Being responsible for an elderly family member or friend is an everyday challenge. And its not just age that can bring about this scenario. Maybe your loved one has a mental disorder, received grave injuries, or went through a traumatic incident that has left him or her fully incapacitated. No matter what the reason for it is, you are suddenly confronted by this big obligation.
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Licensed care providers make sure that their employees receive continuous education and training. This means that the services they provide satisfy industry requirements, and this is an important consideration when deciding on the right care service provider for your loved one. Learn more about the services you could receive from home care professionals by seeing ehow.com/facts_4856608_inhome-care-elderly.html.
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A recent study on local search brings up some interesting points, as well as some things we in the internet marketing industry thought, but?didn?t?have the data to prove.
For example, local search seems to be driven more by portable devices such as smart phones and tablets.? But that?s not to say you should shift your online marketing budget from people using PCs and focus all your efforts on developing the next killer app for your business.
Far from it.? In fact, the research shows that while local searches conducted by those with PCs only account for an average of 5 local searches per week, those with PCs, Smartphones and Tablets did almost 3 local searches PER DAY!? Not only that, but their PC searches for local products and services were higher than those that did local searches with PCs only.
This tells me that the opportunities for local search will continue to grow, and the companies that balance their online marketing campaigns to target both Desktop searchers and Mobile searchers will be the most successful online marketers moving forward.
So what does a combined Desktop/Mobile Marketing campaign look like?
Well that depends on your industry.? The research goes on to say that businesses in the retail, dining and entertainment industries are the ones that tend to have the most mobile searches.? This makes sense to me because if you are looking for a place to dine chances are you want it to be close.? Therefore you may likely search for a restaurant in your area.? Once you find it, you of course want to see how close it is by getting the address and you probably also want to be sure it?s open, so you will check to see if it has its hours posted on the website.
Similarly, if you are looking for a specific item you may search for it in a local fashion to see who lists the product or service on their website.? You may even compare a few businesses to see which options are available locally, as well as the price at different businesses.
Therefore the successful internet marketer in these industries (Dining, Entertainment and Retail) will need to develop a balanced approach to online marketing accounting for both desktop devices and mobile devices.
In other words, if you own or operate a restaurant you will want to make sure it is not only visible on a PC but also offers such things as:? Maps/driving directions, business hours, phone number, a current menu and perhaps even reviews.
The following graphic illustrates which industries are more affected by local search:
What are Local Searchers Searching For?
Local searchers are becoming more demanding when it comes to what information they want to see online.? While the ?usual? items, such as business name, address and phone number are the most searched for, consumers also want to see the company website.? They want to know if it?s open (business hours), what specials, if any they are offering (coupons, product lists, menus) and even consumer reviews and ratings if available (click the image below to see a larger one).
The research also shows that search engines still account for most of the local search.? While people do use other sites such as portals or locally targeted sites (such as the Yellow Pages) search engines account for much of the activity, depending on the industry you are in.
What I found interesting is that sites like Facebook, Twitter and other social sites are not considered by searchers.? In fact these ?other? sources only accounted for between 1% and 7% of the local search traffic generated.? In other words, people don?t ask their Facebook friends who the best hair stylist in town is, they use a search engine primarily and supplement the information with local sites, portals and review sites.
So Who is the Typical ?Avid? Local Searcher?
As time goes on I would expect this demographic to change, but right now your typical ?Avid? local searcher is a 21-35 year old employed male who owns a PC, tablet and smart phone and uses all 3 to search daily.
These ?digital nomads? are very comfortable with their smart phones and tablets and are willing to use them more often to search, especially when they are away from their PC.
Because the devices are ?always on? this avid searcher whips out his phone whenever a question is asked that isn?t answered, or to verify information as needed.
So when he wants a coffee, or someone in his group asks ?where is the best coffee? around here, he performs the search and relies on the search engine to return the best result.
But as I said, I fully expect this demographic to shift.? Young men have always been the ?early adopters? with technology.? So ?while it may be worthwhile to shift some of your local internet marketing budget to target them, one must remember that women are catching up.? And it is the women who make most of the buying decisions in a household.
Therefore over the next 3-5 years? I predict we will see this ?average? demographic shift and get older.? From a 21-35 year old male to a 35-49 year old female.
I also expect the searching habits to change.? While restaurants and entertainment will continue to be highly searched for I expect other industries (such as healthcare, physical fitness and professional services) to gain in local searches as the demographics changes.
Other Important Take-Aways From This Research
While a lot of effort was devoted to how people search locally, particularly with their mobile devices there were a few other things I found interesting:
Of those that own a smartphone, 90% have installed and used a mobile shopping app in the past 30 days.
4 of 10 Avid mobile users have used their phones to ?window shop? on the merchant?s business and then gone online to buy an item.
75% of respondents have posted a review of a business or product on an online review site.
Over half of all users have ?checked in? to a business using a check in app.
? of all ?Avid? local searchers have scanned a QR Code.
? of all ?Avid? local searchers have also used a mobile coupon at a business.
Interestingly, Avid local searchers seem to prefer their local market.? ? read local newspapers online while 2/3 have shopped at a local merchant as opposed to a chain store.
Summary
Based on this research it is clear to me that Local Search is still in its infancy.? While some people have embraced the concept, using their desktop and mobile devices to enhance their local shopping experience, the bulk of internet users have not.? Whether that?s because they are uncomfortable with the idea of local searching, or don?t realize its potential yet, it is clear to me that local search has a great future growth potential online.
The challenges for businesses will be what happens when their competition realize this huge potential?? How does a local mom & pop pizza joint, that?s well positioned locally by taking advantage of things like a mobile enabled website, online menu, customer reviews, driving directions etc. compete when a larger chain (such as Dominos) moves into the local market?
Another huge opportunity I see will be in the form of ?hyper local? search.? These are searches performed by people looking for products or services in their immediate area (as opposed to their city).? These searches will be for places within a few minutes? drive or walk from their current location, as opposed to driving up to 45 minutes away for a similar product or service.
If you own a business and you are looking to attract more local searches?? be sure to contact us so we can show you how we can help.
For more information and to download the research please click here.
You have to feel a little bit for the Columbus Crew today. In a lot of way, luck just wasn?t with the men in the yellow hard hats.
Columbus cannot count itself among the playoff teams this morning, despite finishing with 52 points. Approach most teams at the beginning of the season and ask if they would take it ? most would give it serious consideration, at very least. Some would grab for it.
That?s a total that would have gotten Columbus into the playoffs on any other year; No team has accumulated as many points and then sat home for the ?second season.?
Now, some of that is because this year?s 34-game schedule was longer than most years. But, before you scream ?A-ha!? ? consider this:
The Crew?s 15-12-7 record is playoff-worthy, too, by historic MLS standards. No team has put together a season yet with three more wins than losses and failed to reach the post-season. Heck, Real Salt Lake won the whole bowl of fruit in 2009, and ?they marched into the playoffs with one more loss than win (an 11-12-7 record).
