CLEVELAND (AP) ? Max Scherzer didn't care that his record stayed spotless. All that mattered to him was that Detroit's improved.
Scherzer remained unbeaten and Victor Martinez hit a two-run double in the 10th inning as the Tigers extended their lead in the AL Central with a 4-2 win over the second-place Cleveland Indians on Monday night.
Martinez doubled off Matt Albers (2-1) as the Tigers won three of four in the series and moved 3? games ahead in the division.
Scherzer, attempting to become the first pitcher since Roger Clemens in 1986 to open a season 14-0, finished with a no-decision. He allowed two runs and seven hits in seven innings. The presumed AL starter in next week's All-Star game will take his unblemished mark into a start on Saturday against Texas.
"I don't want to focus much on that (being 13-0)," he said. "This was our best win of the year, and I was proud to be a part of it. The Indians battled so hard tonight and brought their 'A' game, and we did, too.
"It was just a great team win, our best of the year."
Drew Smyly (4-0) worked out of a jam in the ninth and Joaquin Benoit pitched the 10th for his seventh save, striking out Mike Aviles with runners at first and third to end the game.
Matt Tuiasosopo homered for the Tigers, now 9-3 against the Indians.
Detroit was able to widen its lead over Cleveland by two games on this visit, but manager Jim Leyland knows champions aren't crowned in July.
"We came in and had a very good series against a very good team, but I'm not really concerned about the standings," Leyland said. "Of course, I'd rather leave here up 3? games than up 1? games. But trust me, the Indians are not going anywhere, and we're not going anywhere, I don't think."
Albers got two quick outs in the 10th before walking Miguel Cabrera and Prince Fielder. Martinez followed with a drive over the head of center fielder Michael Bourn. The ball caromed off the wall, far enough away for two of Detroit's slowest runners to score. After Fielder slid across the plate, he popped up from the dirt and swung his arm in celebration.
The Indians had been 5-0 in extra-inning games.
Cleveland came in with a reputation for beating Cy Young Award winners. The Indians have defeated seven former recipients this season, including Detroit's Justin Verlander. Scherzer is clearly the midseason favorite to win the AL honor in 2013, and while the Indians didn't hand him a loss, they did prevent him from beating them for the third time this year.
Scherzer wasn't at his best, and he was noticeably agitated on a night when the rain never really stopped. However, the 28-year-old got stronger as the game wore on. He gave up both runs ? on a two-run single in the second by Lonnie Chisenhall ? and five hits in the first three innings, and pitched out of a couple of jams he created.
"He used to be a thrower and now he's a pitcher," Indians first baseman Nick Swisher said. "You've got a guy with all those weapons and he starts to figure it out, that doesn't make anybody happy."
After getting out of a first-and-third bind in the fifth, Scherzer got in a groove and struck out four of the final five batters he faced. In the seventh, he gave up a single to Bourn, who was caught stealing. Scherzer then struck out Asdrubal Cabrera and blew a 97 mph fastball past All-Star second baseman Jason Kipnis to end the inning ? on his 117th pitch.
Scherzer screamed and pumped his fist as he headed to the dugout, slapping hands with catcher Brayan Pena before taking a seat to watch the Tigers hit.
"You can usually judge your outing on the last 15 pitches, and I thought I finished pretty strong," Scherzer said.
Cleveland's Scott Kazmir went pitch for pitch with Scherzer, allowing just two runs and four hits in 5 2-3 innings.
Kazmir held the top four hitters ? Austin Jackson, Torii Hunter, Cabrera and Fielder ? in one of baseball's most feared lineups without a hit in 11 at-bats. The only one of the four to reach base was Cabrera, who walked with one out in the third.
With both the Indians and weather threatening in the second, the game was delayed by rain.
Thunder rumbled nearby and lightning flashed above Progressive Field as Scherzer battled Chisenhall with runners at second and third and two outs. The game was halted on a 2-2 count, and when play resumed 20 minutes later, Chisenhall jumped all over Scherzer's first pitch, ripping a changeup to right for a two-run single.
When he returned to the dugout, Scherzer slammed his glove and cap down in disgust. After the game, he said he was upset that umpire Joe West did not let him finish the at-bat to Chisenhall.
He was mad again in the third, when the Indians loaded the bases on a pair of two-out singles and walk. But Scherzer snagged a comebacker by Aviles and carefully underhanded the ball to first for the final out.
The Indians had their chances against Scherzer, and stranded 10 runners in all.
"It's just kind of one of those games," Swisher said. "We left a small village on the sacks. We've got to do a little better job there, but that's how baseball goes."
NOTES: The Tigers have won 12 of the last 16 against the Indians, outscoring them 100-59 during that stretch. ... Tigers 2B Omar Infante (bruised shin) sat out his fifth straight game, but remains day to day. ... Scherzer had his 19th straight start without a loss, passing Bobo Newsom for the franchise record. ... Detroit went 7-4 on its longest trip this season. The Tigers open a three-game series against the last-place White Sox on Tuesday with Verlander (9-5) facing Jose Quintana (3-2).
by admin ?Announcements, Health & Fitness, Spring Hill News
Registration Begins Monday, July 15
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The Athletics Division of the Williamson County Parks and Recreation Department announces registration on July 15, 2013 for ten-week fall sessions of indoor and outdoor tennis clinics. Registration for all Franklin and Brentwood clinics starts at 9 a.m. on Monday, July 15 at the Indoor Sports Complex, 920 Heritage Way in Brentwood or by phone at (615) 370-3471, ext. 2010. To register for clinics at Longview Recreation Center, 2909 Commonwealth Dr. in Spring Hill, call (615) 302-0971, ext. 2210 after July 15.
Clinics start the week of August 12 and will be offered at these locations: the Indoor Sports Complex in Brentwood; Crockett Park, 1500 Volunteer Pkwy. in Brentwood; Ravenwood High School, 1724 Wilson Pike; Granny White Park, 610 Granny White Pike; Grassland Park, 6759 Manley Ln. in Franklin; the Franklin Recreation Complex, 1120 Hillsboro Rd.; and the Longview Recreation Center at Spring Hill. Adult and junior clinics (age 5 and older) in beginner through advanced skill levels are offered Monday(s) through Saturday(s).? Prices vary depending on the duration of clinic. A full class schedule and fees are available at www.wcprathletics.org.
All fees must be paid in order to secure placement in a class. Space is limited!? Contact Mike Martin, ext. 2116 or Ann Marie Flynn, ext. 2113 at (615) 370-3471 for more information.
Rep. Graves to host open house at Rome District Office
by U.S. Rep. Tom Graves reportsRn T.Com
Washington, D.C. ? On Monday, July 15, U.S. Rep. Tom Graves (R-GA-14) will host an open house at his Rome district office. Constituents from across the 14th Congressional District are invited and Rep. Graves will be there to meet and greet those who attend.
