Monday, December 3, 2012

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Scientists discover how two proteins help keep cells healthy: Implications for cancer drug development

ScienceDaily (Nov. 29, 2012) ? Scientists at The Scripps Research Institute (TSRI) have determined how two proteins help create organelles, or specialized subunits within a cell, that play a vital role in maintaining cell health. This discovery opens the door for research on substances that could interfere with the formation of these organelles and lead to new therapies for cancer.

The study, published online ahead of print on December 2, 2012, by the journal Nature Structural & Molecular Biology, focuses on the structure and function of the two proteins, ATG12 and ATG5. These proteins need to bond correctly to form an organelle called the autophagosome, which acts like a trash bag that removes toxic materials and provides the cell with nutrition through recycling.

"Our study focuses on one of the big mysteries in our field," said Takanori Otomo, the TSRI scientist who led the effort. "These proteins are linked, but no one has explained why clearly. We're very excited to have determined the structure of these linked proteins so that the information is available to do the next level of research."

Asking Questions, Finding Answers

At the beginning of the study, Otomo and colleagues knew that many proteins work together to form autophagosomes as part of the process known as autophagy, which breaks down large proteins, invasive pathogens, cell waste, and toxic materials. As part of this process, one key protein, LC3, attaches to a lipid, or fat molecule, on the autophagosome membrane. Yet LC3 cannot attach to a lipid without the help of ATG12 and ATG5, and a cell will only form an autophagosome if the linkage, or conjugate, between these two molecules has been established.

Otomo and colleagues set out to determine the shape of the ATG12-ATG5 conjugate, and to find out why it was needed for LC3 lipidation.

Using a method called X-ray crystallography, the scientists were able to unveil the details of this conjugate. When ATG12 and ATG5 come together, they form a rigid architecture and create a surface area that is made up of evolutionarily conserved amino acids and facilitates LC3 lipidation. The researchers confirmed this finding by mutating those conserved amino acids , which prevented an autophagosome from forming.

Otomo and colleagues also identified a surface on the ATG12-ATG5 conjugate that binds to ATG3, another enzyme required to attach LC3 to the lipid.

Toward Better Understanding and New Cancer Treatments

With this new knowledge, the researchers hope to design molecules that inhibit autophagosome formation, a direction of research that has implications for cancer treatment. A drug that directly inhibits ATG3 binding, for example, could be used in coordination with current therapies to make cancer treatments more effective, preventing a cancer cell from recycling nutrients and prolonging its survival.

"Ultimately, we'd like to understand the molecular mechanisms of each step of autophagy," he said, "As we make progress toward this goal, we will have a better idea of how to manipulate the pathway for therapeutic purposes. This field is still young and there are a lot of unknowns. This work is just the beginning."

This research was supported by National Institutes of Health (NIH) grant GM092740 and by funds from Japan Science and Technology Agency through the Keio Kanrinmaru Project.

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The above story is reprinted from materials provided by The Scripps Research Institute.

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Journal Reference:

  1. Chinatsu Otomo, Zoltan Metlagel, Giichi Takaesu, Takanori Otomo. Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy. Nature Structural & Molecular Biology, 2012; DOI: 10.1038/nsmb.2431

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

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

Source: http://feeds.sciencedaily.com/~r/sciencedaily/top_news/top_health/~3/efU9jJ_Od0I/121202164103.htm

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Sunday, December 2, 2012

Jovan Belcher, Kansas City Chiefs Player, Kills Girlfriend, Then Himself

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More mannequins, less clutter at heart of JC Penney plan

NEW YORK (Reuters) - More mannequins are on the floors of J.C. Penney stores. About 40,000 more.

They are one of the most visible changes J.C. Penney Co Inc Chief Creative Officer Michael Fisher has made to try to revive the 110-year-old department store chain, whose sales plunged 26.6 percent last quarter and whose shares have tumbled more than 50 percent this year.

Penney has a plan to transform its 700 larger stores by 2015: each store will contain 100 boutiques, offering brand-name fashion and home merchandise ranging from Levi's to PVH Corp's Izod to Martha Stewart.

Eight boutiques have been rolled out so far and the feedback has been good. But these chic spaces take up only a small part of a store, and about 89 percent of the floor is still the so-called "Old J.C. Penney."

That's where Fisher's new mannequins come in. The goal is to spruce up old store areas and stem the sales slide as more boutiques are introduced.

"Customers don't know what to buy. They love a mannequin that shows you how to put the outfit together," said Fisher, 55, as he gave Reuters a tour of Penney's Manhattan store last week.

"We find anything we put on a mannequin sells out."

That may sound like Retail 101 but it reflects a radical rethinking of the Penney shopping experience under CEO Ron Johnson, who joined the company from Apple Inc in late 2011. He poached Fisher from Apple in February this year.

Their strategy is to make Penney look like an upscale specialty store that still offers inexpensive wares, not a bazaar overflowing with ordinary merchandise and discount signs.

Pants, ties and shirts used to be presented in separate blocks in the men's section, but are now mingled together to make it easier for a shopper to imagine mixing and matching - and to encourage customers to buy more than one item. Plastic wrapping has been removed from men's dress shirts for a more upmarket presentation.