Does that make Columbus a good team? No. Robert Warzycha?s club is flawed, just like a lot of them. The point is, the numbers don?t lie, and the Crew just assembled a season that is measurably better than plenty of teams that have made the playoffs in years past. (Yes, Major League Soccer?s long-standing leniency on playoff entry deserves its place in this conversation, but that makes it a much longer conversation. Let?s stay on point for now.)
(MORE: Questions to be answered around Crew Stadium)
Columbus? dead-even goal difference in 2012 (44 goals scored, 44 goals against) is every bit as exciting as tap water. Then again, owing to those traditionally low playoff entry standards, teams have regularly qualified for MLS post-season with a negative goal-difference. (The last team to do so was, ahem, Columbus last year.)
On the other hand ? a Columbus Dispatch columnist did himself some digging, and he came up with what we in the sports biz like to call ?statistical gold.? Michael Arace says the Crew?s major downfall is its inability to finish. Not around goal, that is, but in a season.
Yet, the positives are overshadowed by a larger trend: Not since Sigi Schmid coached the team to an MLS Cup title and left town in 2008 has the Crew managed to close well.
Schmid?s successor, Robert Warzycha, has four seasons on the bench. Warzycha is 44-24-28 (.604) in games played in March through August. His record is 11-16-5 (.421) in September and October games. He is 1-4 (.200) in the playoffs.
Blek!
Warzycha?s job status is hot-topic stuff around Columbus soccer supporters circles. But don?t forget, Hunt Sports Group re-signed the former Polish international to a multi-year deal after last season?? and HSG is a group that knows how to squeeze the green off a dollar, if you know what I mean.
FILE -Part of the Yarmouk military complex in Khartoum, Sudan seen in a satellite image made on October 25 2012, following an alleged attack. A U.S. monitoring group says satellite images of the aftermath of an explosion at a Sudanese weapons factory suggest the site was hit by an airstrike. The Sudanese government has accused Israel of bombing its Yarmouk military complex on Oct 23, killing two people and leaving the factory in ruins. Analysts speculate that the 40 shipping containers which were destroyed in the central area of the image may have contained Iranian missiles bound for Gaza. (AP Photo/ DigitalGlobe via Satellite Sentinel Project, File)
FILE -Part of the Yarmouk military complex in Khartoum, Sudan seen in a satellite image made on October 25 2012, following an alleged attack. A U.S. monitoring group says satellite images of the aftermath of an explosion at a Sudanese weapons factory suggest the site was hit by an airstrike. The Sudanese government has accused Israel of bombing its Yarmouk military complex on Oct 23, killing two people and leaving the factory in ruins. Analysts speculate that the 40 shipping containers which were destroyed in the central area of the image may have contained Iranian missiles bound for Gaza. (AP Photo/ DigitalGlobe via Satellite Sentinel Project, File)
FILE - Sudanese President Omar al-Bashir, center, and Iranian President Mahmoud Ahmadinejad, left, review an honor guard, in Tehran, Iran, in this Wednesday, April, 26, 2006 file photo. Explosions at a military site near Sudan's capital Khartoum on Oct 23 2012, widely believed to be the result of an Israeli airstrike, point to a possible escalation in a hidden front of the rivalry between Iran and Israel which believes arms pipeline through Sudan to Islamic militants on Israel?s borders. (AP Photo/Hasan Sarbakhshian, file)
CAIRO (AP) ? A suspected Israeli airstrike against a weapons factory in Khartoum last week points to a possible escalation in a hidden front of the rivalry between Israel and Iran: The arms pipeline through Sudan to Islamic militants on Israel's borders.
Mystery still surrounds the blast, which killed four people. But analysts say the incident could indicate Iran is trying to send more advanced weapons via Sudan to Hamas in the Gaza Strip or Hezbollah in Lebanon ? and that Israel has become more determined to stop it at a time of increased tensions over Iran's nuclear program.
Consensus has built among Israeli and Arab military analysts that the explosion just after midnight last Wednesday at the Yarmouk factory was indeed an Israeli airstrike as Sudan has claimed. Israel says it neither confirms nor denies being behind it. Sudan, in turn, denied on Monday that Iran had any connection to the factory's production.
In a show of support for the two countries' alliance, two Iranian warships ? a helicopter carrier and destroyer that had been conducting anti-piracy patrols off East Africa's coast ? docked this week at Sudan's main Red Sea port. The Iranian commanders were holding talks with Sudanese officers as part of the countries' "exchange of amicable relations," Sudan's military spokesman said.
Sudan's Foreign Ministry dismissed allegations of an Iranian connection to the Yarmouk facility, saying "Iran does not need to manufacture weapons in Sudan, be it for itself or for its allies."
Experts say that Sudan's value to Iran is not in its modest weapons production capabilities, but in its vast desert expanses that provide cover for weapons convoys bound for Gaza through Egypt's lawless Sinai Peninsula. Israel has long contended that Iran uses the route to supply Hamas. It appears to have struck the supply line at least once before, when a convoy in a remote part of Sudan was blasted by explosions in 2009 ? though Israel never admitted to the attack.
The question now is: What would prompt Israel to conduct a bolder strike hitting a Sudanese government facility in the heart of the capital Khartoum?
The target may have been 40 shipping containers that satellite images show were stacked in the factory compound days before the explosion. Post-explosion imagery released Saturday by the Satellite Sentinel Project, a U.S. monitoring group, show six 52-foot-wide craters all centered at the spot where the containers had been, the blast's epicenter.
The group said the craters were consistent with an airstrike and that whatever it hit was a "highly volatile cargo," causing a powerful explosion that destroyed at least two structures in the compound and sent ordnance flying into nearby neighborhoods.
What was in the containers remains unknown ? leaving observers to speculate.
Retired Israeli Brigadier General Shlomo Brom, a military expert, said there is a "strong possibility" that Israel had identified an "imminent threat" within the factory.
Brom, a research associate at the Institute for National Security Studies at Tel Aviv University, said the containers could have been part of Iran's efforts to smuggle "a new category of weapons" to Gaza. The weapons could be "something with air defense capability ... or could very well belong to the category of rockets and missiles, but just larger, stronger, and longer range," he said.
Gen. Sameh Seif Elyazal, a former Egyptian army general, said his understanding was that a strike was carried out against short-range missiles being assembled in the factory "under Iranian supervision," bound for the Hamas and Hezbollah militant groups. He said that his analysis was based on "private conversations with Israeli officials" that had been conveyed to him through others. He did not elaborate.
Elyazal said Iranian-made weapons smuggled through Sudan reach Hamas militants in Gaza and Hezbollah fighters in Lebanon.
"Iran wants to put Israel under pressure from the north, through Hezbollah and from the east through Gaza," he said.