?I?m excited to invite the community to our Rome office and look forward to meeting more people and hearing about the issues impacting their families,? said Rep. Graves. ?I hope the open house encourages more constituents to stay in touch and use my staff and me as a resource for all of their federal issues. After all, the Rome office belongs to the people of this district, and we are here to serve them.?
The open house will be an informal gathering with light refreshments served. Rep. Graves? constituent service representatives will also be on hand for those who need assistance dealing with a federal agency, such as the Social Security Administration or Veterans Affairs Department.
What: Rep. Tom Graves hosts an open house at the 14th Congressional District?s Rome office.
When: Monday, July 15, from 3:30 p.m. ? 5:30 p.m.
Where: 600 E. First Street, Suite 301, Rome, Georgia 30161.
Free parking is available on site.
Constituents who have questions about the event should call the Rome office at 706-290-1776. This event is free and open to the public.
According to stats released by Google, Jelly Bean is now the most-used version of the Android operating system.
The data, which is based on smartphones and tablets accessing the Google Play store, shows that versions 4.1.x and 4.2.x power more than a third of all Android devices, ousting Android 2.3.x Gingerbread, a version first released back in February 2011, from the top spot.
(Source: Google)
Over the past month, Jelly Bean's usage share ? called distribution by Google ? has increased by 4.9 percentage points compared to the previous month. Jelly Bean's gains are at the expense of other Android versions, in particular Ice Cream Sandwich, which has seen its distribution fall by 2.3 percentage points, and Gingerbread, which has seen its distribution fall by 2.5 percentage points.
While Jelly Bean is now the most popular version of Android, overall the landscape is a three-way split between the aging Gingerbread and Ice Cream Sandwich releases, and the current Jelly Bean release.
The data also clearly shows how Jelly Bean alone is now the only version of Android that is experiencing growth, which is good news for developers because it means the ecosystem is getting less fragmented as the months progress. However, even if the current trends hold true for the near future, devices running Ice Cream Sandwich and Gingerbread are going to be around for quite some time.
Beginning in April 2013,?Google started delivering data collected from each device when the user visited the Google Play Store. Previously, the data was collected when the device simply checked in to Google servers. Google believes that the new data "more accurately reflects those users who are most engaged in the Android and Google Play ecosystem."
But thing are not all rosy for Android. Despite the fact that Jelly Bean now has the lion's share of usage, and despite the fact that Android as a whole is estimated to command almost 70 percent of the smartphone market, the money is slow to appear. As pointed out by AppleInsider, Google pulled in a little over $50 billion throughout 2012, compared to Apple's $54 billion for the last quarter alone.
In other words, Apple is leveraging its 22 percent market share much more effectively than Google is leveraging its almost 70 percent market share.
All of which goes to show, it's not the market share that matters, but what you do with it.
BEIJING ? A new study links heavy air pollution from coal burning to shorter lives in northern China. Researchers estimate that the half-billion people alive there in the 1990s will live an average of 5 1/2 years less than their southern counterparts because they breathed dirtier air.
China itself made the comparison possible: for decades, a now-discontinued government policy provided free coal for heating, but only in the colder north. Researchers found significant differences in both particle pollution of the air and life expectancy in the two regions, and said the results could be used to extrapolate the effects of such pollution on lifespans elsewhere in the world.
The study by researchers from China, Israel and the United States was published Tuesday in the Proceedings of the National Academy of Sciences.
While previous studies have found that pollution affects human health, "the deeper and ultimately more important question is the impact on life expectancy," said one of the authors, Michael Greenstone, a professor of environmental economics at Massachusetts Institute of Technology.
"This study provides a unique setting to answer the life expectancy question because the (heating) policy dramatically alters pollution concentrations for people who appear to be of otherwise identical health," Greenstone said in an email. "Further, due to the low rates of migration in China in this period, we can know people's exposure over long time periods," he said.
The policy gave free coal for fuel boilers to heat homes and offices to cities north of the Huai River, which divides China into north and south. It was in effect for much of the 1950-1980 period of central planning, and, though discontinued after 1980, it has left a legacy in the north of heavy coal burning, which releases particulate pollutants into the air that can harm human health. Researchers found no other government policies that treated China's north differently from the south.
The researchers collected data for 90 cities, from 1981 to 2000, on the annual daily average concentration of total suspended particulates. In China, those are considered to be particles that are 100 micrometers or less in diameter, emitted from sources including power stations, construction sites and vehicles.
The researchers estimated the impact on life expectancies using mortality data from 1991-2000. They found that in the north, the concentration of particulates was 184 micrograms per cubic meter ? or 55 percent ? higher than in the south, and life expectancies were 5.5 years lower on average across all age ranges.
The researchers said the difference in life expectancies was almost entirely due to an increased incidence of deaths classified as cardiorespiratory ? those from causes that have previously been linked to air quality, including heart disease, stroke, lung cancer and respiratory illnesses.
Total suspended particulates include fine particulate matter called PM2.5 ? particles with diameters of no more than 2.5 micrometers. PM2.5 is of especially great health concern because it can penetrate deep into the lungs, but the researchers lacked the data to analyze those tiny particles separately.
The authors said their research can be used to estimate the effect of total suspended particulates on other countries and time periods. Their analysis suggests that every additional 100 micrograms of particulate matter per cubic meter in the atmosphere lowers life expectancy at birth by about three years.
The study also noted that there was a large difference in particulate matter between the north and south, but not in other forms of air pollution such as sulfur dioxide and nitrous oxide.
Francesca Dominici, a professor of biostatistics at Harvard School of Public Health who has researched the health effects of fine particulate matter in the U.S., said the study was "fascinating."
China's different treatment of north and south allowed researchers to get pollution data that would be impossible in a scientific setting.
Dominici said the quasi-experimental approach was a good approximation of a randomized experiment, "especially in this situation where a randomized experiment is not possible."
She said she wasn't surprised by the findings, given China's high levels of pollution.
"In the U.S. I think it's pretty much been accepted that even small changes in PM2.5, much, much, much smaller than what they are observing in China, are affecting life expectancy," said Dominici, who was not involved in the study.
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WASHINGTON (AP) -- Two senators want to improve the opportunity to vote for hundreds of thousands of American military personnel abroad. They would penalize states that are too slow in sending out absentee ballots.
Ahead of the Fourth of July holiday, Sens. Chuck Schumer, D-N.Y., and John Cornyn, R-Texas, say they will seek to eliminate waivers for states that fail to mail ballots overseas 45 days before an election. States that miss the deadline would be required to use express mail to get the ballots to service members.
The senators say the changes aim to improve a 2010 law designed to address widespread deficiencies with absentee balloting. A congressional report estimated that 25 percent of ballots cast by military and other overseas voters in the 2008 presidential election went uncounted.
Anne Jones, 62, and Robin Jones, 73, at their home in Menlo Park, Calif. He took a test that revealed proteins typical of Alzheimer's disease.
Ramin Rahimian for NPR
Anne Jones, 62, and Robin Jones, 73, at their home in Menlo Park, Calif. He took a test that revealed proteins typical of Alzheimer's disease.
