UPDATED 12:15 p.m. ET: Peter Madoff, the?brother of convicted scammer Bernie Madoff, pleaded guilty Friday to doctoring records to hide?the?Ponzi scheme orchestrated by his older sibling that swindled thousands of people out of billions of dollars and stunned the world?in?the throes of the financial crisis.
"I am deeply ashamed of my actions," he told a hearing in downtown Manhattan federal court on Friday morning, several hours after he was taken into custody by FBI agents at his lawyer's office in midtown Manhattan.
"I want to apologize to anyone who was harmed and my family. I'm here to take responsibility for my actions," Peter Madof
Peter Madoff, 66,?had been?arrested earlier?Friday at his lawyer's office in?midtown Manhattan and had been expected to enter the guilty plea for which he's expected to get 10 years in prison. He?entered the plea?in the same courthouse where his brother, 74, was convicted and sentenced in March 2009 to 150 years in prison for the largest Ponzi scheme ever.
"Peter Madoff enabled the largest fraud in human history. He will now be jailed well into old age, and he will forfeit virtually every penny he has. We are not yet finished calling to account everyone responsible for the epic fraud of Bernard Madoff and the epic pain of his many victims," said Manhattan U.S. Attorney Preet Bharara in a statement.
Federal prosecutors on Wednesday revealed in a letter that Peter Madoff had been criminally charged with participating in his brother's fraud. He and his brother are the only?Madoff family members to have been arrested and charged in the Ponzi scheme.
The letter, filed in federal court in Manhattan, said Peter Madoff would?plead guilty to charges of conspiracy to commit securities fraud and falsifying records as well as other charges. He agreed not to seek a sentence other than 10 years in prison, the letter said.
Peter Madoff also agreed to forfeit about $143.1 billion, including all real and personal property, the letter said. The amount is symbolic, being more than twice the estimated size of the fraud.
John Wing, a lawyer for Peter Madoff, did not immediately respond to a request for comment.
Peter Madoff was chief compliance officer at Bernard L. Madoff Investment Securities LLC when his brother was arrested on December 11, 2008.
Prosecutors have not said whether criminal cases are also being prepared against Bernard Madoff's son, Andrew, who was co-director of trading, or his niece, Shana, who was a compliance officer at the firm.
In May, Irving Picard, the trustee seeking money for victims of the Ponzi scheme, named members of Madoff's family in an expanded $255.3 million lawsuit, claiming they should have detected Bernard Madoff's Ponzi scheme at the firm that operated "as if it were their family piggy bank."
Besides Madoff's brother Peter, Picard sued Andrew Madoff, who was co-director of trading; the estate of son Mark, co-director of trading who committed suicide in December 2010; and Shana Madoff.
In the lawsuit, Picard described Peter Madoff as a savvy investor who once served as vice-chairman of the board of governors of the Financial Industry Regulatory Authority.
Picard is seeking $90.4 million from Peter, $81.3 million from Mark Madoff's estate, $73.8 million from Andrew and $15.3 million from Shana.
Lawyers for Andrew and Shana Madoff did not immediately return calls seeking comment.
Between 1993 and 2008, Peter Madoff was paid over $36 million in salary and bonuses, Picard said, and the firm funded his lavish lifestyle, including $140,000 for a Ferrari in 1995 and a home on Manhattan's upscale Park Avenue.
Peter Madoff is charged with one count of conspiracy to commit securities fraud and mail fraud as well as making false statements about the firm's compliance program and investment advisory business.
He is also charged with falsifying records.
About a dozen people have now been implicated in criminal wrongdoing related to the Madoff firm.
Five have pleaded not guilty: Annette Bongiorno, Daniel Bonventre, Joann Crupi, Jerome O'Hara and George Perez.
Frank DiPascali, the former chief financial officer often called Bernard Madoff's right-hand man, pleaded guilty in August 2009 and has been praised by prosecutors for his cooperation. He has yet to be sentenced.
Picard has estimated customers of the Madoff firm lost about $20 billion. On Monday, the U.S. Supreme Court let stand a lower court ruling on the trustee's methods for calculating losses. That decision could help Picard repay customers faster.?
Thursday, September 11, 2003 Copyright ? Las Vegas Review-Journal
INTERNET EXTRA: Eldorado edges Desert Pines in girls tennis
REVIEW-JOURNAL
Teresa Del Rosario and Amanda Joya won their final doubles set, lifting Eldorado's girls to a 24-21 victory over visiting Desert Pines on Wednesday.
Del Rosario and Joya finished 2-1, as did Sundevils singles players Amber Hee, Dorianne Bautista and Ilene Burneal.
Lindsey Axberg went 3-0 in singles for Desert Pines.
At Basic, Tory Jackson and Jennifer Carey won their final doubles set, breaking a tie and giving the Wolves a 24-21 victory over Silverado.
Jenny Howe and Ashley Rather went 3-0 in doubles for the Skyhawks.
At Green Valley, Kirsten Garlock was 2-0 in singles as the Gators defeated Boulder City, 45-0.
Christina Delaberta and C.J. Akslerad went 2-0 in doubles for Green Valley.
At Coronado, Michele Hoover (3-0) and Brittany Hanna (2-0) went undefeated in singles as the Cougars routed Foothill, 42-3.
The doubles teams of Brianne Dalton and Jasmine Smith, and Sara Terry and Michelle Lindsey each went 2-0 for Coronado.