Another trick of the trade Fisher is using is the "ballet bar" clothing rack, which has one bar set a few inches above another - so tops and bottoms can be displayed together, again to suggest a whole outfit to the shopper.

These changes are not without risk - they could backfire and alienate Penney's traditional, discount-obsessed shopper.

"It's going to be for people who have more money," said long-time Penney shopper Elizabeth Sadallah, 52, as she hunted for bargains at a Penney store in Elmhurst, New York.

Patty Edwards, chief investment officer at Trutina Financial, warned that Penney may be overdoing the overhaul, even as she called the new boutiques "gorgeous" and "Apple-esque" in their design.

"Here's my concern: that's not their consumer," she said, adding that it was more urgent for Penney to improve its marketing to convince shoppers they are getting good deals.

Penney, which has about 1,100 stores, has stagnated for years, and was slow to recover from the last recession compared with Macy's Inc or Kohl's Corp . But analysts blame the hemorrhage in revenue this year to Johnson's move to scrap most coupons and sales events in favor of an "everyday low price" strategy.

Edwards said Penney's recent effort to highlight its relatively low prices by putting manufacturers' suggested retail price on price tags is a step in the right direction.

AIMING HIGHER

Fisher and Johnson worked together on Apple's stores, which are widely admired and generate $6,060 in annual sales per square foot, according to research from RetailSales.

While Apple's 390 stores are very different from Penney's much larger chain, there is clearly room for improvement.

Johnson has said Penney's new boutiques are generating sales at an annual rate of $269 a square foot, twice what the old parts of the stores do. Johnson also has said Penney can eventually get to numbers comparable to a specialty chain's. Last year, Gap Inc posted sales of $391 per square foot.

Fisher, who worked for Bloomingdale's for 17 years and guided Coach Inc's expansion in Japan, grew up in Pottstown, Pennsylvania, and remembers a time when shopping at the local Penney was a special treat - a nicer place than the local Sears , he said.

That is the Penney he wants to help recreate, from sprucing up the kids sections to offer more than basics, to taking a page from IKEA for the home section, where products will be displayed as they would appear in a room.

Fisher said the importance of de-cluttering struck him one day when he saw a woman struggling to get to merchandise as she pushed a stroller at the Penney store in Manhattan.

"That's been my challenge, to turn 'J.C. Penney' into 'jcp' and treat it as a fashion specialty store," he said, referring to the hipper name the company is rebranding itself as.

Fisher sees signs of progress. Pointing to a young, hip shopper in red, skinny jeans, sneakers and a hoodie, he said he doubted that guy would have shopped in a Penney store before.

(Reporting by Phil Wahba in New York; Additional reporting by Poornima Gupta; Editing by Edward Tobin, Tiffany Wu and Maureen Bavdek)

Source: http://news.yahoo.com/more-mannequins-less-clutter-heart-jc-penney-plan-205717573--sector.html

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Saturday, December 1, 2012

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Economics and Investing: - SurvivalBlog.com

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Odds 'n Sods: was the previous entry in this blog.

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10 Questions To Ask When Choosing An Accountant | Tax Help HQ

The vast majority of small businesses could use the services of an accountant. The number of ways in which it is possible to introduce errors into your business through accounting practices is staggering. Your accounting includes issues related to payroll, monitoring profitability, inventory control, avoiding penalties and interest on taxes, and much, much more. It is wise to select a competent professional in this field to help you navigate the minefield of accounting pitfalls. Selecting such a professional can be difficult, especially since not all accountants are created equal. Here are some questions to ask to help ensure that you are selecting the best accountant you can for your business.

1. Are they recommended by a trusted colleague?

One way to start the search for an accountant is to ask people that you already trust for suggestions. Your banker, insurance agent, attorney, and financial planner most likely know and work with accountants on a regular basis. Also inquire to the companies that you do business with, such as you barber, florist, butcher, and plumber. Chances are, these sorts of business owners use an accountant for some business functions, since these tend to be the types of business owners that are excellent at what they do, but not so great with dealing with the complexities of taxes and accounting.

2. Ask around your Chamber of Commerce.

If you are familiar with your local Chamber, they can be an excellent resource. You can ask at Chamber events for referrals to accountants, and you are likely to meet many such service providers at Chamber functions, trade events, and leads groups. Also, many Chambers have an internal complaint system and can let you know whether or not complaints have been issued locally against an accountant or firm.

3. Do they have any complaints with the Better Business Bureau?

When many individuals decide to take action and make a complaint against a firm, they often think first of the BBB. Check with your local division, or look them up online, and make sure that the company you are considering hiring has a good record with the BBB. If they have a Gold Star award from the BBB, then you?re on the right track to working with a company that is reputable and stands by their word. The BBB?s new letter grading system can also help you in selecting a good firm.

4. Have they ever been investigated by your state Attorney General?s office or state board of accountancy?

This is another place to do your own due diligence. Complaints with the state AG or Board of Accountancy is an automatic red flag and should be highly considered before selecting a firm.