Ramin Rahimian for NPR
If you're having chest pain, your doctor can test you for a heart attack. If you're having hip pain, your doctor could test for osteoarthritis.
But what if you're depressed? Or anxious? Currently there are no physical tests for most disorders that affect the mind. Lab tests like these could transform the field of mental illness. So far efforts to come up with biomarkers for common mental health disorders have proved largely fruitless.
That doesn't stop people from trying. Doctors are looking to create them, and patients are taking them, too, even though they know that existing biomarkers ? for Alzheimer's disease, for instance ? have serious limitations.
Six years ago, Robin Jones of Menlo Park, Calif., found himself in a parking lot. He had no idea where his car was. That was unlike him. A 67-year-old scientist who worked on nuclear energy plants, he was good with details. "It was, you know, I can't believe this," Jones says now. "I can always remember where the car is."
At work, he had a hard time finding the right words. He'd come home and tell his wife, Anne, "Something's different."
Robin Jones made an appointment at the Stanford Center for Memory Disorders, where he went through the standard cognitive evaluation for Alzheimer's disease ? memorizing lists of words and so on.
Jones did pretty well on the tests. Better, says Stanford neurologist Michael Greicius, than you'd expect from someone in the early stages of the disease.
"He didn't fit neatly into this classic presentation of Alzheimer's disease," Greicus says, "and that's one of the reasons we talked fairly early on about looking at biomarkers."
When Greicius says "biomarkers," he's referring to a very new thing in Alzheimer's disease and a very old thing in many other diseases: objective lab tests. Those are physical measures that can help doctors understand what is going on in a patient's body.
Robin and Anne Jones take a walk near their home. They say that an Alzheimer's biomarker test made it easier to plan for the future.
Ramin Rahimian for NPR
One Alzheimer's test checks spinal fluid for proteins that are signatures of the disease. Another uses a PET scan to look for physical evidence of brain changes.
Jones chose the spinal fluid test. "It seemed to me it would sharpen up my understanding of what was happening," he says.
These tests don't offer the certainty of, say, a pregnancy test. Some people who test positive for the Alzheimer's-linked proteins show no outward signs of the disease.
But a positive result, in combination with symptoms like Jones experienced, is a pretty definitive diagnosis of Alzheimer's, Greicius says.
Researchers say the Alzheimer's tests, limited as they are, give a hint as to what may be ahead with other mental disorders, like bipolar disorder or post-traumatic stress disorder (PTSD).
As evidence, they point to the transformation that's happened with biological tests for disorders like heart disease and cancer.
"When I was a medical student 40 years ago, patients would come in with chest pains and we would spend a lot of time talking to them," says Dr. Michael Weiner, a professor in radiology and biomechanical engineering at the University of California, San Francisco.
"Nowadays you draw blood enzymes," Weiner says. "And if a person has a rise in certain enzymes that come out of the heart, we say they had a heart attack. And if there's no rise in the enzymes, we say you didn't have a heart attack."
These days, Weiner is looking for patterns in brain imaging to see if the scans can reveal PTSD or traumatic brain injury.
But the brain is vastly more complicated than the heart. And it is taking Weiner and others much longer than many might have hoped to find biomarkers for mental disorders.
Weiner shows three MRIs of three different people. One is a healthy 23-year-old man. Another is a 32-year-old man who has quite severe PTSD. The third is of an older woman with Alzheimer's disease.
He points in each scan to a part of the brain called the hippocampus that's involved in memory. He says this part of the brain tends to be smaller in people with Alzheimer's and PTSD than in healthy people.
That's true when groups of people are averaged together. But when it comes down to individuals, it's impossible to tell who's in trouble, and who's not, he says.
"Here's the hippocampus in a healthy person and here's a hippocampus in the person with PTSD," Weiner says, "and they both look pretty much the same."
Despite the difficulties, scientists are still hunting mental health biomarkers that would be clearcut and simple ? similar to the kind of blood and urine tests we're all familiar with.
One multimillion-dollar effort, funded by private foundations and the U.S. military, is looking for biomarkers for PTSD and traumatic brain injury. the idea is to explore whether changes in certain brain chemicals like cortisol and norepinephrine, which have been associated with anxiety and fear, could be signals of PTSD, according to Dr. Charles Marmar, head of psychiatry at New York University Langone Medical Center, who is leading the project. "There is a biological footprint of learned fear," Marmar says. The question is, he adds, "are there downstream effects?"
If there were, it would be easier to identify soldiers with PTSD and get them treatment.
In the case of Robin Jones, he and his wife were just looking for a clearer diagnosis.
Anne Jones was the first to find out the results of her husband's Alzheimer's test. The spinal tap test came back positive for tau and amyloid proteins, both suggestive of Alzheimer's disease.
"Sad, yes, there was sadness," she says. "But there is a certain amount of relief. There's relief knowing why your arm hurts or why you have a bad cough. Knowing how to sort of chart out the rest of our time together."
The test helped the couple realize that soon he was going to need her in ways he hadn't before. They decided she should take a trip by herself, to Florence, Italy, to see the great works of art she had studied in college.
And when she came back she felt refreshed, she says, and ready for the challenges ahead.
MOUNTAIN VIEW -- In a far corner of a former Navy base near the edge of San Francisco Bay, construction crews have embarked this summer on building nine brand-new Google (GOOG) "noodles" -- a collection of long, oddly curved buildings that will be a new workplace for several thousand employees of the Internet search giant.
Google's planned Bay View campus, sitting on 42 acres of the former Moffett Field in Mountain View, represents the company's first effort to build its own offices from the ground up, instead of taking over buildings from other companies.
And while Google has kept a tight lid on many details, company officials promise the new campus will have the outlandish amenities Google is known for -- including gourmet cafeterias, an elevated bike path and maybe a zip line -- and a design that's friendly both to workers and the surrounding baylands, with lots of windows for natural light and optimum views, native landscaping and a cutting-edge water treatment system.
"We love our existing home, but it's an office park," said Anthony Ravitz, a civil engineer who oversees environmental issues for Google's real estate division. The new complex is designed "to give us a better sense of place," he added. "The idea is for there to be a very different look and feel."
Google has a long-term
lease on the site from NASA, which is operating the old Moffett property as a federal research park. The new campus is just east of the current Googleplex, a sprawling assortment of buildings scattered on both sides of Shoreline Boulevard that Google has leased or bought over the years.
The project is the first in a wave of campus expansions in Silicon Valley, where Facebook and Apple (AAPL) are also planning major new buildings. But not everyone's thrilled with Google's plans.
Some Mountain View residents worry it will disrupt the natural surroundings and draw more commuters to clog local roads. Since the site is on federal land, Google didn't undergo a city planning review, but the company says it's sensitive to environmental and traffic concerns.
"We're encouraging people to leave their cars at home," Google Vice President David Radcliffe told city officials at a meeting about the project. The company says 7 percent of its 12,000 Mountain View employees ride bicycles to work, and it hopes to triple that figure.