Iran has long backed Hamas, which took control of the Gaza Strip in 2007. Iran's relations with Hamas have been strained after the Palestinian militant group this year cut its ties with Syria ? Tehran's biggest Arab ally ? over that country's bloody civil war. Iran has since cut back some aid to the group, but a senior Hamas leader visited Tehran last month and Hamas officials say the group's military wing in particular continues to receive funding from Iran.
Iran "has sought alternate routes" for its arms shipments to Hamas after Israel cracked down on maritime lanes direct to Gaza that Tehran previously used, said Michael Eisenstadt, Director of the Military and Security Studies Program at the Washington Institute for Near East Policy.
The Sudan route "complicates matters for Israel," he said.
Hezbollah is another possible destination. But despite the civil war, Syria is believed to remain the primary route for Tehran to supply its powerful Shiite guerrilla ally in Lebanon.
Iranian arms shipments gain added significance amid the dispute of Iran's nuclear program, which Israel and the U.S. contend is aimed at producing a bomb. Israel has held out the possibility of attacking Iranian nuclear facilities. Iran denies any intention to build a bomb and has warned it will retaliate for any Israeli attack ? raising fears Hezbollah, Hamas or other Iranian-backed militant groups would carry out strikes on Israel.
Speaking to Israel Radio after the Wednesday explosion in Khartoum, Israeli Vice Premier Moshe Yaalon said "there's no doubt that there is an axis of weapons from Iran via Sudan that reaches us, and not just us."
The contentions surrounding last week's explosion also point to the close ties between Iran and Sudan, dating back to the 1989 coup that brought President Omar al-Bashir to power, when Iran's Revolutionary Guard helped supply him weapons.
Though wanted by the International Criminal Court for alleged atrocities in the western Sudanese region of Darfur, al-Bashir visited Tehran most recently in August for a Nonaligned Movement summit. Iran has made significant investments in water and engineering projects in Sudan.
China is the main arms source for Sudan's government. But Iran, which signed a military relations deal with Khartoum in 2008, is also a supplier.
Notably, Khartoum appears to receive Iranian drones to use in its multiple domestic wars against rebel groups, said Jonah Leff, who monitors Sudan for the Small Arms Survey. Rebels shot down two such drones, in 2008 and in March this year.
An Iranian role at the Yarmouk facility remains uncertain. The facility, which opened in 1996, was touted by Sudan as a source of pride, showing its weapons manufacturing capabilities. Still, the factory only produces ammunition. Leff said there is no evidence Iranian weapons are being assembled there, suggesting it was beyond the facility's capabilities.
But, he said, workers from Yarmouk have traveled to Iran for training.
There have also been reports of Iranian experts residing at Yarmouk, said Hani Raslan, an expert on Sudan at the Ahram Centre for Political and Strategic Studies in Cairo. Raslan also said he suspects the strike was aimed at weakening the Iranian arms smuggling network.
Fawaz A. Gerges, who heads the Middle East Center at the London School of Economics, says the strike has its symbolic aspect as well, allowing Israel to "flex its muscle and capacity and will to strike."
"Regardless of what particular weapons were destroyed, Israel sent a message to Sudan and to Iran," Gerges said.
___
Associated Press writers Sarah El Deeb in Cairo, Lauren E. Bohn and Josef Federman in Jerusalem, and Brian Murphy in Dubai contributed to this report.
In 1997, Congress cracked down on a popular tax shelter that allowed rich people to take advantage of the exempt status of charities without actually giving away much money.
Individuals who had already set up these vehicles were allowed to keep them. That included Mitt Romney, then the chief executive officer of Bain Capital, who had just established such an arrangement in June 1996.
The charitable remainder unitrust, as it is known, is one of several strategies Romney has adopted over his career to reduce his tax bill. While Romney?s tax avoidance is legal and common among high-net-worth individuals, it has become an issue in the campaign. President Barack Obama attacked him in their second debate for paying ?lower tax rates than somebody who makes a lot less.?
In this instance, Romney used the tax-exempt status of a charity -- the Mormon Church, according to a 2007 filing -- to defer taxes for more than 15 years. At the same time he is benefitting, the trust will probably leave the church with less than what current law requires, according to tax returns obtained by Bloomberg this month through a Freedom of Information Act request.
In general, charities don?t owe capital gains taxes when they sell assets for a profit. Trusts like Romney?s permit funders to benefit from that tax-free treatment, said Jonathan Blattmachr, a trusts and estates lawyer who set up hundreds of such vehicles in the 1990s.
Near Zero
?The main benefit from a charitable remainder trust is the renting from your favorite charity of its exemption from taxation,? Blattmachr said. Despite the name, giving a gift or getting a charitable deduction ?is just a throwaway,? he said. ?I used to structure them so the value dedicated to charity was as close to zero as possible without being zero.?
When individuals fund a charitable remainder unitrust, or ?CRUT,? they defer capital gains taxes on any profit from the sale of the assets, and receive a small upfront charitable deduction and a stream of yearly cash payments. Like an individual retirement account, the trust allows money to grow tax deferred, while like an annuity it also pays Romney a steady income. After the funder?s death, the trust?s remaining assets go to a designated charity.
Romney?s CRUT, which is only a small part of the $250 million that Romney?s campaign cites as his net worth, has been paying him 8 percent of its assets each year. As the Romneys have received these payments, the money that will potentially be left for charity has declined from at least $750,000 in 2001 to $421,203 at the end of 2011.
Tax Returns
The Romney campaign declined to answer written questions about the trust.
?The trust has operated in accordance with the law,? Michele Davis, a campaign spokeswoman, said in an e-mail.
Paul Comstock, a financial adviser to LDS Philanthropies, an arm of the Mormon Church, said that while he wasn?t familiar with the trust, Romney and his trustee might arrange to compensate the church for the dwindling amount with other gifts.
?It may be that they?ve made provisions for the charity someplace else that will make up for what this isn?t going to give them,? Comstock said.
Bloomberg News obtained the trust?s tax returns from 2007 to 2011 from the Internal Revenue Service. Romney hasn?t disclosed the trust?s tax returns and is under no legal obligation to do so. He did make some disclosures about the trust?s investments in Massachusetts filings from 2002 to 2007 and as a presidential candidate in the current campaign.
After Death
Funds held by Romney?s trust are scheduled to be distributed after the death of Romney and his wife to ?a charitable organization to be designated by Romney,? according to the 2007 filing, disclosing assets he held while governor of Massachusetts. ?In the absence of such a designation the funds will go to the Church of Jesus Christ of Latter-Day Saints.?
Davis declined to comment on whether Romney has designated another charity since then.
Romney has been an active member of the church, which expects members to donate 10 percent of their income. Over the years, he has donated millions of dollars of stock in Bain-owned companies to the church, securities filings show.