At Valley, Raquel Martinez and Leslie Larson each went 3-0 in singles to lead Las Vegas to a 31-14 victory over the Vikings.
Valley's Sharyl Collins and Gaby Baca went 3-0 in doubles.
At Cimarron-Memorial, Amy Dixon went 3-0 in singles, helping the Spartans defeat Shadow Ridge, 27-18.
Cimarron's Melissa Faller and Juliane Busch went 3-0 in doubles.
Rebecca Schneider and Desi D'Arienco went 2-1 in doubles for the Mustangs.
At Centennial, the doubles teams of Ashton Aguilar and Ashley Max, Adrienne Aguilar and Teresa Healy, and Tory Healy and Gabrielle Gibson each went 2-0, leading the Bulldogs to a 34-11 victory over Cheyenne.
Katrina Agnir was 3-0 in singles for the Desert Shields.
At Durango, the Trailblazers defeated Clark, 43-2.
At Overton, Rancho defeated Moapa Valley, 45-0.
? BOYS -- At Clark, Charleston Chua went 2-0 in singles to lead the Chargers to a 25-20 victory over Durango.
Alan Phung and Bryan Ngo went 3-0 in doubles for the Trailblazers.
At Bonanza, Alec Runyon and Jonathan Ribaste went 3-0 in doubles as the Bengals defeated Bishop Gorman, 42-3.
Ernie Domanico was 3-0 in singles for Bonanza.
At Shadow Ridge, Caleb McWaters and Frank Galizia went 3-0 in doubles to lead Cimarron-Memorial to a 39-6 victory over the Mustangs.
At Cheyenne, Cameron McDonald was 3-0 in singles as Centennial defeated the Desert Shields, 26-19.
The Bulldogs' Jeff Lavigne and Adam Miller went 2-0 in doubles.
At Foothill, Shai Perry and Mike Lukowski each went 3-0 in singles as Coronado defeated the Falcons, 39-6.
The doubles teams of Kevin Schlegel and Andy McCosh, and Gustavo Garbin and Jesse Caps also went 3-0 for Coronado.
Foothill's Bjorn Blomquist was 2-1 in singles.
At Las Vegas, brothers Angel and Mike Getsov were 3-0 in doubles, leading Valley to a 27-18 victory over the Wildcats.
Las Vegas' Ted Shively was 3-0 in singles.
At Silverado, Trent Alenick and Jonathan Frogoso each went 3-0 in singles as the Skyhawks defeated Basic, 30-15.
Silverado's Anthony Rivero went 2-0 in singles, and Chris Painter and Ryan Nardi went 2-0 in doubles.
At Rancho, Mason Stratton was 3-0 in singles, and Jace Davis and Sebastian Kloos went 2-0 in doubles, leading Moapa Valley to a 35-10 victory over the Rams.
Rancho's Daniel Goodwin and Chris Smyser went 2-1 in doubles.
At Boulder City, Casey Quenzler was 3-0 in singles, leading Green Valley to a 33-12 victory over the Eagles.
We're all a bit tired of the "X is Twilio for Y" brand of analogies (though it's refreshing to see more of Twilio in this equation than Airbnb these days), but if ever there were an industry in need of some modern, standardizing APIs it would be education. Thankfully, Clever, a San Francisco-based startup and member of Y Combinator's current batch, is today launching a solution that brings some of the Twilio vision to education.
'Dateline NBC,' the signature broadcast for NBC News in primetime, premiered in 1992. Since then, it has been pioneering a new approach to primetime news programming. The multi-night franchise, supplemented by frequent specials, allows NBC to consistently and comprehensively present the highest-quality reporting, investigative features, breaking news coverage and newsmaker profiles.
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A pivotal plea for brands in today?s increasingly online universe is building a personal attribute with their customers. While broadcasting still stays a viable and effective hold point, consumers design one-to-one relations with their favourite brands and retailers ? online channels straightforwardly concede this.
Consequently, online remoteness and confidence is a essential issue, not slightest given a new EU Directive. This legislation, rather than being noticed as increasing red tape, should be embraced as an event by brands and online stores to build some-more insinuate relations with their customers.
The credentials to this is that we, as consumers, design brands to strengthen a information and have remoteness during a forefront of their business. Yet we frequently hear stories about a association that has been obliged for a detriment of a customers? financial or login sum or people that have been influenced by an online security breach.
LinkedIn, a business-oriented amicable networking site, was a latest to be affected by a information breach where millions of customers? passwords were stolen.
Worryingly, too many brands are unwell to recognize consumers? expectations around this subject as important, and are not doing adequate to solve their miss of trust when they emporium online. So as some-more association websites ask people give adult their personal information, it?s distinct because so many demonstrate concerns and reservations about how their information is being rubbed by companies and what remoteness policies are in place.
According to a new G2 eCulturesEUROPE Report that surveyed over 6,500 European online users, there is an expectancy of brands to hoop personal information responsibly, and consumers are open for brands to boost communication and rendezvous about their remoteness policy. These companies contingency take a event to boost patron loyalty, as good as have an impact on their bottom-line.
Fort Campbell, KY ? If you haven?t tried out some of the Outdoor Recreation Adventure Programs yet ? July is the perfect time to sign up! Outdoor Recreation will start the month off with a King?s Bluff Climbing Trip on July 7th from 9:00am until 2:00pm. Ages 12 and above are invited to participate and the cost is $35.00 per person; transportation and equipment are provided.