At another meeting, Google real estate director John Igoe vowed that half the Googlers on the new campus will arrive on bikes or company shuttle buses.
Google won't say which business units or exactly how many workers will occupy the new structures, although sources estimate 3,500 to 5,000 people. Google initially talked about building employee housing on the site when it announced the NASA lease in 2008, but a spokeswoman said there's no housing in the current plans. She declined to elaborate.
Company officials also wouldn't disclose the cost of the new campus, slated to open in 2015.
But at heights ranging from three to five stories, the buildings amount to 1.1 million square feet of office space, which Google hopes will earn top marks from the LEED certification program for energy and environmental design.
All the buildings will be connected by an elevated pathway for walking or bicycling, said architect Ryan Mullenix, who described it as an "infinite loop" that will let a worker on any floor of any building get to a meeting in any other building in less than five minutes.
The nine buildings will use radiant heating and cooling from a system of pipes that circulate chilled or heated water from a central plant on the campus, said Peter Rumsey, a design engineer on the project.
A separate ventilation system will bring in fresh air from outdoors, instead of recirculating what's inside.
And because the buildings are long and narrow, with plenty of windows, Google says more than 70 percent of the interior space will use natural light during the day.
The buildings are arranged at various angles and each structure is "bent" rather than shaped like a perfect rectangle. Ravitz said that's why designers have been calling them "noodles."
The alignment of the buildings is designed to provide optimal views of the bay and surrounding landscape, according to Ravitz, who said designers also studied air patterns so the structures will serve as wind breaks for a series of outside areas where Google hopes workers will picnic, stroll or even hold meetings.
"We want to create a transparent campus, where people will feel connected to what's outside," he said, "so the buildings almost to some degree go away."
Google is planning mostly natural landscaping for the campus, with trees and native plants that are favored by local butterflies and other wildlife.
It also will create eight acres of new wetland habitat on the site, said Cheryl Barton, a landscape architect on the project.
At least one of the buildings will have a "green" roof with live plantings and open-air space for meetings or informal gatherings, Barton said. Google says the other roofs will have environmentally friendly features, but the details have not yet been decided.
Google representatives have hinted at other amenities: A company fact sheet lists a "rooftop vineyard" on one building, along with zip lines and a "wind-driven music farm." A spokeswoman declined to give details, saying they are "ideas in the works."
Contact Brandon Bailey at 408-920-5022; follow him at Twitter.com/BrandonBailey.
The research in the Journal of the American Medical Association is described as the largest of its kind and was based on the records of 2.5 million children born in Sweden from 1982 to 2007.
Researchers in Britain and the United States focused on 30,959 (1.2 percent) of those children who were born following an IVF procedure, and looked at diagnoses of autism and intellectual disability.
Overall, when compared to children born from spontaneous conception, children born from any IVF treatment were at no higher risk of autism and an 18 percent higher risk of intellectual disability, their analysis found.
This risk however disappeared when researchers factored in the potential problems associated with multiple births, which are common in IVF.
Researchers also compared six different types of IVF procedures available in Sweden and whether fresh or frozen embryos were used.
The only procedure that stood out was called intracytoplasmic sperm injection (ICSI), a technique to remedy male infertility that involves injecting a single sperm into an egg.
Children born after that procedure, whether via fresh or frozen embryos, were at a 51 percent higher risk for intellectual disability than those born after other types of IVF, or a rise from 62 cases to 93 cases per 100,000.
ICSI was developed in 1992 and is used in about half of all IVF treatments, the researchers said. "When we separated the different IVF treatments, we found that 'traditional' IVF is safe," said Sven Sandin, co-author of the study from King's College London's Institute of Psychiatry.
"But that IVF involving ICSI, which is specifically recommended for paternal infertility is associated with an increased risk of both intellectual disability and autism in children," Sandin said.
The study noted that "the prevalence of these disorders was low, and the increase in absolute risk associated with IVF was small," and further research should be done to test associations in other populations.
Developed in 1992, ICSI is recommended for male infertility and is now used in about half of all IVF treatments.
About five million children have been born as a result of IVF worldwide between 1978 and 2012. Marcelle Cedars, a doctor at the University of California-San Francisco, said in an accompanying editorial that the "data are reassuring regarding the absence of risk of autistic disorder and the small absolute risk of mental retardation."
However, he urged more study of the implications of IVF.
"The number of children born as a result of IVF will continue to increase and much remains to be learned about the long-term implications. Understanding and eliminating even a small risk of neurodevelopmental impairment are important goals."
[IMG]http://img833.imageshack.us/img833/6214/01mi.jpg[/IMG] This program has a lot of good information and I think it's worth your time. Even though the files appear to be from June of 2011 there are a lot of best practices talked about and those never go out of style. I was not able to find the actual pitch page and this product does not seem to be available on the Glazer-Kennedy website (maybe because Bill Glazer is no longer there!) Technical note: Because of really long folder names and endlessly nested folders, I had to compress the file structure and truncate folder names so this torrent could sit on a PC and not crash the system. Therefore some of the webpage files may not play properly. Don't worry, all the content is here. If you are master of the online universe there is probably nothing here for you, but I learned some new things. RECOMMENDED
Presenters:
Bill Glazer
Yanik Silver
Perry Marshall
Tom Kulzer
Jim Edwards & Rick Raddatz
Brian Sacks
Dave Dee
Marty Foley
Alex Mandossian
Jeff Walker
Sydney Johnston
Stephen Pierce
Here's a rundown of what's covered:
MODULE 01: Insider Secrets To Online Copy! Bill Glazer and Yanik Silver discussed the killer copy secrets that make websites sell products like crazy. This session will set you straight about how to write for the web, capture attention and convince people to order your products!
MODULE 02: How To Get Targeted Traffic To Your Site Instantly In 15-Minutes Or Less and Not Overpay! Finally, you get a chance to discover how to launch an effective Google Adwords campaign. Perry Marshall divulges his formula to suck in targeted traffic immediately from inexpensive Google ads that work like magic. Best part: You'll learn how to set your Pay-per-click bids just right. This way you get all the traffic you can handle without breaking the bank.
MODULE 03: How To Follow-Up On Every Qualified Visitor Automatically While You Sleep! Tom Kulzer will show you how to use the magic of little automatic email robots or autoresponders to follow up on leads with no manual labor and turn them into paying customers. You don't know when a prospect is ready to buy so you have to be there all the time. By far, the easiest and most cost effective way to dramatically increase your bottom line is simply increasing your follow-up efforts. And it's easy after you hear about the technology here that makes it totally hands-off. Plus, how to make sure your email actually gets through the SPAM filters and squarely into your prospects inbox.
MODULE 04: How To Make Your Website Come Alive With Audio and Even Video! Jim Edwards and Rick Raddatz will show you how to use amazing new technology (that's actually inexpensive and brain dead simple) to Bring Life To Your Websites And Engage Each Visitor To Stay Longer!