The church recommends such trusts on its website as one of many options for donors.
?Probably one of the advantages of a charitable remainder trust is that it helps with capital gains tax,? said Carl McLelland, an attorney in the planned giving office for LDS Philanthropies.
Capital Gains
CRUTs were more common in the 1990s when capital gains rates were higher. In 1996, when Romney set up his trust in Massachusetts, the federal rate was 28 percent, compared with 15 percent today. At the time, a Massachusetts state resident who sold shares for a gain of $1 million could have faced a combined state and federal capital gains tax of as much as 40 percent, reducing his take to $600,000.
By contrast, if he contributed the stock to a CRUT, and it sold the shares, it typically wouldn?t owe any tax since it is a charitable trust. The CRUT could reinvest the $1 million and earn a return on the full amount.
?The power of this is the tax deferral,? said Jay A. Friedman, a partner at accounting firm Perelson Weiner LLP in New York. ?The money is all growing tax free and he only pays tax on what is distributed to him.?
Concerned that CRUTS weren?t sufficiently philanthropic, Congress mandated in July 1997 that the present value of what was projected to be left for charity must equal at least 10 percent of the initial contribution. Existing CRUTS weren?t affected by the new law.
Dwindling Principal
Romney?s trust was projected to leave to charity an amount with a present value of a little less than 8 percent of the initial contribution, according to an analysis by Friedman. Thus, the specifics of Romney?s trust wouldn?t have passed legal muster if it had been set up 13 months later, he said.
Because the trust?s investments have been earning a return far below its annual payouts to the Romneys, its principal has dwindled rapidly.
In 2001, five years after it was established, the trust had a value of between $750,000 and $1.25 million. Since then, it has pursued a conservative investment strategy -- regardless of the ups and downs of the stock market -- buying a mix of money- market funds, federally-backed bonds and federal bond funds. Since 2007, it has moved its assets entirely into cash. By 2011, its investments earned a return of $48, down from between $60,001 and $100,000 in 2001. It paid $36,696 to the Romneys in 2011.
Romneys Favored
The current investing strategy favors the Romneys over the charity because they get a guaranteed payout, said Michael Arlein, a trusts and estates lawyer at Patterson Belknap Webb & Tyler LLP.
?The Romneys get theirs off the top and the charity gets what?s left,? he said. ?So by definition, if it?s not performing as well, the charity gets harmed more.?
The trustee for Romney?s CRUT is R. Bradford Malt, chairman of the law firm Ropes & Gray LLP, and manager for Romney?s various family trusts as well as his personal attorney. Ropes & Gray has also been for years the main outside counsel for Bain Capital.
If the CRUT maintains the same investing strategy, assets will continue to shrink, said Jerome M. Hesch, a tax and estate planning attorney at the law firm Carlton Fields. The trustee acted prudently in protecting against losses during a stock market decline, he said.
Nevertheless, ?what?s going to go to charity is probably close to nothing,? Hesch said.
Lotto wheeling is a technique of grouping same-number combinations which are put together to create a collection of numbers from which you can use in betting in multi-numbered lottery games. So when you buy a lottery ticket, you are then to assemble the number combinations in your ticket in a manner that the winning number combinations must fall under the cluster of numbers that you have arranged. Using the lotto wheeling system augments the chances of winning especially in multi-numbered lottery games wherein the probability of winning is so scarce and high.
With the rapid development of technology, the once manual lotto wheeling system has now evolved into a more conventional and efficient form: the lotto wheeling software which features a more accurate calculation of winning number combinations.
There are lots of lotto wheeling software available in the web these days, all promising the same tag line: the most accurate software program. But this should not blind you. Before considering a particular software, it is most advantageous to decide first what really matters. With that idea, for sure the common end that we want to achieve is winning. So once you have identified your ultimate purpose, you then need to gear yourself towards the factors or things that ensure your ultimate goal of winning.
To be able to attain that goal, it is important to choose a software that enhances the guarantee of your winning in the lottery draw. The word guarantee here does not necessarily mean that your winning possibility is 100 percent sure, but that your possibility of having winning number combinations is higher. The ideal software for this is the one which does not give you a random set of numbers out of nowhere, but the one which show you the calculation based on the formula depicted.
Another important thing to ponder about is that, it should be multi-faceted fitting for a multiple number of games. There are software programs which show you the way to calculate the numbers correctly in a profound manner, describing all the steps and formula and how to attain the most sound prediction. Apart from this, it also provides you with information not only on the very lottery game that you are currently looking at, but also on other lottery games.
And last but not the least find out which technique is the most effective then work out through it. Others believe that balanced wheel is more efficient as it creates a higher tendency for winning. Nevertheless, there are plenty of lottery wheeling strategies out there that wait to be tried out and tested.
So, the best way to win the lottery especially in multi-numbered lotto games is through making an extra effort to search for the best possible lotto wheeling software. If you are not so sure of what you want to use (since there are many software programs out there), it is just fine to try out all the available software programs in the web by taking advantage of the free trial they offer. From there, you will be able to judge for yourself which one is the best.
BOSTON ? Massachusetts shut down another compounding pharmacy after a surprise inspection last week found conditions that called into question the sterility of its products, state officials said Sunday.
The pharmacy, Infusion Resource in Waltham, voluntarily surrendered its license over the weekend, said Dr. Madeleine Biondolillo, director of the Bureau of Health Care Safety and Quality at the Massachusetts Public Health Department. Inspectors who visited Infusion Resource on Tuesday found ?significant issues with the environment in which medications were being compounded,? Dr. Biondolillo said during a news conference here. She would not disclose details, but said that in another troubling discovery, patients had apparently been receiving intravenous medications at the pharmacy, against state regulations.
The findings led the state to immediately issue a cease-and-desist order, Dr. Biondolillo said, preventing Infusion Resource from dispensing any drugs. But she added that as of yet, there was no evidence of any contaminated drugs produced there.
The latest shutdown comes amid a continuing investigation of New England Compounding Pharmacy, the company believed responsible for a national meningitis outbreak in which 25 people have died, at least 344 others have fallen ill and as many as 14,000 people are thought to have been exposed. State and federal inspections in recent weeks found unsanitary conditions at New England Compounding, from surfaces coated with mold and bacteria to residue on sterilization equipment.
New England Compounding has suspended operations and laid off most of its employees.
Gov. Deval Patrick last week directed the state?s Board of Registration in Pharmacy to immediately start unannounced inspections of compounding pharmacies that prepare sterile, injectable medications. There are 25 such pharmacies in Massachusetts, and Mr. Patrick has acknowledged that the state rules governing them were insufficient. Although the Food and Drug Administration can inspect compounding pharmacies and issue warnings, the agency says states have ultimate jurisdiction.