King?s Bluff is some of the best climbing in Middle Tennessee and is located just 15 minutes from post. Please bring appropriate clothing, water, snacks, and a packed lunch. This trip is geared towards beginners so all are welcome. Preregistration is required by 4:00pm on July 6th.
Are you interested in learning how to kayak or just want to work on your skills? Come out on July 8th from 6:00pm until 9:00pm for the Whitewater Kayak Pool Clinic and the Outdoor Recreation staff will work with you on various techniques which include boat selection, proper fitting, paddle strokes, bracing and even the Eskimo roll. These sessions are designed for all experience levels. Ages 12 and over may participate and must preregister by 4:00pm on July 6th. Participants will meet at Gardner Pool for the class.
Are you looking for something the entire Family can do together? On July 14th and 15th, Outdoor Rec will be hosting a LBL Family Camping Weekend. With 170,000 acres and over 300 miles of undeveloped shore line, Land Between the Lakes is the perfect summer getaway. Outdoor Recreation will be providing canoes, kayaks, bikes, dinner and breakfast. Fishing is allowed but make sure you obtain the proper licenses from the Outdoor Recreation Main Office prior to departure. The trip leaves on July 14th at 1:00pm and will return on July 15th at approximately noon. The cost is $19.00 per person. This is a great way to relax under the stars with your Family. Please bring your own tent or any additional items you may need for the trip. Preregistration is required by 4:00pm on July 12th.
Put those new-found kayaking skills to use and join Outdoor Recreation on July 21st for a Caney Fork Kayak Trip. This trip will leave at 8:00am and return at 6:00pm. The cost is $25.00 and ages 10 and above may participate. The Caney Fork is a Class I river with world class trout fishing. Let Outdoor Recreation help you enjoy a wonderful day on the river paddling their sit-on-top kayaks. Don?t forget to obtain a fishing license and trout stamp if you plan to fish. You?ll be floating a 5 to 8 mile stretch of water so remember to bring plenty of sun screen, food and water. Preregistration is required by 4:00pm on July 19th.
Outdoor Recreation will be taking you on a Lock Four Mountain Biking trip on July 22nd from 8:00am until 4:00pm. Ages 14 and above are invited to participate. The cost is $19.00 per person. Located in Gallatin, TN, Lock Four is one of the best mountain biking destinations in the
Nashville area. With over 8 miles of exciting single track on Old Hickory Lake, Lock Four has something to offer cyclists of all levels of experience. Don?t forget to bring food, water and closed toe shoes. Helmets and bikes will be provided. Preregistration is required by 4:00pm on July 20th.
Take a relaxing Family Floats on July 25th from 4:00pm until 8:00pm. Ages 6 and above may participate and the cost is $10.00 per person. All transportation and equipment is included. You will paddle a five mile stretch of the Cumberland River. Located in downtown Clarksville, the Cumberland River is a great location to spend the afternoon canoeing. Preregistration is required by 4:00pm on July 24th.
The Ocoee River, located in Southeastern Tennessee, is one of the gems in the whitewater industry. On July 28th, Outdoor Recreation will be taking a trip to this home of the 1996 US Olympics where they will paddle 5+ miles with rapids ranging from Class III to IV. The cost is $85.00 per person. Transportation and all rafting equipment are included. Participants must be at least 14 years old. Please bring secure shoes (no flip flops), lunch and extra money for souvenirs or dinner on the ride home. Preregistration is required by 4:00pm on July 17th.
For more information about their July activities, please call Outdoor Recreation Adventure Programs at 270.412.7854.
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Bikes, Breakfast, Caney Fork Kayak Trip, Caney Fork River, Canoeing, Canoes, Cumberland River, Dinner, Downtown Clarksville, Family Floats, Fishing, Fishing License, Fort Campbell KY, Gardner Pool, Kayaks, King's Bluff Climbing Trip, Kings bluff, Land Between the Lakes National Recreation Area, LBL, LBL Family Camping Weekend, Lock Four Mountain Biking, Middle Tennessee, Mountain Biking, Nashville TN, Ocoee River, Old Hickory Lake, Outdoor Recreation, Outdoor Recreation Adventure Programs, Preregistration, Rapids, Tennessee, Trout, Trout Fishing, Whitewater Kayak Pool Clinic
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If you have been on the web for more than each day you?ve almost certainly heard some ?guru? somewhere advocate that you Air Max Pas Cher generate a Cash Magnet Website ? a web site which is very automated and assists you earn money 24 hours a day. Whilst that may *sound* fantastic, what they usually overlook to let you know is How to do that.
Well, I am likely to let you know appropriate now, within this post!
Very first, what is a Cash Magnet Website A Cash Magnet Web site could be defined as one that is outfitted having an built-in suite of both e-commerce and web advertising and marketing tools inside a style that may let you to be one of the most profitable with the the very least amount of work.
Most e-commerce methods are equipped using the following necessities: a buying cart, acceptance and processing of credit cards, a maintenance technique that allows you to add|alter products, an order-retrieval technique that permits you to satisfy orders.
Even so, what most of them are missing are marketing and advertising resources. You will find numerous marketing and advertising tactics that happen to be essential inside the creation of the effective e-commerce web site: e mail advertising and marketing (broadcasting) of prospective customers|buyers, productive use of autoresponders (generate automated email messages), on the internet publication, online form|survey to capture your prospect?s email deal with digital product delivery (in case you sold an electronic product), ad (ad) monitoring, back again end sales, affiliate plan.