MODULE 05: Real World Example of How to Grow a 7-Figure Internet Business in 12 Months or Less! This is how you can make a vast fortune because it maximizes your visibility and profitability. One of the least understood facts about marketing is that you increase results by mixing and matching the proper media. In this session you'll learn how to combine the power of traditional media with the efficiency of the Internet. This combination produces fast results but it must be done in a very specific manner to work most effectively. You'll learn how when you listen in. This session will be presented by Bill Glazer interrogating Brian Sacks.
MODULE 06: How To Create a $50k-$100k Niche Within 21-Days Or Less! Dave Dee will give you the scoop on how to scope out niche markets you can dominate in less than one month. He has perfected a bona fide system for penetrating almost any niche market lightning fast. Using the techniques Dave teaches you could easily enjoy your own high income Internet business starting within a month.
MODULE 07: The Big Secret to Tracking and Testing that Can Double or Triple Profits From Your Website Without Getting An Additional Single Visitor! Here's how to turn your website visitors into paying buyers. We're shocked so few people know how to engineer this buying process. But you won't be left out of the loop after this session.
MODULE 08: How To Discover Exactly What Your Customers Want Without Any Guessing! This session reveals how to get people to disclose their hidden desires. So you sell them exactly what they're willing to spend money on. Stop guessing what your prospects and customers want to buy from you. Alex Mandossian will tell you how to get inside your customer's mind so you can ethically tap into his wallet. The psychological secrets he reveals will serve you regardless of the product or service you sell online or offline.
MODULE 09: Creating an Unstoppable Product Launch (or Relaunch)! After this session you'll know more about generating a flood of sales than if you read a hundred worthless e-books. Jeff Walker shares his revolutionary Product Launch Formula. There's no theory here - just practical steps anyone can take to create a massive launch or relaunch for almost any product.
MODULE 10: Sydney Johnston teaches you How To Quickly and Easily Sell on eBay! Learn the truth about selling loads and loads of products using the world's #1 auction juggernaut. If you thought eBay is just for clearing out junk in your basement you're dead-bang wrong! eBay is the fourth most visited site on the Net and over $14 Billion dollars in business flow through this site. I'm talking everything from multi-million dollar estates to Fred Flintstone slippers. There are over 100 million registered users who are already looking for your product.
MODULE 11: How To Bring Visitors Back To Your Site Over and Over Again While Keeping Them Excited! Check out these amazing after sale follow up systems that consistently bring customers back begging for more. The big bucks are made by reselling satisfied customers more products and services. With that in mind, Stephen Pierce will reveal his surefire approach to enhance the lifetime value of each and every customer.
MODULE #12: Blueprint for Online Success: Putting All the Pieces Together! This is going to be one of those sessions you'll want to listen to over and over again because it contains the big-picture view of how all the parts of your Internet business come together. It's Bill and Yanik recapping, reviewing and putting everything together for you so you can blast right out of the gate even from a complete standstill online.
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Strengths: I feel like evaluating the strengths and weaknesses of the Rams team might be the hardest task for any team in the NFC West for 49ers fans. Last season, when they played the 49ers, they looked really solid. They were deceptive on Offense and especially on Special Teams (lol fake punts) and hard-nosed on Defense. And while they shouldn't play at that level during every game this season, this does speak to their strengths.
The Rams' greatest strength (except for, maybe, their Head Coach, Jeff Fisher) has got to be their D. The Des, Chris Long and Robert Quinn, had 11.5 and 10.5 sacks respectively. Heck, even DT Michael Brockers had four sacks and was a pretty good run-stopper. Along with Kendall Langford, this unit is packed up by some solid LBs that include rookie Alec Ogletree and James Laurinaitis. The strong D is rounded out by CBs Cortland Finnegan and Janoris Jenkins.
Weaknesses: Where the Rams are weak on Defense, however, is at the Safety position. Both starters left in Free Agency, and Darian Stewart and Rodney McLeod are in a competition with rookie T.J. McDonald. This is probably not the most awe-inspiring group of Safeties.
Much of the offense is suspect too, though probably not as bad as people think. While I'm a believer in Sam Bradford, this will be a big year for him. The Front Office went out to get weapons for him, most notably (the likely over-paid, but bursting with potential) TE Jared Cook and WR Tavon Austin. In addition, the team attempted to shore up its o-line with the (unfortunately injury-prone) OT Jake Long. His presence kicks Rodger Saffold to the right side of the line, thus giving a greater degree of stability to the o-line. Determining how much of a weakness (or an asset) this Offense will be for the Rams is going to come down to how well Bradford responds to his new o-line and receiving targets.
Ultimately, I think it will be the lack of a running game that might hurt the Rams the most. With RB Steven Jackson leaving, the Rams will be running Daryl Richardson and Isaiah Pead out. They could also turn to rookie Zac Stacy. Pro Football Focus rated Richardson as a -1.8 rusher (-6.8 overall), and Pead barely played enough last season such that we can have a clear idea of what type of rusher he is.
I rarely use Windows Explorer for managing files. I just do everything from an enhanced DOS box (Take Command) using some additional utilities that I wrote, such as a command-line regular expression file renaming utility.
Convince me that there is a Windows Explorer replacement that I should get because I'll use it more often for file management. I don't mind paying a reasonable bit of money for it.
Asking price: ?30 Condition of item: Excellent Location: S60
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CUSTOM - Choose your Own Words for your Dictionary Definition Charm Bracelet by Gwen DELICIOUS Jewelry Design
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When the symptoms are persistent, when they do not resolve with normal interventions (like diet change, exercise, laxatives, rest) it is imperative for a woman to see her doctor. Persistence of symptoms is key. Because these signs and symptoms of ovarian cancer have been described as vague or silent, only around 19 percent of ovarian cancer is found in the early stages. Symptoms typically occur in advanced stages when tumor growth creates pressure on the bladder and rectum, and fluid begins to form.
Every woman should undergo a regular rectal and vaginal pelvic examination. If an irregularity of the ovary is found, alternatives to evaluation include transvaginal sonography and/or tumor markers. The most common tumor marker is a blood test called the CA-125.
Unfortunately, most women with ovarian cancer are diagnosed with advanced-stage disease (Stage III). This is because the symptoms of ovarian cancer (particularly in the early stages) often are not acute or intense, and present vaguely. In most cases, ovarian cancer is not detected during routine pelvic exams, unless the doctor notes that the ovary is enlarged. The sooner ovarian cancer is found and treated, the better a woman?s chance for recovery. It is important to know that early stage symptoms are not silent ? so women should be extra alert and watch out for early symptoms.
Potential symptoms of ovarian cancer include:
Bloating
Pelvic or abdominal pain
Trouble eating or feeling full quickly
Feeling the need to urinate urgently or often
Other symptoms of ovarian cancer can include:
Fatigue
Upset stomach or heartburn
Back pain
Pain during sex
Constipation Menstrual changes
Did You Know?