At the news conference on Sunday, Dr. Lauren Smith, the interim commissioner of the Massachusetts Department of Public Health, said the state was bringing on five additional inspectors to help with unannounced visits to compounding pharmacies. The goal is to inspect all of them by Jan. 1, she added.
Dr. Smith also said the state had asked Sophia Pasedis, a member of the pharmacy board who works at Ameridose, a sister company to New England Compounding that is also under investigation and currently shut down, to resign from the board. State officials said earlier this month that Ms. Pasedis had recused herself from any board actions concerning New England Compounding and Ameridose. But on Sunday, Dr. Smith said there was ?no definitive proof? that Ms. Pasedis, the vice president of regulatory affairs and compliance at Ameridose, had consistently done so.
Ms. Pasedis has so far declined to step down, Dr. Smith said, but her term expires next month. She has been on the pharmacy board since 2004.
Dr. Biondolillo said the manager of record at Infusion Resource used to work at Ameridose.
Infusion Resource was last inspected by the state when it opened in December 2009, she said, and was found to be in compliance at the time. The state has not received any complaints about the pharmacy since then, she added.
In an e-mailed statement, Bernard F. Lambrese, the chief executive of Infusion Resource, said, ?No issues were cited relating to the integrity of our products nor to the quality of our compounding practices.? He added that the pharmacy was working to address concerns cited by the inspectors, including the condition of the flooring in the room where the pharmacy mixes drugs, and would then seek to be relicensed.
Dr. Biondolillo said that Infusion Resource supplies specialized medications to patients after they have been discharged from a hospital. According to its Web site, Infusion Resource is part of a company based in East Providence, R.I.
Also on Sunday, Representative Edward J. Markey, a Massachusetts Democrat in whose district New England Compounding is located, issued a report on the practice of compounding that stated there had been ?adverse medical incidents? related to compounding in at least 34 states.
Citing F.D.A. records, the report said there had been 23 deaths and at least 86 serious illnesses associated with the practice of compounding. The statistics did not include the current meningitis outbreak.
The report also included a review of state pharmacy boards and found that they do not generally undertake enforcement actions that relate to the safety or scope of compounding. Instead, the report said, their focus tends to be more on traditional pharmacy activities, including licensing and controlled substances.
Massachusetts officials have said that tracking volume from compounding pharmacies was not part of their regulatory mandate. But Dr. Smith said the state would soon issue emergency rules requiring compounding pharmacies to submit frequent reports on production and distribution of injectable drugs.
?I know that we face great challenges,? she said. ?At the same time, though, we have a rare opportunity to create meaningful change.?
Sabrina Tavernise contributed reporting from Washington.
Name of Applicant:?G M Owais Ahmed Grade:?XII School:?Narayana Junior College City:?Kurnool State:?Andhra Pradesh Country: India
No generation is more at ease with online, collaborative technologies than today?s young people??digital natives?, who have grown up in an immersive computing environment. Where a notebook and pen may have formed the tool kit of prior generations, today?s students come to class armed with smart phones, laptops and iPods. This era of pervasive technology has significant implications for higher education. Nearly two-thirds (63%) of survey respondents from the public and private sectors say that technological innovation will have a major impact on teaching methodologies over the next five years. ?Technology allows students to become much more engaged in constructing their own knowledge, and cognitive studies show that ability is key to learning success,? says New York City-based Queens College vice-president of institutional advancement, Susan Henderson. Online degree programmes and distance learning have gained a firm foothold in universities around the world. What was once considered a niche channel for the delivery of educational content has rapidly become mainstream, creating wider access to education, new markets for content and expanded revenue opportunities for academic institutions. Sixty percent of those polled say that the technological change occurring in our midst will alter the perception of the college campus from a one-dimensional (physical) concept to a multi-dimensional (physical and online) one. ?Law school students enrolled in hybrid programmes that integrate distance and in-class education outperform those who study exclusively in one environment,? says Tom Delaney, associate dean and CIO of the New York University (NYU) School of Law, of the results of a recent limited trial at his school. New technologies are also affecting other areas of campus administration. Social-networking tools are helping to build connections with alumni and support career service activities. E-marketing campaigns expand the reach and success of recruiting and fundraising efforts, and drive down the cost of direct-mail campaigns. And automated, self-service programmes reduce administrative requirements, streamline course registration and enhance academic life. Although university participants view these changes as having a largely positive impact, many institutions struggle with the twin challenges of rising information technology (IT) costs and the need to avoid technological obsolescence. In addition, insufficient resources, a lack of adequate instructional design staff and other technological support issues can also impede the adoption of new technologies. Despite these challenges, most believe that technology will become ever more interwoven into the fabric of academic life. HOW TECHNOLOGY IS CHANGING IN TODAY`S CLASSROOMS: Technology is enabling multi-modal teaching, changing curricula and spawning rich forms of online research and collaboration. Nearly 60% of survey respondents say that professors will soon teach in more than one medium. At NYU?s top-ranked tax law programme, for instance, classroom courses are filmed with three cameras and a sound mixer. ?The course goes online within 30 minutes,? says Mr Delaney. ?Within 24 hours, students interested in reviewing a certain case or topic can click an online index that charts the content of the entire class and [can] view the portion that interests them.? When asked to compare different communications technologies, 52% of survey respondents state that online collaboration tools would make the greatest contribution in terms of improving educational quality over the next five years?the top response?while 48% point to the dynamic delivery of content and software that supports individually paced learning. Sophisticated learning-management systems and enhanced video and presentation tools are among other innovations that respondents say are likely to have a profound effect on the academic experience. It is interesting to note that despite the growing array of technology-enabled teaching tools available, nearly three-quarters of participants say that the greatest potential benefit of technology is something far more straightforward?namely, the expanded access to educational and reference resources that it provides. According to the survey results, online-collaboration tools, software that supports individually paced learning, and learning-management systems are among the communications technologies most expected to improve academics over the next five years. Web 2.0 technologies such as wikis, instant messaging and social networking?which have been influential in improving connectivity in many settings and are in use now at a large number of institutions?are expected to decline in use over that period. By contrast, online gaming and simulation software are cited by 54% of higher-education respondents and 59% of corporate respondents as an innovation likely to be adopted among universities over the next five years. Faculty members, administrators and CIOs are also exploring how web applications and freeware such as Google docs can improve efficiency and reduce costs. Collectively, such advances may lead to profound changes in the way courses are taught. ?Teaching will become more outcome-based and student-centred,? says Polley Ann McClure, CIO of Cornell University in Ithaca, New York. ?To be truly transformative,? she adds, ?instructional paradigms will have to shift.? Instead of focusing on memorisation of material by their students, instructors will focus on the application of knowledge to particular problems. Says Ms McClure: ?Students need to feel that they can plot their own academic path. If a student wants to, they should be allowed to take the final exam on the first day of school, and get credit for the portion of the course they?ve passed. If they answer 80% of the test correctly, for example, testing software would identify the issues