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A prospect clicks on an ad in an internet journal. This action increments a counter for this distinct ad to help you establish how well it is Air Max Pas Cher working. They do not make a decision to purchase as of but but become a member of your newsletter. They may be now regarded as a potential customer. You begin to deliver them a monthly email publication. In addition, an autoresponder kicks in to thank them for joining the publication in addition to scheduling them to obtain e mail two times on a monthly basis for the next ninety times reiterating your item advantages and inviting them to buy.
Upon delivering them one of your ?juicy? delivers which they couldn?t refuse, they lastly buy. They?ll instantly be removed from your prospect list and added for your customer checklist.
Based on the specific product or service they have purchased, they are going to get a collection of emails each two weeks for your subsequent 6 months providing complementary goods. This may be the engine that may generate your again end product sales and keep your clients coming back to your website.
Being able to play out a scenario for example this making use of a single integrated technique would be fairly impressive don?t you believe The world wide web massive boys do this with costly e-commerce platform suites made by vendors like IBM, Microsoft and Oracle. Getting your system automatically execute these adhere to up duties frees you as much as invest a lot more time on your business, your health or your loved ones!
=====> What can you do to obtain an Air Max Pas Cher funds magnet website
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=====> Are there any other solutions to automate your business in addition to operating with a complete solution supplier
You?ll be able to accomplish some level of automation with no an integrated shopping cart method, however, it?s going to demand handbook intervention and naturally it would be incomplete. I think that one of the most critical asset of one?s e-commerce enterprise is your e-mail lists. For that reason, focus on the implementation of a good autoresponder|checklist server method to ?enhance? your current e-commerce web site. There are many very good ones around the market place.
Look for providers that Nike Air Max allow you to: develop several lists, add prospects through a web type, e mail, or manually via a conduite console, deliver out an limitless number of autoresponder messages, mail out an unlimited variety of e-mail broadcasts, set up and distribute a newsletter.
When setting up your autoresponder method, develop a single list for your ?prospects? and an additional 1 to your ?customers?. Now, this is where you are available in: when a person orders your product, you may must carry out the extra task of logging into your autoresponder system and manually remove them from the potential customer checklist and add them towards the client checklist. This action will then trigger your customer autoresponder sequence of messages to be sent.
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By incorporating a three-step ladder that disappears into its front facade, this extra-tall shelf lets you maximize the storage space in your home, without requiring you to fetch a step ladder every time you need something off the top tier. More »
For many the term arthritis is linked to senior years, but that isn't the truth. Arthritis is really a fancy word intended for joint inflammation and may affect someone any kind involving time age group. The most prevalent word to go into detail arthritis symptoms is usually rheumatism.
Chiropractic treatment method for arthritis depends upon what form of chiropractor, regardless of whether she or he is an aligned chiropractic doctor or perhaps a mixed chiropractic doctor. Straight doctors of chiropractic manipulate the backbone to take care of the subluxation together with some other imbalances. Merged chiropractors normally take care of the problem which has a spinal adjustment along with using other treatments like acupressure.
Medical doctor Lynn Kelly, Deb. Chemical. has discovered the improperly transferring joints due to misalignments with the bones as being the top reason behind arthritis. Vertebral manipulations will forever involve requirements from the our bones "popping". Needs is definitely the knees and other joints relieving tiny gasoline pockets (mostly regarding nitrogen) because of the adjustment from the backbone.
Doctors of chiropractic are conditioned to know whenever a condition is outside their scope regarding practice. In times similar to this, the person is known somebody who can properly cure the situation, like a pain management medical doctor. Movement is important and highly useful to the upkeep regarding arthritic bones. This assists stimulate cartilage health and fitness, creation, and elimination of destruction. Preventative actions might be assessed for rheumatoid arthritis starting when young.
? To prevent future handicap, ensure that any injuries for the joints are handled at the earliest opportunity to let proper curing.
? Any individual who works with a place that will require standing or strolling for a long time should wear correct and cozy shoes or boots.
? An effective as well while healthy body weight loss will slow up the level of pressure which is positioned on the knees and other joints.
? Joint parts maintain well being through natural mineral deposits, antioxidants as well as nutritional vitamins.
Even though direct source of rheumatoid arthritis symptoms is unidentified, immune program seems to be dictate the problem. In most cases, the afflicted joints of rheumatoid arthritis will be the fingers and arms, foot, shoulder blades, and hips. Numerous individuals with arthritis recognize in the event the weather will probably change because their very own joints start harming. This is your opportunity a typical symptom related to arthritis; firm joints the next day which are worsened by movements.