5. What services do they provide, and what services do you NEED?

Think about exactly what you?re looking for in a service provider. Do you need full service accounting, outsourcing all functions to another person or firm? Or do you just need year-end tax preparation? Knowing the answer to what services you need will help you pick the best person to do what you need, and will affect your budget for getting it done. For example, if you just need tax preparation, then you might be better off with an experienced tax preparer instead of a CPA firm that mostly does auditing and general accounting. If you only need payroll services, then you might want to hire a payroll company rather than a bookkeeper that does payroll on the side. If you need the books updated weekly or monthly, most communities have competent, independent full charge bookkeepers that you can hire.

If you?re looking for somebody to come set up your books and show you how to use your accounting software, you may want to consider a general CPA or a competent bookkeeper. If you do all your own books using Peachtree, Quickbooks, MS Money, or another popular commercial software package, it can be very helpful to have somebody to call should something go wrong. The large commercial accounting software publishers all provide some sort of certified expert rating system for individuals that are experts on using their software. You may want to look for and consult with such a certified expert on your particular accounting software. For example, Intuit offers its Quickbooks Certified ProAdvisor program to consultants. Finding one of these certified individuals can really help you a lot if you?re doing the books yourself.

If your only interest is in tax compliance, look for a CPA that specializes in taxation, or an Enrolled Agent (EA). An EA is an individual licensed directly by the U.S. Treasury to handle tax matters, and this individual can represent you before the IRS just like a CPA or an attorney. By nature of the credential, EAs are dedicated tax professionals and are generally more competent in areas of tax issues than a general CPA, unlicensed tax preparer, or bookkeeper.

Selecting the type of professional you need is a serious consideration in this process, and depends largely on what you plan on doing yourself, and what you expect to need help with.

6. Are they licensed in some way?

Credentials are not always the most important thing to consider, but they do reflect at least a minimum level of professional competency, in theory. If they are a CPA, they?ve passed a rigorous four part examination and have at least a bachelor?s degree in accounting and two years of professional experience, at a minimum. If they are an Enrolled Agent, they have passed a very rigorous three part exam covering individuals, businesses, and practices and ethics that is administered directly by the Internal Revenue Service.

The individual preparing your tax returns, doing your books, or processing your payroll doesn?t necessarily need credentials in order to do the tax and do it right, so experience is a critical piece of the puzzle you?ll want to inquire about.

Do keep in mind that if you?re audited by the IRS, only CPAs, EAs, or attorneys can represent you, unless you wish to represent yourself, which is not recommended.

7. How much experience do they have?

How many years have they been doing what they do? What type of companies do they generally work with, such as which industries and what size companies? Inquire as to how many of each of your type of entity they work with each year. If they?re experienced working with your type of legal entity, within your industry, or your size of company, they might be a good fit.

8. How do they charge, and how much?

Don?t be afraid to ask about the money. Some firms will charge by the hour, or on a piece rate for the type of work being done. Bookkeepers will usually charge an hourly rate, while tax preparers often charge a flat rate per form and schedule. If your tax return is pretty complex, expect to pay more, which could be a base rate plus an hourly rate for doing accounting work to generate the numbers needed for various line items on the return. If you?ll be seeking software assistance, find out what they will charge for this, usually at an hourly rate. It can?t hurt to know whether you?ll be over your head in terms of what you can reasonably afford for the services you are seeking.

A word of caution: Price should not be the ultimate determining factor when decided who to use and what services to do yourself. If you?re genuinely over your head when it comes to certain tasks, don?t be afraid to spend the money. There?s an old saying that goes like this, ?Do what you do best, hire out the rest.? Accounting can be one of the most frustrating aspects of owning a business, and trying to do it all yourself can take time away from what you should be doing, which is running your business to the best of your ability to generate a profit.

9. Are you comfortable with the individual?

Even if you hire a large firm to do your accounting, there is still going to be an individual person that will be doing the work and with whom you will work with almost exclusively. You need to sit down with this person and make sure that you are comfortable working with them. If anything makes you uncomfortable in any way, you need to find somebody else. Think about it: This person is going to have access to an incredible amount of private financial information, so it has to be somebody you feel comfortable trusting.

10. Don?t be afraid to make a change.

Even after selecting somebody to work with, don?t be afraid to find somebody else if things aren?t working out. Your accounting is too important to the success of your business to leave it in the hands of an incompetent person or somebody you don?t completely trust. Problems with your current accountant could range from having just plain bad interpersonal chemistry to gross incompetence on their part, or perhaps you have the wrong specialist to meet your needs. Regardless, don?t hesitate to take your business elsewhere, since your accounting, bookkeeping, and taxes are simply that important to the life of your business.

Using the ten steps outlined in this article will give you a great start towards finding the accountant that is right for you. Identify the type of professional that can best provide the services you need, ask around for referrals, then check them out and interview them personally. This process will ensure that you get the best accountant for your business needs.

Source: http://taxhelphq.com/blog/personal-finance/10-questions-to-ask-when-choosing-an-accountant/?utm_source=rss&utm_medium=rss&utm_campaign=10-questions-to-ask-when-choosing-an-accountant

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