behind the 20% of wrong answers and focus student attention on those areas instead.? It?s a view that others across the higher-education spectrum share. ?The professor?s role is evolving from instructor to mentor,? says Sam Scalise, CIO of Sonoma State University, in California?s wine country. ?Homework, quizzes and projects will have to be designed in such a way as to require genuine thoughtfulness on the part of the student. That paradigm shift offers enormous potential for advancing educational quality.? Finally, respondents foresee an interesting range of possibilities regarding how technology is most likely to affect future academic offerings, spurred by innovative faculty research, student engagement and the pursuit of academic collaboration. Over the next five years, 56% of respondents expect to see a greater number of interdisciplinary majors, combining chemical engineering and environmental studies for instance, and 43% foresee broader inter-university collaboration among students from multiple institutions. Looking beyond the five-year horizon, more than two-thirds of all respondents say that students will be able to craft individualised degree programmes, either within their own university or by bundling coursework from different institutions. And more than one-half see the publishing world evolving as a result of all these developments, with textbooks and printed documents eventually being replaced by online materials. ?The rise of online peer review may mean that some texts exist exclusively in virtual form, where they can be updated and refined in real time,? says Linda O?Brien, CIO of the University of Melbourne in Australia. THE EXPANDING ROLE OF ONLINE LEARNING: More than two-thirds of those surveyed from academic settings say their institutions offer online courses today. The specialisation, customisation and convenience that distance education affords has found an eager audience among students, working professionals and employers. Many academic institutions, and especially those with a public-service mandate, consider online learning key to advancing their mission, placing post-graduate education within reach of people who might otherwise not be able to access it. Recently named the top wired university in the US by PC Magazine, the University of Illinois at Urbana Champaign offers a case in point. As Scott D Johnson, CIO and associate dean for online learning in the College of Education, observes, ?As a public, land-grant university, our mission is grounded on the premise of education for all.? In January 2008 the university marked a significant leap forward in what had already been a long history in distance education, by launching the University of Illinois Global Campus?an integrated online programme created in collaboration with the colleges and academic departments at the university?s residential campuses. ?The ability to offer greater access to educational opportunities was the primary catalyst,? Dr Johnson acknowledges. ?There are many people who desire certification or degree programmes who simply cannot attend a residential programme, be they single mothers, working professionals or non-traditional students. It?s part of our public mission to reach those people, and we see e-learning as a vital tool in making that possible.? While distance-education programmes continue to grow in number and to improve in quality, most survey participants see online courses as a supplement to face-to-face classes, and nearly two-thirds of respondents maintain that traditional degrees carry greater credibility than those earned online. Corporate participants hold this view most staunchly. Few participants (11%) say that online and in-class students are likely to take the same classes together and compete for top grades. Perceptions may be shifting, however. A number of elite institutions, such as Johns Hopkins in Maryland and Stanford University in California, offer highly regarded online courses, and students who complete coursework through Stanford?s Educational Program for Gifted Youth (EPGY) and matriculate as undergraduates may use these credits towards their bachelor?s degrees. CONCLUSION: IN THE TRENDING YEARS WORLD WILL DO THE WHOLE WORK ALL THROUGH COMPUTERS AND LATEST TABS ARE AVAILABLE.
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Researchers look beyond space and time to cope with quantum theoryPublic release date: 28-Oct-2012 [ | E-mail | Share ]
Contact: Jenny Hogan jenny.hogan@quantumlah.org 65-651-64302 Centre for Quantum Technologies at the National University of Singapore
Physicists have proposed an experiment that could force us to make a choice between extremes to describe the behaviour of the Universe.
The proposal comes from an international team of researchers from Switzerland, Belgium, Spain and Singapore, and is published today in Nature Physics. It is based on what the researchers call a 'hidden influence inequality'. This exposes how quantum predictions challenge our best understanding about the nature of space and time, Einstein's theory of relativity.
"We are interested in whether we can explain the funky phenomena we observe without sacrificing our sense of things happening smoothly in space and time," says Jean-Daniel Bancal, one of the researchers behind the new result, who carried out the research at the University of Geneva in Switzerland. He is now at the Centre for Quantum Technologies at the National University of Singapore.
Excitingly, there is a real prospect of performing this test.
The implications of quantum theory have been troubling physicists since the theory was invented in the early 20th Century. The problem is that quantum theory predicts bizarre behaviour for particles such as two 'entangled' particles behaving as one even when far apart. This seems to violate our sense of cause and effect in space and time. Physicists call such behaviour 'nonlocal'.
It was Einstein who first drew attention to the worrying implications of what he termed the "spooky action at a distance" predicted by quantum mechanics. Measure one in a pair of entangled atoms to have its magnetic 'spin' pointing up, for example, and quantum physics says the other can immediately be found pointing in the opposite direction, wherever it is and even when one could not predict beforehand which particle would do what. Common sense tells us that any such coordinated behaviour must result from one of two arrangements. First, it could be arranged in advance. The second option is that it could be synchronised by some signal sent between the particles.
In the 1960s, John Bell came up with the first test to see whether entangled particles followed common sense. Specifically, a test of a 'Bell inequality' checks whether two particles' behaviour could have been based on prior arrangements. If measurements violate the inequality, pairs of particles are doing what quantum theory says: acting without any 'local hidden variables' directing their fate. Starting in the 1980s, experiments have found violations of Bell inequalities time and time again.
Quantum theory was the winner, it seemed. However, conventional tests of Bell inequalities can never completely kill hope of a common sense story involving signals that don't flout the principles of relativity. That's why the researchers set out to devise a new inequality that would probe the role of signals directly.
Experiments have already shown that if you want to invoke signals to explain things, the signals would have to be travelling faster than light more than 10,000 times the speed of light, in fact. To those who know that Einstein's relativity sets the speed of light as a universal speed limit, the idea of signals travelling 10,000 times as fast as light already sets alarm bells ringing. However, physicists have a getout: such signals might stay as 'hidden influences' useable for nothing, and thus not violating relativity. Only if the signals can be harnessed for faster-than-light communication do they openly contradict relativity.
The new hidden influence inequality shows that the getout won't work when it comes to quantum predictions. To derive their inequality, which sets up a measurement of entanglement between four particles, the researchers considered what behaviours are possible for four particles that are connected by influences that stay hidden and that travel at some arbitrary finite speed.
Mathematically (and mind-bogglingly), these constraints define an 80-dimensional object. The testable hidden influence inequality is the boundary of the shadow this 80-dimensional shape casts in 44 dimensions. The researchers showed that quantum predictions can lie outside this boundary, which means they are going against one of the assumptions. Outside the boundary, either the influences can't stay hidden, or they must have infinite speed.
Experimental groups can already entangle four particles, so a test is feasible in the near future (though the precision of experiments will need to improve to make the difference measurable). Such a test will boil down to measuring a single number. In a Universe following the standard relativistic laws we are used to, 7 is the limit. If nature behaves as quantum physics predicts, the result can go up to 7.3.
