain entry into the cell. By inactivating a receptor gene and inserting additional anti-HIV genes, the virus was blocked from entering the cells, thus preventing it from destroying the immune system, said Matthew Porteus, MD, an associate professor of pediatrics at Stanford and a pediatric hematologist/oncologist at Lucile Packard Children's Hospital.
"We inactivated one of the receptors that HIV uses to gain entry and added new genes to protect against HIV, so we have multiple layers of protection what we call stacking," said Porteus, the study's principal investigator. "We can use this strategy to make cells that are resistant to both major types of HIV."
He said the new approach, a form of tailored gene therapy, could ultimately replace drug treatment, in which patients have to take multiple medications daily to keep the virus in check and prevent the potentially fatal infections wrought by AIDS. The work was done in the laboratory, and clinical trials would still be needed to determine whether the approach would work as a therapy.
"Providing an infected person with resistant T cells would not cure their viral infection," said Sara Sawyer, PhD, assistant professor of molecular genetics and microbiology at the University of Texas-Austin and a co-author of the study. "However, it would provide them with a protected set of T cells that would ward off the immune collapse that typically gives rise to AIDS."
The study will be published in the Jan. 22 issue of Molecular Therapy.
One of the big challenges in treating AIDS is that the virus is notorious for mutating, so patients must be treated with a cocktail of drugs known as highly active antiretroviral therapy or HAART which hit it at various stages of the replication process. The researchers were able to get around that problem with a new, multi-pronged genetic attack that blocks HIV on several fronts. Essentially, they hope to mimic HAART through genetic manipulation.
The technique hinges on the fact that the virus typically enters T cells by latching onto one of two surface proteins known as CCR5 and CXCR4. Some of the latest drugs now used in treatment work by interfering with these receptors' activity. A small number of people carry a mutation in CCR5 that makes them naturally resistant to HIV. One AIDS patient with leukemia, now famously known as the Berlin patient, was cured of HIV when he received a bone marrow transplant from a donor who had the resistant CCR5 gene.
Scientists at Sangamo BioSciences in Richmond, Calif., have developed a technique using a protein that recognizes and binds to the CCR5 receptor gene, genetically modifying it to mimic the naturally resistant version. The technique uses a zinc finger nuclease, a protein that can break up pieces of DNA, to effectively inactivate the receptor gene. The company is now testing its CCR5-resistant genes in phase-1 and -2 trials with AIDS patients at the University of Pennsylvania.
The Stanford scientists used a similar approach but with an added twist. They used the same nuclease to zero in on an undamaged section of the CCR5 receptor's DNA. They created a break in the sequence and, in a feat of genetic editing, pasted in three genes known to confer resistance to HIV, Porteus said. This technique of placing several useful genes at a particular site is known as "stacking."
Incorporating the three resistant genes helped shield the cells from HIV entry via both the CCR5 and CXCR4 receptors. The disabling of the CCR5 gene by the nuclease, as well as the addition of the anti-HIV genes, created multiple layers of protection.
Blocking HIV infection through both the CCR5 and CXCR4 receptors is important, Porteus said, as it hasn't been achieved before by genome editing. To test the T cells' protective abilities, the scientists created versions in which they inserted one, two and all three of the genes and then exposed the T cells to HIV.
Though the T cells with the single- and double-gene modifications were somewhat protected against an onslaught of HIV, the triplets were by far the most resistant to infection. These triplet cells had more than 1,200-fold protection against HIV carrying the CCR5 receptor and more than 1,700-fold protection against those with the CXCR4 receptor, the researchers reported. The T cells that hadn't been altered succumbed to infection with 25 days.
Porteus said he views the work as an important step forward in developing a gene therapy for HIV.
"I'm very excited about what's happened already," he said. "This is a significant improvement in that first-generation application."
He said a potential drawback of the strategy is that while the nuclease is designed to create a break in one spot, it could possibly cause a break elsewhere, leading to cancer or other cell aberration. He said it's also possible the cells may not tolerate the genetic change.
"It's possible the cells won't like the proteins they're asked to express, so they won't grow," he said.
But he said he believes both problems are technically surmountable. He said the researchers' next step is to test the strategy in T cells taken from AIDS patients, and then move on to animal testing. He said he hopes to begin clinical trials within three to five years.
Though the method is labor-intensive, requiring a tailored approach for each patient, it would save patients from a lifelong dependence on antiretroviral drugs, which have adverse side effects, Porteus noted.
He said he also hopes to adapt these techniques for use against other diseases, such as sickle cell anemia, one of his areas of interest. Porteus works with patients in the Pediatric Bone Marrow Transplant service at Packard Children's.
In addition to Sawyer, he collaborated with Richard Voit, a former Stanford graduate student who is now an MD/PhD candidate at the University of Texas Southwestern Medical Center, and Moira McMahon, PhD, a former postdoctoral scholar at Stanford who is now at the University of California-San Diego.
###
The study was supported by a grant from the American Foundation for AIDS Research and by a Laurie Krauss Lacob Faculty Scholar Award from the Lucile Packard Foundation for Children's Health.
Information about Stanford's Department of Pediatrics, which also supported the work, is available at http://pediatrics.stanford.edu.
The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html.
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Immune cells engineered in lab to resist HIV infection, Stanford study showsPublic release date: 22-Jan-2013 [ | E-mail | Share ]
Contact: Ruthann Richter richter1@stanford.edu 650-725-8047 Stanford University Medical Center
STANFORD, Calif. Researchers at the Stanford University School of Medicine have found a novel way to engineer key cells of the immune system so they remain resistant to infection with HIV, the virus that causes AIDS.