According to the severity with the problem, chiropractic aligners primarily a way to help patients using arthritis since they're educated to tackle the actual source of the condition. As opposed to offering medications in which temporarily mask this specific, chiropractic therapy extends to the core with the condition causing osteoarthritis, or soreness within the joints. Chiropractor Mesa AZ
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install tiled flooring, tiled floor ins - Install Tiled Flooring At Your Home by Colleen S.Lee Send Feedback to Colleen S.Lee Request Reprint |
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When you decide to go through the flooring installation of your home, one of the types of flooring that most people prefer to get along with is the tiled flooring types. The main reasons for most of the people opt for this flooring is because of the easy maintenance and also an attractive look it gives to the room. Because of this reason, most of the people prefer to have the tiled flooring from bathrooms to living rooms to get with the best environmental effect. Materials If you think about installing the tiled flooring for your home, then you will most likely end up with the result as it is not even a difficult task. But, it is necessary to have some preparation and also have the knowledge about some installation tips in order to make the installation as the best one. You should also have to be prepared with the materials and tools that are available for installation. The tools and materials can easily be got from the stores nearer to you. It is essential to have hammer, goggles, pencils, glass cutters, carpenter's square, tape measure and also the notched towel as tools. You should also have to have the materials such as tiles, tile spacers, and grout sealer, silicon caulk to make the installation in an efficient way without any interruptions and also to avoid the damages in the future. Tiling and preparation After getting with the tools that you need for the installation of tiled flooring, it is necessary to go through the preparation of tiles and the things that you need to follow are as follows: * It is required to prepare the tiles as sufficient for the installation process and also have to select them with the best sizes as suitable for your room * Another thing that you need to consider is about the floors and it is good to make the floor as cleaned one without the old flooring. This will probably make the installation as easy one and also you have to make the floor as flat, then only the tile flooring will become a better one otherwise there may be chances for the damaging of tiles * It is also efficient to make the floor tiles as centered one in the room, so that the room can get with the great appearance * When you install the tiles for your room, it is better to measure out the sizes of walls too. It is better to install the tiled flooring depending on the appearance of walls If you think about all of these things, afterward you can make the installation correctly and effectively as per your requirement. Purchasing the tiles In recent days, several people have a preference to install the tiled flooring for their home; there are numerous options available for people to go through the tiles in a better way. Because of this reason, it is better to go through the shops from where you can get with the highest quality tiles according to your needs and also with different designs and colors as suitable for your home.
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Immune system molecule weaves cobweb-like nanonets to snag Salmonella, other intestinal microbesPublic release date: 21-Jun-2012 [ | E-mail | Share ]
Contact: Carole Gan carole.gan@ucdmc.ucdavis.edu 916-734-9047 University of California - Davis Health System
Discovery provides clues to deficiencies in inflammatory bowel disease, Crohn's disease
A team of researchers led by UC Davis Health System has found that human alpha-defensin 6 (HD6) a key component of the body's innate defense system binds to microbial surfaces and forms "nanonets" that surround, entangle and disable microbes, preventing bacteria from attaching to or invading intestinal cells.
The research describes an entirely new mechanism of action for defensins, an important group of molecules known to bolster the defenses of circulating white blood cells, protect cellular borders from invasive pathogens and regulate which "friendly" microbes can colonize body surfaces. The discovery provides important clues to inflammatory bowel diseases, especially Crohn's disease, which may be caused, in part, by deficiencies in HD6 levels or function.
A paper describing the work appears in the June 22 issue of the journal Science.
"During the past 25 years, researchers have learned a lot about the biological function of defensins, but the role of HD6, a particular molecule that is highly expressed in the intestines, was a mystery," said Charles L. Bevins, professor of microbiology and immunology at UC Davis. "We now know that HD6 has a very unique role in the body's innate immune system. Its ability to latch onto microbial surfaces and self-assemble to cast a fibrous net around bacteria, including pathogens like Salmonella and Yersinia, as well as fungi and protozoan parasites, gives the intestine, a critical part of the body, a powerful and broad spectrum of defense against potential threats."
Bevins is co-senior author of the paper along with his UC Davis colleague Professor Andreas Bumler, an expert in bacterial pathogenesis; UCLA Emeritus Professor Robert I. Lehrer, whose laboratory was the first to discover defensins in the early 1980s; and Professor Wuyuan Lu, a synthetic protein chemist from the University of Maryland School of Medicine whose work provided clues to HD6's subtle and unique properties. First author Hiutung Chu, a graduate student in the Bevins lab who is now a fellow at the California Institute of Technology, was a driving force on the nine-year quest to solve the HD6 puzzle.
About the protein HD6
Defensins are a family of structurally related, small peptides with antibiotic activity found throughout nature in plants and animals. Humans make six different alpha-defensins. Two of these, HD5 and HD6, are secreted by Paneth cells, specialized secretory cells located within the folds of the small intestinal lining. HD5 has well-known antibacterial properties while the function of HD6 had been unknown. The defensin-rich secretions of Paneth cells work in conjunction with nearby intestinal stem cells to maintain micro flora balance and renew intestinal cellular surfaces.
Chu's graduate work focused on characterizing the biological activity of HD6 in studies using cultured intestinal epithelial cells and transgenic mouse models. Although Chu and Bevins anticipated HD6 activity would be very similar to other alpha-defensins, which kill pathogens by poking holes in the microbial membrane, their early research studies repeatedly showed that HD6 did not kill bacteria. Puzzled, they then looked for other possible functions, collaborating with UC Davis professors Angela Gelli and Scott Dawson to see if HD6 might kill only certain bacteria, fungi or parasites. It did not.
After two years into the project and feeling frustrated about the negative results, Bevins and Chu carefully reviewed the experimental data. That's when they recognized two crucial pieces of information. The first was that whenever HD6 was added to suspensions of either bacteria or fungi, a white haze, or precipitate, formed in the solution (see image below). The second was that early studies conducted in collaboration with Bumler had shown that while HD6 did not kill the bacterial pathogen Salmonella, it protected transgenic mice from an otherwise lethal infection.
"When we put these two results together, we were able to systematically show that HD6 was inhibiting microbial invasion and uncover HD6's unique structure and function at multiple levels," said Bevins.