So if the result is greater than 7 in other words, if the quantum nature of the world is confirmed what will it mean?
Here, there are two choices. On the one hand, there is the option to defy relativity and 'unhide' the influences, which means accepting faster-than-light communication. Relativity is a successful theory that researchers would not call into question lightly, so for many physicists this is seen as the most extreme possibility.
The remaining option is to accept that influences must be infinitely fast or that there exists some process that has an equivalent effect when viewed in our spacetime. The current test couldn't distinguish. Either way, it would mean that the Universe is fundamentally nonlocal, in the sense that every bit of the Universe can be connected to any other bit anywhere, instantly. That such connections are possible defies our everyday intuition and represents another extreme solution, but arguably preferable to faster-than-light communication.
"Our result gives weight to the idea that quantum correlations somehow arise from outside spacetime, in the sense that no story in space and time can describe them," says Nicolas Gisin, Professor at the University of Geneva, Switzerland, and member of the team.
###
The researchers that carried out the work, in addition to Dr Bancal and Prof Gisin, are Dr Stefano Pironio from the Free University of Bruxelles in Belgium, Professor Antonio Acn from the Institute of Photonic Sciences (ICFO) in Barcelona, Dr Yeong-Cherng Liang from the University of Geneva, and Professor Valerio Scarani from the Centre for Quantum Technologies and the Department of Physics of the National University of Singapore.
Reference: J.-D. Bancal et al, Quantum nonlocality based on finite-speed causal influences leads to superluminal signalling", Nature Physics, DOI:10.1038/NPHYS2460 (2012).
Researcher Contacts
Dr Jean-Daniel Bancal
Centre for Quantum Technologies, National University of Singapore
+65 65165626
cqtbjd@nus.edu.sg
Professor Nicolas Gisin
University of Geneva, Switzerland
+41 2 2379 0502 (office) / +41 79 7762317 (mobile)
Nicolas.Gisin@unige.ch
Professor Antonio Acin
ICFO-The Institute of Photonic Sciences, Spain
+34 93 553 40 62
Antonio.Acin@icfo.es
[ | E-mail | Share ]
?
AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
Researchers look beyond space and time to cope with quantum theoryPublic release date: 28-Oct-2012 [ | E-mail | Share ]
Contact: Jenny Hogan jenny.hogan@quantumlah.org 65-651-64302 Centre for Quantum Technologies at the National University of Singapore
Physicists have proposed an experiment that could force us to make a choice between extremes to describe the behaviour of the Universe.
The proposal comes from an international team of researchers from Switzerland, Belgium, Spain and Singapore, and is published today in Nature Physics. It is based on what the researchers call a 'hidden influence inequality'. This exposes how quantum predictions challenge our best understanding about the nature of space and time, Einstein's theory of relativity.
"We are interested in whether we can explain the funky phenomena we observe without sacrificing our sense of things happening smoothly in space and time," says Jean-Daniel Bancal, one of the researchers behind the new result, who carried out the research at the University of Geneva in Switzerland. He is now at the Centre for Quantum Technologies at the National University of Singapore.
Excitingly, there is a real prospect of performing this test.
The implications of quantum theory have been troubling physicists since the theory was invented in the early 20th Century. The problem is that quantum theory predicts bizarre behaviour for particles such as two 'entangled' particles behaving as one even when far apart. This seems to violate our sense of cause and effect in space and time. Physicists call such behaviour 'nonlocal'.
It was Einstein who first drew attention to the worrying implications of what he termed the "spooky action at a distance" predicted by quantum mechanics. Measure one in a pair of entangled atoms to have its magnetic 'spin' pointing up, for example, and quantum physics says the other can immediately be found pointing in the opposite direction, wherever it is and even when one could not predict beforehand which particle would do what. Common sense tells us that any such coordinated behaviour must result from one of two arrangements. First, it could be arranged in advance. The second option is that it could be synchronised by some signal sent between the particles.
In the 1960s, John Bell came up with the first test to see whether entangled particles followed common sense. Specifically, a test of a 'Bell inequality' checks whether two particles' behaviour could have been based on prior arrangements. If measurements violate the inequality, pairs of particles are doing what quantum theory says: acting without any 'local hidden variables' directing their fate. Starting in the 1980s, experiments have found violations of Bell inequalities time and time again.
Quantum theory was the winner, it seemed. However, conventional tests of Bell inequalities can never completely kill hope of a common sense story involving signals that don't flout the principles of relativity. That's why the researchers set out to devise a new inequality that would probe the role of signals directly.
Experiments have already shown that if you want to invoke signals to explain things, the signals would have to be travelling faster than light more than 10,000 times the speed of light, in fact. To those who know that Einstein's relativity sets the speed of light as a universal speed limit, the idea of signals travelling 10,000 times as fast as light already sets alarm bells ringing. However, physicists have a getout: such signals might stay as 'hidden influences' useable for nothing, and thus not violating relativity. Only if the signals can be harnessed for faster-than-light communication do they openly contradict relativity.
The new hidden influence inequality shows that the getout won't work when it comes to quantum predictions. To derive their inequality, which sets up a measurement of entanglement between four particles, the researchers considered what behaviours are possible for four particles that are connected by influences that stay hidden and that travel at some arbitrary finite speed.
Mathematically (and mind-bogglingly), these constraints define an 80-dimensional object. The testable hidden influence inequality is the boundary of the shadow this 80-dimensional shape casts in 44 dimensions. The researchers showed that quantum predictions can lie outside this boundary, which means they are going against one of the assumptions. Outside the boundary, either the influences can't stay hidden, or they must have infinite speed.
Experimental groups can already entangle four particles, so a test is feasible in the near future (though the precision of experiments will need to improve to make the difference measurable). Such a test will boil down to measuring a single number. In a Universe following the standard relativistic laws we are used to, 7 is the limit. If nature behaves as quantum physics predicts, the result can go up to 7.3.
So if the result is greater than 7 in other words, if the quantum nature of the world is confirmed what will it mean?
Here, there are two choices. On the one hand, there is the option to defy relativity and 'unhide' the influences, which means accepting faster-than-light communication. Relativity is a successful theory that researchers would not call into question lightly, so for many physicists this is seen as the most extreme possibility.
The remaining option is to accept that influences must be infinitely fast or that there exists some process that has an equivalent effect when viewed in our spacetime. The current test couldn't distinguish. Either way, it would mean that the Universe is fundamentally nonlocal, in the sense that every bit of the Universe can be connected to any other bit anywhere, instantly. That such connections are possible defies our everyday intuition and represents another extreme solution, but arguably preferable to faster-than-light communication.