Although there is no consistently reliable screening test to detect ovarian cancer, the following tests are available and should be offered to women, especially those at high risk for ovarian cancer.
Pelvic Exam: Women age 18 and above should have a mandatory annual vaginal exam. Women age 35 and above should receive an annual rectovaginal exam (physician inserts fingers in the rectum and vagina simultaneously to feel for abnormal swelling and to detect tenderness).
Transvaginal Sonography: This ultrasound, performed with a small instrument placed in the vagina, is appropriate especially for women at high risk for ovarian cancer or for those with an abnormal pelvic exam.
CA-125 Test: This blood test determines if the level of CA-125, a protein produced by ovarian cancer cells, has increased in the blood of a woman at high risk for ovarian cancer or with an abnormal pelvic examination.
While CA-125 is an important test, it unfortunately is not always accurate. Some non-cancerous diseases of the ovaries also increase the CA-125 levels, and some ovarian cancers may not produce enough CA-125 levels to cause a positive test.
Positive Tests
If any of these tests are positive, a woman should consult with a gynecologic oncologist who may conduct a CT scan and X-Rays and study the results. However, the only way to more accurately confirm ovarian cancer is with a biopsy, a procedure in which the doctor takes a sample of the tumor and examines it under a microscope.
Research into new ovarian cancer screening tests is ongoing and new diagnostic tests may be on the horizon. NOCC monitors the latest scientific developments, so please come back and visit our site for updates.
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Treatment
After your diagnosis, your doctor will develop your customized treatment plan. Women should always discuss their treatment options with a physician, because the best and most appropriate treatment will be different based on the stage of disease, the woman?s age and the overall condition of her health.
There are three main treatment types for ovarian cancer: 1) Surgery ? Surgery to remove the cancerous growth is the most common method of diagnosis and therapy for ovarian cancer. It is best performed by a qualified gynecologic oncologist. 2) Chemotherapy ? Chemotherapy is the treatment of cancer using chemicals (medications) that travel through the bloodstream to destroy cancer cells or stop them from growing both in and outside the ovaries. Chemotherapy is used in the majority of cases as a follow-up therapy to surgery. 3) Radiation Therapy ? Radiation therapy uses high-energy X-rays to kill cancer cells and shrink tumors (only rarely used in the treatment of ovarian cancer in the United States).
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Complementary Therapies
Some women with ovarian cancer turn toward the whole-body approach of complementary therapy to enhance their fight against the disease, as well as to relieve stress and minimize side effects such as fatigue, pain and nausea.
Complementary therapies are diverse practices and products that are used in conjunction with conventional medicine. Many women have tried and benefited from the following complementary therapies. You might want to speak with other women with cancer or your healthcare team to see which therapies they found most helpful or might work best for you and your lifestyle.
Acupuncture ? An ancient Chinese method of healing in which small sterilized needles are inserted into the body?s energy centers to promote healing. Aromatherapy ? The use of essential oils from flowers, herbs and trees to promote health and well being. Herbal Medicine ? Use of remedies using plant parts to treat symptoms and illnesses. (Consult your healthcare professional prior to using herbal medicine). Massage ? Manipulating the body?s muscle and connective tissue through rubbing, kneading and patting to promote relaxation and well being. Meditation ? Conscious relaxation and focused breathing to relax the mind and body. Qi Gong (chee-GUNG) ? A type of Chinese medicine that combines movement, meditation and breathing to enhance the flow of qi (an ancient term given to what is believed to be vital energy) in the body, improve blood circulation and enhance immune function. Stress Reduction ? Use of stress reduction methods such as exercise, meditation, etc. which have been found to be beneficial in reducing cancer progression and recurrence. Yoga, Tai Chi ? Postures, movements and breathing exercises to strengthen and heal the body, mind and spirit.
Carson City, Nev. ? It?s colorless, odorless and deadly, and safety officials say carbon monoxide poisoning likely contributed to more drowning deaths over the past decades than imagined.
The hazard is not something people tend to think about when on a boat enjoying the sunshine and great outdoors. But the dangers are real.
"It?s a problem people don?t recognize," Edwin Lyngar, a boating safety educator with the Nevada Department of Wildlife, said Friday. "People will start feeling nauseous and think they?re sea sick when they actually have mild carbon monoxide poisoning."
Last weekend, 22-year-old Lucas Allyn died after boating at Bear Lake in Utah when he was overcome by carbon monoxide. According to the Deseret News, Allyn spent a good part of the day at the rear of a boat ? near its exhaust ? hoisting skiers and swimmers out of the water.
"It happened in the open air. You would think it unbelievable until you think about how the gases recirculate near the back of the boat," Dr. Robert Baron, a medical adviser for Glen Canyon National Recreation Area, told the newspaper.
On Sunday, 12 people were treated in southern Nevada after being sickened while house boating on Lake Mead. Five were flown to a hospital in Las Vegas, four were taken by ambulance and three others were treated at the scene. All have since recovered.
"They were running their generator to keep the air conditioning going," said Christie Vanover, spokeswoman for the Lake Mead National Recreation Area. She said another boat parked next to it, causing the exhaust to circulate back into the house boat.
Lyngar said carbon monoxide poisoning while boating "is far more common than we thought."
He pointed to the ban on "teak surfing," where people hold onto a swim platform at the back of a boat and are pulled through the water. Platforms are near exhaust systems.
"People used to do that for fun," he said. "There were several fatalities nationwide." It is now illegal in many states.
story continues below
Lyngar recalled another incident several years ago on Lake Powell, a reservoir on the Colorado River along the Utah-Arizona line. A girl died after washing her hair using the exhaust port from a generator.
"That exhaust is filled with carbon monoxide, but that spout also has warm water," Lyngar said.
Lyngar said a regional group that has studied deaths on the Colorado River concluded that carbon monoxide poisoning "was more prevalent than we thought."
"Going over the record of old accidents, we think a lot more of these are carbon monoxide-related," he said.
"I would say 10, 20 years ago we did not look at this as seriously as we do now," he said. "Over the last decade or two, we?ve recognized how serious it can be."
Baron, who has reviewed death and illness reports on Lake Powell for more than 25 years, agreed.
He and others have collected data showing more than 800 incidents of death or illness on U.S. waterways attributed to carbon monoxide since the mid-1990s.
"There is absolutely many more than that number," he told The Deseret News. "It?s still an under-recognized event."
Lyngar said it?s a good idea for boaters to have carbon monoxide detectors on board ? and pay attention to them. Also, people should not linger in the back of a boat near exhaust.
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OAKLAND, Calif. (AP) ? The Golden State Warriors have landed a coveted free agent ? just not the one everybody was talking about.
The Warriors reached an agreement with swingman Andre Iguodala on a $48 million, four-year deal Friday, two people with knowledge of the situation said.
The people spoke on condition of anonymity to The Associated Press because NBA rules prevent confirmation of moves until July 10. One said the Warriors cleared more than $24 million in salary cap space by sending Richard Jefferson, Andris Biedrins and Brandon Rush to the Utah Jazz along with unspecified draft picks.