On the road to discovery
The UC Davis team then collaborated with Lehrer, whose research focuses on the study of defensins and other antimicrobial peptides that serve as natural antibiotics. In his laboratory, he had a surface plasmon resonance instrument that measured molecular binding in real time. This technique captured the progressive assembly of HD6 molecules, from binding to bacterial proteins at the microbial cell surface to the self-assembly to form fibrils and the sequential addition of fibrils (see images below).
Through the expertise of Lu, a synthetic protein chemist and expert in defensin structure and function relationships, the team obtained sufficient quantities of the highest-grade HD6 peptide and subtle molecular variants of HD6 to test their hypotheses experimentally. Lu was able to identify critical structural components of HD6 that enabled it to self-assemble into fibrils. One feature unique to HD6 is the manner in which four HD6 molecules combine to form a building block whose further assembly creates both fibers and nets. The researchers also found that changing just one of the 32 amino-acid residues of the HD6 molecule -- histidine-27 -- impaired HD6's ability to form a tetramer in the x-ray crystal structure. As a result, HD6 lost the special binding that Lehrer found in his real-time experiments, blocked the ability of HD6 to form nanonets and abrogated its ability to inhibit bacterial invasion.
The Bumler laboratory created vital bacterial mutants affecting the molecules that HD6 initially binds to on the surface of the microbe. When those molecules were knocked out in the transgenic mouse model, HD6 did not form the fibrils on the bacterial surface.
"This series of experiments provided the vital 'glue' to bind the many facets of the story together, and to convince ourselves and our peers that we had finally solved the mechanism of HD6 action," commented Bevins.
Clues to innate immunity and inflammatory bowel diseases
The UC Davis research describes how HD6 contributes to the body's innate immunity, which protects from microbes that the immune system might not have any experience in managing.
"The innate immune system has to be able to deal with diverse microbes that might have all kinds of tricks that cause infection," said Bevins. "After we've been exposed to a microbe or an infection the first time and survive it, the adaptive immune system can recognize and remember specific pathogens to generate immunity and to mount stronger defenses each time the pathogen is encountered. HD6 is a major player in helping the body prevent potentially dangerous pathogens from coming into close physical contact with intestinal epithelial cells of the intestine, as well as the stem cells that continuously renew the epithelial cell surface."
Previously published studies from the Bevins lab have linked alpha-defensins and Crohn's disease, a chronic inflammatory bowel disease that investigators associated with HD5 and HD6 deficiencies. The secretions of these defensins typically occur at the base of the out pouches (so-called crypts) of the small intestinal surface, where they are ready to fend off bacteria that become dangerously close to the intestinal lining. Individuals with Crohn's disease, however, tend to accumulate invasive bacteria in this same area, developing a chronic inflammation that is self-perpetuating.
"With less of these important defense molecules, microbes that would normally exist in the gut, can irritate the intestinal surface and cause the chronic inflammation that characterizes Crohn's disease," said Bevins. "We know a lot about HD5's antimicrobial activities, so it makes sense why reduced HD5 levels might contribute or allow this condition to progress. Now we have a clue how HD6 levels play a role."
Future studies on Crohn's disease by this team aim to better understand exactly why alphadefensin-expression is reduced in individuals with Crohn's disease, and perhaps devise strategies to boost the body's production of these vital molecules.
"The multidisciplinary approach that we used to 'crack' the obscure and complex action of HD6 exemplifies the power of team science," Bevins said. "Not to be underestimated, however, is the courage and tenaciousness of graduate student Hiutung Chu in leading the experimental investigations. Many blind alleys were visited as we investigated this molecule, and those frustrating diversions can erode confidence and morale. Hiutung deserves tremendous credit for persevering through those setbacks."
###
Other authors on the paper include Marzena Pazgier from the University of Maryland School of Medicine, Grace Jung from the David Geffen School of Medicine at UCLA, Bo Shen at the Cleveland Clinic Foundation, Nita H. Salzman at the Medical College of Wisconsin and Mark A. Underwood, Glenn M.Young, Sean-Paul Nuccio, Patricia A. Castillo, Maarten F. deJong, Maria G. Winter, Sebastian E. Winter and Jan Wehkamp, all from the University of California, Davis.
This research was supported by grants from the National Institutes of Health.
[ | 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.
Immune system molecule weaves cobweb-like nanonets to snag Salmonella, other intestinal microbesPublic release date: 21-Jun-2012 [ | E-mail | Share ]
Contact: Carole Gan carole.gan@ucdmc.ucdavis.edu 916-734-9047 University of California - Davis Health System
Discovery provides clues to deficiencies in inflammatory bowel disease, Crohn's disease
A team of researchers led by UC Davis Health System has found that human alpha-defensin 6 (HD6) a key component of the body's innate defense system binds to microbial surfaces and forms "nanonets" that surround, entangle and disable microbes, preventing bacteria from attaching to or invading intestinal cells.
The research describes an entirely new mechanism of action for defensins, an important group of molecules known to bolster the defenses of circulating white blood cells, protect cellular borders from invasive pathogens and regulate which "friendly" microbes can colonize body surfaces. The discovery provides important clues to inflammatory bowel diseases, especially Crohn's disease, which may be caused, in part, by deficiencies in HD6 levels or function.
A paper describing the work appears in the June 22 issue of the journal Science.