"Our result gives weight to the idea that quantum correlations somehow arise from outside spacetime, in the sense that no story in space and time can describe them," says Nicolas Gisin, Professor at the University of Geneva, Switzerland, and member of the team.
###
The researchers that carried out the work, in addition to Dr Bancal and Prof Gisin, are Dr Stefano Pironio from the Free University of Bruxelles in Belgium, Professor Antonio Acn from the Institute of Photonic Sciences (ICFO) in Barcelona, Dr Yeong-Cherng Liang from the University of Geneva, and Professor Valerio Scarani from the Centre for Quantum Technologies and the Department of Physics of the National University of Singapore.
Reference: J.-D. Bancal et al, Quantum nonlocality based on finite-speed causal influences leads to superluminal signalling", Nature Physics, DOI:10.1038/NPHYS2460 (2012).
Researcher Contacts
Dr Jean-Daniel Bancal
Centre for Quantum Technologies, National University of Singapore
+65 65165626
cqtbjd@nus.edu.sg
Professor Nicolas Gisin
University of Geneva, Switzerland
+41 2 2379 0502 (office) / +41 79 7762317 (mobile)
Nicolas.Gisin@unige.ch
Professor Antonio Acin
ICFO-The Institute of Photonic Sciences, Spain
+34 93 553 40 62
Antonio.Acin@icfo.es
[ | E-mail | Share ]
?
AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
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ScienceDaily (Oct. 28, 2012) ? Amyotrophic lateral sclerosis, also called Lou Gehrig's disease, is a devastatingly cruel neurodegenerative disorder that robs sufferers of the ability to move, speak and, finally, breathe. Now researchers at the Stanford University School of Medicine and San Francisco's Gladstone Institutes have used baker's yeast -- a tiny, one-celled organism -- to identify a chink in the armor of the currently incurable disease that may eventually lead to new therapies for human patients.
"Even though yeast and humans are separated by a billion years of evolution, we were able to use the power of yeast genetics to identify an unexpected potential drug target for ALS," said Aaron Gitler, PhD, an associate professor of genetics at Stanford. "Many neurodegenerative disorders such as ALS, Parkinson's and Alzheimer's exhibit protein clumping or misfolding within the neurons that is thought to either cause or contribute to the conditions. We are trying to figure out why these proteins aggregate in neurons in the brain and spinal cord, and what happens when they do."
In 2008, Gitler received a New Innovator award from the National Institutes of Health to use yeast as a model for understanding human neurodegenerative diseases and as a way to identify new targets for drug development.
Gitler is the co-senior author of the research, published online Oct. 28 in Nature Genetics. Robert Farese, Jr., MD, a senior investigator at the Gladstone Institutes, is the other co-senior author. Stanford graduate student Maria Armakola shares co-first authorship with Matthew Higgins, PhD, a postdoctoral scholar at Gladstone.
Most cases of ALS have no clear-cut cause. However, it has recently been shown that an RNA-binding protein called TDP-43 accumulates in clumps in the cytoplasm of spinal cord neurons in many people with the condition, and mutations in this protein have been found in some people with the ALS. Researchers like Gitler and Farese have been able to mimic the disease in yeast by expressing TDP-43 at higher-than-normal levels, which causes the protein to form lethal clumps in the cells' cytoplasm.
"In humans, the progression of the disease can take years before symptoms arise," said Gitler. "But in yeast, we see protein clumping in the cytoplasm within two days and the cells rapidly begin to die." With their model system in place, Gitler and Farese set out to see whether it was possible to protect yeast cells from this effect by tinkering with the function of other proteins in the cell.
In this study, the researchers discovered that blocking the production of a protein called Dbr1 in a yeast model stops the TDP-43 clumping and allows the cells to live normally. The researchers confirmed the results in human nerve cells grown in the laboratory and in rat neurons overexpressing TDP-43.
"In this study we made no assumptions as to how TDP-43 injures cells," said Farese, "but instead screened the whole yeast genome to find genes that might prevent the toxicity. Independently, both our lab and the Gitler lab found that loss of Dbr1, an enzyme involved in RNA processing, could do this."
Dbr1 serves as part of the cellular clean-up crew that mops up the bits of unwanted RNA generated as part of the protein production line. In our DNA, most genes consist of coding regions, called exons, broken up into several segments by non-coding regions, called introns. Cells can make many different, related proteins from the same stretch of DNA by mixing and matching different exons in a process called splicing.
When the DNA is first copied, or transcribed, into RNA, the introns as well as the exons are included. But the cell quickly splices out the introns, which are released into the cytoplasm as little loops, or lariats. Dbr1, in turn, clips the loops to open them and make them accessible to the cell's disposal system.
Blocking the production of Dbr1 causes the RNA lariats to build up in the cytoplasm. The researchers showed -- by creating lariats with a binding site for a fluorescent tracking protein -- that the mutant TDP-43 binds to these excess lariats rather than clumping. The effect is like using a paper towel to mop up a spill on your computer keyboard: binding to the lariats appears to keep TDP-43 from causing havoc elsewhere.
"Normally, TDP-43 is found in the nucleus," said first author Armakola. "But in the diseased cells, it aggregates in the cytoplasm and forms clumps. We developed a novel way to track where these lariats go in living cells, and we saw that when Dbr1 is missing, the lariats act as a sink to sequester TDP-43."
The researchers note that it's still not entirely clear whether the cells die because the mutant TDP-43 is drawing essential RNA transcripts or regulatory molecules away from the nucleus and into the cytoplasm, or because it's not performing its normal RNA-binding function in the nucleus. Both could contribute to the progression of the disease.
The results in the yeast, rodent and human cells, however, suggest that therapeutic approaches aimed at blocking Dbr1 function, or even creating artificial lariat-like formations to draw away the mutant molecule, should be explored.
"Next, we'd like to explore blocking Dbr1 function in animals such as flies, worms and rodents," said Armakola. "We're also interested in identifying small molecule inhibitors of Dbr1."
Other Stanford co-authors include graduate student Matthew Figley. The research was supported by the NIH, the Ellison Medical Foundation, the Packard Center for ALS Research at Johns Hopkins, the Consortium for Frontotemporal Research, the ALS Association, the Taube-Koret Center, the Hellman Family Foundation, the Pew Charitable Trusts, the Rita Allen Foundation, the Searle Scholars Program, the Keck Foundation and the National Center for Research Resources.
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The above story is reprinted from materials provided by Stanford University Medical Center. The original article was written by Krista Conger.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.
Journal Reference:
Maria Armakola, Matthew J Higgins, Matthew D Figley, Sami J Barmada, Emily A Scarborough, Zamia Diaz, Xiaodong Fang, James Shorter, Nevan J Krogan, Steven Finkbeiner, Robert V Farese Jr & Aaron D Gitler. Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nature Genetics, 28 October 2012 DOI: 10.1038/ng.2434
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.
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Public release date: 28-Oct-2012
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