Yahoo Sports, which first reported the deal, said the Warriors were only taking back Kevin Murphy and his non-guaranteed $788,000 deal for next season.
While the Warriors had hoped to sign Dwight Howard, the team was informed by the seven-time All-Star he would not be signing with them. Instead, Golden State unloaded its expiring contracts for what it believes was the next best player on the market.
The complicated moves give the rejuvenated franchise, fresh off an appearance in the second round of the playoffs and with a stockpile of promising young talent, a potent scorer and perimeter defender to team with point guard Stephen Curry and company. And for Iguodala, it's a chance to play with another contender.
Iguodala averaged 13 points, 5.4 assists and 5.3 rebounds last season for the Denver Nuggets, who lost in six games to the Warriors in the opening round of the playoffs. He spent his first eight years in the NBA with the Philadelphia 76ers and has averaged 15.1 points on 46 percent shooting for his career.
The Nuggets were hoping to entice Iguodala to come back to the Mile High City, especially because he could return on a five-year deal while the most he could get elsewhere was four years. The Nuggets offered Iguodala a five-year deal worth $60 million with $52 million guaranteed, a person familiar with the situation said, adding that Iguodala would've made only $4 million in the final year of a frontloaded deal.
Sacramento, led by new general manager and former Denver executive Pete D'Alessandro, also sought Iguodala's services. The Kings reportedly offered Iguodala a four-year deal worth at least $52 million but pulled the deal when Iguodala didn't immediately agree, in part, because they didn't want to be used as leverage.
The departure of Denver's top defender could be a big blow to a team that won a franchise-best 57 games during the regular season only to flop in the first round again. This already had been a tumultuous offseason for the Nuggets, who had NBA Executive of the Year Masai Ujiri leave to take over as general manager in Toronto. Later, the team severed ties with Coach of the Year George Karl.
A few Nuggets players turned to Twitter to express their feelings on Iguodala's decision to bolt for the Warriors.
"It was a pleasure. Great guy!" forward Wilson Chandler wrote.
Speedy point guard Ty Lawson said: "Smh!!!!" (shaking my head) and later added, "Business is business."
Iguodala even sent a message to Curry that ended with the phrase, "LETS GET IT!!!!" Curry responded by saying it would be a great four years.
On the flip side, the biggest boon for Utah might be three veterans with expiring contracts, which will give the Jazz tons of space when a slew of top free agents hit the open market next summer. Jefferson is due about $11 million, Biedrins $9 million and Rush $4 million in the final year of their deals.
While production from Jefferson and Biedrins has declined substantially, Rush was considered Golden State's top reserve and perimeter defender until he tore a ligament in his left knee in the home opener. Rush has averaged 9.1 points and 3.6 rebounds since he was drafted 13th overall out of Kansas in 2008 by Portland, which immediately traded him to Indiana.
"Only makes me work harder," Rush tweeted.
The Warriors had been chasing Iguodala for years, but the right move never came together until now.
General manager Bob Myers had said all along that despite the team's perceived salary cap restrictions that a big-time free agent could be signed this summer. The Warriors also will renounce their rights to restricted free agent guard Jarrett Jack and forward Carl Landry to clear space for Iguodala ? a price they believe is more than enough for his addition, which could push promising rookie Harrison Barnes into a reserve role.
Jack and Landry had helped the Warriors go from a 23-43 team during the lockout-shortened season to a 47-35 team last year, earning the conference's sixth seed and eliminating Denver in the first round. But mounting injuries wore the Warriors down and the eventual Western Conference champion San Antonio Spurs sent Golden State home in six games.
"Well," Jack wrote on Twitter, "it was fun while it lasted."
___
AP Sports Writer Pat Graham in Denver contributed to this report.
___
Antonio Gonzalez can be reached at: www.twitter.com/agonzalezAP
Firebugs everywhere are breaking out their favorite little explosive treats today. In states where doing that is legal, of course. But even with all the Roman candles in the world, you'd be hard-pressed to look this cinematic during a pyromaniac binge.
Using a tried and true GoPro-ceiling-fan bullet time rig, photographer Jeremiah Warren put together a jaw-dropping amateur pyro-effects reel that's as impressive as it is festive. With the instructions on Jeremiah's blog, you can build your own slow-mo rig for about $100. Or you could just buy a bunch more fireworks instead. Follow your heart. [Jeremiah Warren via PetaPixel]
Bitcoin fans are familiar with using cloud computing to generate a commodity -- but what would happen if cloud computing was the commodity? The Deutsche Börse should find out when it opens its newly-unveiled Cloud Exchange in the first quarter of 2014. The independent market will let organizations buy remote computing and storage in respective 8GB and 1TB blocks, with traders agreeing on when and where the number crunching takes place. Theoretically, this creates a neutral, competitive space for exchanging server power: buyers can easily spot the best value, while sellers can efficiently offload their unused cycles. Whether or not the Cloud Exchange works that way in practice, we're just hoping that it isn't as volatile as an old-fashioned stock exchange.
Unique epigenomic code identified during human brain developmentPublic release date: 4-Jul-2013 [ | E-mail | Share ]
Contact: Kat Kearney kkearney@salk.edu 619-296-8455 Salk Institute
Salk findings uncovers dynamic changes in the epigenome that occur during brain circuitry formation
LA JOLLA, CA Changes in the epigenome, including chemical modifications of DNA, can act as an extra layer of information in the genome, and are thought to play a role in learning and memory, as well as in age-related cognitive decline. The results of a new study by scientists at the Salk Institute for Biological Studies show that the landscape of DNA methylation, a particular type of epigenomic modification, is highly dynamic in brain cells during the transition from birth to adulthood, helping to understand how information in the genomes of cells in the brain is controlled from fetal development to adulthood. The brain is much more complex than all other organs in the body and this discovery opens the door to a deeper understanding of how the intricate patterns of connectivity in the brain are formed.
"These results extend our knowledge of the unique role of DNA methylation in brain development and function," says senior author Joseph R. Ecker, professor and director of Salk's Genomic Analysis Laboratory and holder of the Salk International Council Chair in Genetics. "They offer a new framework for testing the role of the epigenome in healthy function and in pathological disruptions of neural circuits."
A healthy brain is the product of a long process of development. The front-most part of our brain, called the frontal cortex, plays a key role in our ability to think, decide and act. The brain accomplishes all of this through the interaction of special cells such as neurons and glia. We know that these cells have distinct functions, but what gives these cells their individual identities? The answer lies in how each cell expresses the information contained in its DNA. Epigenomic modifications, such as DNA methylation, can control which genes are turned on or off without changing letters of the DNA alphabet (A-T-C-G), and thus help distinguish different cell types.