"During the past 25 years, researchers have learned a lot about the biological function of defensins, but the role of HD6, a particular molecule that is highly expressed in the intestines, was a mystery," said Charles L. Bevins, professor of microbiology and immunology at UC Davis. "We now know that HD6 has a very unique role in the body's innate immune system. Its ability to latch onto microbial surfaces and self-assemble to cast a fibrous net around bacteria, including pathogens like Salmonella and Yersinia, as well as fungi and protozoan parasites, gives the intestine, a critical part of the body, a powerful and broad spectrum of defense against potential threats."
Bevins is co-senior author of the paper along with his UC Davis colleague Professor Andreas Bumler, an expert in bacterial pathogenesis; UCLA Emeritus Professor Robert I. Lehrer, whose laboratory was the first to discover defensins in the early 1980s; and Professor Wuyuan Lu, a synthetic protein chemist from the University of Maryland School of Medicine whose work provided clues to HD6's subtle and unique properties. First author Hiutung Chu, a graduate student in the Bevins lab who is now a fellow at the California Institute of Technology, was a driving force on the nine-year quest to solve the HD6 puzzle.
About the protein HD6
Defensins are a family of structurally related, small peptides with antibiotic activity found throughout nature in plants and animals. Humans make six different alpha-defensins. Two of these, HD5 and HD6, are secreted by Paneth cells, specialized secretory cells located within the folds of the small intestinal lining. HD5 has well-known antibacterial properties while the function of HD6 had been unknown. The defensin-rich secretions of Paneth cells work in conjunction with nearby intestinal stem cells to maintain micro flora balance and renew intestinal cellular surfaces.
Chu's graduate work focused on characterizing the biological activity of HD6 in studies using cultured intestinal epithelial cells and transgenic mouse models. Although Chu and Bevins anticipated HD6 activity would be very similar to other alpha-defensins, which kill pathogens by poking holes in the microbial membrane, their early research studies repeatedly showed that HD6 did not kill bacteria. Puzzled, they then looked for other possible functions, collaborating with UC Davis professors Angela Gelli and Scott Dawson to see if HD6 might kill only certain bacteria, fungi or parasites. It did not.
After two years into the project and feeling frustrated about the negative results, Bevins and Chu carefully reviewed the experimental data. That's when they recognized two crucial pieces of information. The first was that whenever HD6 was added to suspensions of either bacteria or fungi, a white haze, or precipitate, formed in the solution (see image below). The second was that early studies conducted in collaboration with Bumler had shown that while HD6 did not kill the bacterial pathogen Salmonella, it protected transgenic mice from an otherwise lethal infection.
"When we put these two results together, we were able to systematically show that HD6 was inhibiting microbial invasion and uncover HD6's unique structure and function at multiple levels," said Bevins.
On the road to discovery
The UC Davis team then collaborated with Lehrer, whose research focuses on the study of defensins and other antimicrobial peptides that serve as natural antibiotics. In his laboratory, he had a surface plasmon resonance instrument that measured molecular binding in real time. This technique captured the progressive assembly of HD6 molecules, from binding to bacterial proteins at the microbial cell surface to the self-assembly to form fibrils and the sequential addition of fibrils (see images below).
Through the expertise of Lu, a synthetic protein chemist and expert in defensin structure and function relationships, the team obtained sufficient quantities of the highest-grade HD6 peptide and subtle molecular variants of HD6 to test their hypotheses experimentally. Lu was able to identify critical structural components of HD6 that enabled it to self-assemble into fibrils. One feature unique to HD6 is the manner in which four HD6 molecules combine to form a building block whose further assembly creates both fibers and nets. The researchers also found that changing just one of the 32 amino-acid residues of the HD6 molecule -- histidine-27 -- impaired HD6's ability to form a tetramer in the x-ray crystal structure. As a result, HD6 lost the special binding that Lehrer found in his real-time experiments, blocked the ability of HD6 to form nanonets and abrogated its ability to inhibit bacterial invasion.
The Bumler laboratory created vital bacterial mutants affecting the molecules that HD6 initially binds to on the surface of the microbe. When those molecules were knocked out in the transgenic mouse model, HD6 did not form the fibrils on the bacterial surface.
"This series of experiments provided the vital 'glue' to bind the many facets of the story together, and to convince ourselves and our peers that we had finally solved the mechanism of HD6 action," commented Bevins.
Clues to innate immunity and inflammatory bowel diseases
The UC Davis research describes how HD6 contributes to the body's innate immunity, which protects from microbes that the immune system might not have any experience in managing.
"The innate immune system has to be able to deal with diverse microbes that might have all kinds of tricks that cause infection," said Bevins. "After we've been exposed to a microbe or an infection the first time and survive it, the adaptive immune system can recognize and remember specific pathogens to generate immunity and to mount stronger defenses each time the pathogen is encountered. HD6 is a major player in helping the body prevent potentially dangerous pathogens from coming into close physical contact with intestinal epithelial cells of the intestine, as well as the stem cells that continuously renew the epithelial cell surface."
Previously published studies from the Bevins lab have linked alpha-defensins and Crohn's disease, a chronic inflammatory bowel disease that investigators associated with HD5 and HD6 deficiencies. The secretions of these defensins typically occur at the base of the out pouches (so-called crypts) of the small intestinal surface, where they are ready to fend off bacteria that become dangerously close to the intestinal lining. Individuals with Crohn's disease, however, tend to accumulate invasive bacteria in this same area, developing a chronic inflammation that is self-perpetuating.