A new study describes the use of a kind of molecular scissors to cut and paste a series of HIV-resistant genes into T cells, specialized immune cells targeted by the AIDS virus. The genome editing was made in a gene that the virus uses to gain entry into the cell. By inactivating a receptor gene and inserting additional anti-HIV genes, the virus was blocked from entering the cells, thus preventing it from destroying the immune system, said Matthew Porteus, MD, an associate professor of pediatrics at Stanford and a pediatric hematologist/oncologist at Lucile Packard Children's Hospital.
"We inactivated one of the receptors that HIV uses to gain entry and added new genes to protect against HIV, so we have multiple layers of protection what we call stacking," said Porteus, the study's principal investigator. "We can use this strategy to make cells that are resistant to both major types of HIV."
He said the new approach, a form of tailored gene therapy, could ultimately replace drug treatment, in which patients have to take multiple medications daily to keep the virus in check and prevent the potentially fatal infections wrought by AIDS. The work was done in the laboratory, and clinical trials would still be needed to determine whether the approach would work as a therapy.
"Providing an infected person with resistant T cells would not cure their viral infection," said Sara Sawyer, PhD, assistant professor of molecular genetics and microbiology at the University of Texas-Austin and a co-author of the study. "However, it would provide them with a protected set of T cells that would ward off the immune collapse that typically gives rise to AIDS."
The study will be published in the Jan. 22 issue of Molecular Therapy.
One of the big challenges in treating AIDS is that the virus is notorious for mutating, so patients must be treated with a cocktail of drugs known as highly active antiretroviral therapy or HAART which hit it at various stages of the replication process. The researchers were able to get around that problem with a new, multi-pronged genetic attack that blocks HIV on several fronts. Essentially, they hope to mimic HAART through genetic manipulation.
The technique hinges on the fact that the virus typically enters T cells by latching onto one of two surface proteins known as CCR5 and CXCR4. Some of the latest drugs now used in treatment work by interfering with these receptors' activity. A small number of people carry a mutation in CCR5 that makes them naturally resistant to HIV. One AIDS patient with leukemia, now famously known as the Berlin patient, was cured of HIV when he received a bone marrow transplant from a donor who had the resistant CCR5 gene.
Scientists at Sangamo BioSciences in Richmond, Calif., have developed a technique using a protein that recognizes and binds to the CCR5 receptor gene, genetically modifying it to mimic the naturally resistant version. The technique uses a zinc finger nuclease, a protein that can break up pieces of DNA, to effectively inactivate the receptor gene. The company is now testing its CCR5-resistant genes in phase-1 and -2 trials with AIDS patients at the University of Pennsylvania.
The Stanford scientists used a similar approach but with an added twist. They used the same nuclease to zero in on an undamaged section of the CCR5 receptor's DNA. They created a break in the sequence and, in a feat of genetic editing, pasted in three genes known to confer resistance to HIV, Porteus said. This technique of placing several useful genes at a particular site is known as "stacking."
Incorporating the three resistant genes helped shield the cells from HIV entry via both the CCR5 and CXCR4 receptors. The disabling of the CCR5 gene by the nuclease, as well as the addition of the anti-HIV genes, created multiple layers of protection.
Blocking HIV infection through both the CCR5 and CXCR4 receptors is important, Porteus said, as it hasn't been achieved before by genome editing. To test the T cells' protective abilities, the scientists created versions in which they inserted one, two and all three of the genes and then exposed the T cells to HIV.
Though the T cells with the single- and double-gene modifications were somewhat protected against an onslaught of HIV, the triplets were by far the most resistant to infection. These triplet cells had more than 1,200-fold protection against HIV carrying the CCR5 receptor and more than 1,700-fold protection against those with the CXCR4 receptor, the researchers reported. The T cells that hadn't been altered succumbed to infection with 25 days.
Porteus said he views the work as an important step forward in developing a gene therapy for HIV.
"I'm very excited about what's happened already," he said. "This is a significant improvement in that first-generation application."
He said a potential drawback of the strategy is that while the nuclease is designed to create a break in one spot, it could possibly cause a break elsewhere, leading to cancer or other cell aberration. He said it's also possible the cells may not tolerate the genetic change.
"It's possible the cells won't like the proteins they're asked to express, so they won't grow," he said.
But he said he believes both problems are technically surmountable. He said the researchers' next step is to test the strategy in T cells taken from AIDS patients, and then move on to animal testing. He said he hopes to begin clinical trials within three to five years.
Though the method is labor-intensive, requiring a tailored approach for each patient, it would save patients from a lifelong dependence on antiretroviral drugs, which have adverse side effects, Porteus noted.
He said he also hopes to adapt these techniques for use against other diseases, such as sickle cell anemia, one of his areas of interest. Porteus works with patients in the Pediatric Bone Marrow Transplant service at Packard Children's.
In addition to Sawyer, he collaborated with Richard Voit, a former Stanford graduate student who is now an MD/PhD candidate at the University of Texas Southwestern Medical Center, and Moira McMahon, PhD, a former postdoctoral scholar at Stanford who is now at the University of California-San Diego.
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The study was supported by a grant from the American Foundation for AIDS Research and by a Laurie Krauss Lacob Faculty Scholar Award from the Lucile Packard Foundation for Children's Health.
Information about Stanford's Department of Pediatrics, which also supported the work, is available at http://pediatrics.stanford.edu.
The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html.
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Public release date: 22-Jan-2013
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