"With less of these important defense molecules, microbes that would normally exist in the gut, can irritate the intestinal surface and cause the chronic inflammation that characterizes Crohn's disease," said Bevins. "We know a lot about HD5's antimicrobial activities, so it makes sense why reduced HD5 levels might contribute or allow this condition to progress. Now we have a clue how HD6 levels play a role."
Future studies on Crohn's disease by this team aim to better understand exactly why alphadefensin-expression is reduced in individuals with Crohn's disease, and perhaps devise strategies to boost the body's production of these vital molecules.
"The multidisciplinary approach that we used to 'crack' the obscure and complex action of HD6 exemplifies the power of team science," Bevins said. "Not to be underestimated, however, is the courage and tenaciousness of graduate student Hiutung Chu in leading the experimental investigations. Many blind alleys were visited as we investigated this molecule, and those frustrating diversions can erode confidence and morale. Hiutung deserves tremendous credit for persevering through those setbacks."
###
Other authors on the paper include Marzena Pazgier from the University of Maryland School of Medicine, Grace Jung from the David Geffen School of Medicine at UCLA, Bo Shen at the Cleveland Clinic Foundation, Nita H. Salzman at the Medical College of Wisconsin and Mark A. Underwood, Glenn M.Young, Sean-Paul Nuccio, Patricia A. Castillo, Maarten F. deJong, Maria G. Winter, Sebastian E. Winter and Jan Wehkamp, all from the University of California, Davis.
This research was supported by grants from the National Institutes of Health.
[ | 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.
WARSAW, Poland (AP) - The most powerful man in soccer called goal-line technology a "necessity" Wednesday, only hours after Ukraine was denied what appeared to be a legitimate goal in its must-win match against England at the European Championship.
"After last night's match GLT is no longer an alternative but a necessity," FIFA President Sepp Blatter wrote on Twitter.
Marko Devic's shot in the 62nd minute of Tuesday's match looped up off England goalkeeper Joe Hart and appeared to cross the goal line before it was cleared by defender John Terry. The official standing near the post didn't signal for a goal, leaving the referee no option but to play on.
If the goal had been awarded, Ukraine would have pulled even at 1-1. But the co-hosts instead lost 1-0, a result that eliminated them from the tournament.
Ukraine's players complained furiously, coach Oleg Blokhin raged on the touchline and Twitter was quickly awash with indignation, reaction and opinion on goal-line technology.
The high-profile incident added to the momentum behind providing referees with high-tech aids to make accurate decisions.
UEFA is using Euro 2012 to trial the five-official system that features a referee, two linesmen and two additional assistants beside the goal. It's UEFA President Michel Platini's preferred alternative to goal-line technology.
FIFA will decide on July 5 whether to approve the five-official system and either of the two goal-line technology systems currently being tested in England and Denmark.
Speaking at a media briefing in Warsaw on Monday, Platini said he expects goal-line technology to be approved at the IFAB meeting.
"Yes, Blatter will do it," Platini said. "He will (introduce) the technology, but I think it's a big mistake. ... it's the beginning of the technology, the arrival of the technology."
There have been a number of memorable goal-line incidents to which critics often hark back whenever a fresh controversy occurs.
The most famous came in the 1966 World Cup final, when Geoff Hurst's shot that hit the underside of the crossbar and bounced down was ruled a goal. It gave England a 3-2 lead and Hurst later completed his hat trick for a 4-2 win.
In a match between the same two countries at the 2010 World Cup, a long shot by England midfielder Frank Lampard bounced down behind goalkeeper Manuel Neuer's line before spinning back out. Uruguayan referee Jorge Larrionda looked across at his linesman and allowed play to continue. The goal would have made it 2-2, but instead England lost 4-1.
Platini said Monday that if an official had been beside the goal that day, he would have spotted that Lampard's shot crossed the line.
"Of course, because it's his job to see if the ball is inside the line," Platini said.
Two days later, those words are coming back to haunt him.
---
AP Sports Writer Graham Dunbar contributed to this report.
? 2012 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
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More newsSergei Supinsky / AFP - Getty Images
Portugal becomes?a dark horse
PST: Two weeks ago Portugal looked like a good bet to finish last in Group B. Now, they?re bonafide dark horses ? as good a bet as any to win Euro 2012, beyond Germany and Spain.
When he first took the job, new Trail Blazers general manager Neil Olshey called interim Portland coach Kaleb Canales the ?in-house favorite? for the job.
That was just Olshey being polite.
The reality is the search is wide open and Canales should be polishing his resume. Here is what Olshey told the Columbian.
Olshey didn?t speak specifically, but he did say Monday that the search would be ?exhaustive? and that there are ?guys we?re targeting.? Could Canales be one of those guys? Sure. But while much of the public may have thought this anyway, it doesn?t quite appear to be his job to lose.
Smart money suggests the usual suspects ? Brian Shaw, Mike Malone, and Patrick Ewing ? will get a look, as well as some veteran coaches. Mike Dunlap is off the market, but my guess is that doesn?t concern Portland too much. Expect this to be a little quieter search than the Bobcats did, as well.
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We're all a bit tired of the "X is Twilio for Y" brand of analogies (though it's refreshing to see more of Twilio 
Fort Campbell, KY ? If you haven?t tried out some of the Outdoor Recreation Adventure Programs yet ? July is the perfect time to sign up! Outdoor Recreation will start the month off with a King?s Bluff Climbing Trip on July 7th from 9:00am until 2:00pm. Ages 12 and above are invited to participate and the cost is $35.00 per person; transportation and equipment are provided.
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Public release date: 21-Jun-2012
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