In this new study, published July 4 in Science, the scientists found that the patterns of DNA methylation undergo widespread reconfiguration in the frontal cortex of mouse and human brains during a time of development when synapses, or connections between nerve cells, are growing rapidly. The researchers identified the exact sites of DNA methylation throughout the genome in brains from infants through adults. They found that one form of DNA methylation is present in neurons and glia from birth. Strikingly, a second form of "non-CG" DNA methylation that is almost exclusive to neurons accumulates as the brain matures, becoming the dominant form of methylation in the genome of human neurons. These results help us to understand how the intricate DNA landscape of brain cells develops during the key stages of childhood.
The genetic code in DNA is made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). DNA methylation typically occurs at so-called CpG sites, where C (cytosine) sits next to G (guanine) in the DNA alphabet. About 80 to 90 percent of CpG sites are methylated in human DNA. Salk researchers previously discovered that in human embryonic stem cells and induced pluripotent stem cells, a type of artificially derived stem cell, DNA methylation can also occur when G does not follow C, hence "non-CG methylation." Originally, they thought that this type of methylation disappeared when stem cells differentiate into specific tissue-types such as lung or fat cells. The current study finds this is not the case in the brain, where non-CG methylation appears after cells differentiate, usually during childhood and adolescence when the brain is maturing.
By sequencing the genomes of mouse and human brain tissue as well as neurons and glia (from the frontal cortex of the brain) during early postnatal, juvenile, adolescent and adult stages, the Salk team found that non-CG methylation accumulates in neurons through early childhood and adolescence, and becomes the dominant form of DNA methylation in mature human neurons. "This shows that the period during which the neural circuits of the brain mature is accompanied by a parallel process of large-scale reconfiguration of the neural epigenome," says Ecker, who is a Howard Hughes Medical Institute and Gordon and Betty Moore Foundation investigator.
The study provides the first comprehensive maps of how DNA methylation patterns change in the mouse and human brain during development, forming a critical foundation to now explore whether changes in methylation patterns may be linked to human diseases, including psychiatric disorders. Recent studies have demonstrated a possible role for DNA methylation in schizophrenia, depression, suicide and bipolar disorder. "Our work will let us begin to ask more detailed questions about how changes in the epigenome sculpt the complex identities of brain cells through life," says co-first author Eran Mukamel, from Salk's Computational Neurobiology Laboratory.
"The human brain has been called the most complex system that we know of in the universe," says Ryan Lister, co-corresponding author on the new paper, previously a postdoctoral fellow in Ecker's laboratory at Salk and now a group leader at The University of Western Australia. "So perhaps we shouldn't be so surprised that this complexity extends to the level of the brain epigenome. These unique features of DNA methylation that emerge during critical phases of brain development suggest the presence of previously unrecognized regulatory processes that may be critically involved in normal brain function and brain disorders."
At present, there is consensus among neuroscientists that many mental disorders have a neurodevelopmental origin and arise from an interaction between genetic predisposition and environmental influences (for example, early-life stress or drug abuse), the outcome of which is altered activity of brain networks. The building and shaping of these brain networks requires a long maturation process in which central nervous system cell types (neurons and glia) need to fine-tune the way they express their genetic code.
"DNA methylation fulfills this role," says study co-author Terrence J. Sejnowski, a Howard Hughes Medical Institute Investigator, holder of the Francis Crick Chair and head of Salk's Computational Neurobiology Laboratory. "We found that patterns of methylation are dynamic during brain development, in particular for non-CG methylation during early childhood and adolescence, which changes the way that we think about normal brain function and dysfunction."
By disrupting the transcriptional expression of neurons, adds co-corresponding author M. Margarita Behrens, a staff scientist in the Computational Neurobiology Laboratory, "the alterations of these methylation patterns will change the way in which networks are formed, which could, in turn, lead to the appearance of mental disorders later in life."
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Other researchers on the study were Joseph R. Nery, Mark Urich, Clare A. Puddifoot, Nicholas D. Johnson, Jacinto Lucero and Matthew D. Schultz from the Salk Institute; Julian Tonti-Filippini from the University of Western Australia; Yun Huang and Anjana Rao of the La Jolla Institute for Allergy and Immunology; Miao Yu and Chuan He of the University of Chicago; Andrew J. Dwork and Fatemeh G. Haghighi of Columbia University; Holger Heyn and Manel Esteller of Bellvigte Biomedical Research Institute; and Shijun Hu and Joseph C. Wu of the Stanford University School of Medicine.
The work was supported by the National Institute of Mental Health, the Howard Hughes Medical Institute, the Gordon and Betty Moore Foundation, the California Institute for Regenerative Medicine, the Leukemia and Lymphoma Society, the Australian Research Council, and the Center for Theoretical Biological Physics at the University of California, San Diego.
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Unique epigenomic code identified during human brain developmentPublic release date: 4-Jul-2013 [ | E-mail | Share ]
Contact: Kat Kearney kkearney@salk.edu 619-296-8455 Salk Institute
Salk findings uncovers dynamic changes in the epigenome that occur during brain circuitry formation
LA JOLLA, CA Changes in the epigenome, including chemical modifications of DNA, can act as an extra layer of information in the genome, and are thought to play a role in learning and memory, as well as in age-related cognitive decline. The results of a new study by scientists at the Salk Institute for Biological Studies show that the landscape of DNA methylation, a particular type of epigenomic modification, is highly dynamic in brain cells during the transition from birth to adulthood, helping to understand how information in the genomes of cells in the brain is controlled from fetal development to adulthood. The brain is much more complex than all other organs in the body and this discovery opens the door to a deeper understanding of how the intricate patterns of connectivity in the brain are formed.
"These results extend our knowledge of the unique role of DNA methylation in brain development and function," says senior author Joseph R. Ecker, professor and director of Salk's Genomic Analysis Laboratory and holder of the Salk International Council Chair in Genetics. "They offer a new framework for testing the role of the epigenome in healthy function and in pathological disruptions of neural circuits."
A healthy brain is the product of a long process of development. The front-most part of our brain, called the frontal cortex, plays a key role in our ability to think, decide and act. The brain accomplishes all of this through the interaction of special cells such as neurons and glia. We know that these cells have distinct functions, but what gives these cells their individual identities? The answer lies in how each cell expresses the information contained in its DNA. Epigenomic modifications, such as DNA methylation, can control which genes are turned on or off without changing letters of the DNA alphabet (A-T-C-G), and thus help distinguish different cell types.
In this new study, published July 4 in Science, the scientists found that the patterns of DNA methylation undergo widespread reconfiguration in the frontal cortex of mouse and human brains during a time of development when synapses, or connections between nerve cells, are growing rapidly. The researchers identified the exact sites of DNA methylation throughout the genome in brains from infants through adults. They found that one form of DNA methylation is present in neurons and glia from birth. Strikingly, a second form of "non-CG" DNA methylation that is almost exclusive to neurons accumulates as the brain matures, becoming the dominant form of methylation in the genome of human neurons. These results help us to understand how the intricate DNA landscape of brain cells develops during the key stages of childhood.
The genetic code in DNA is made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). DNA methylation typically occurs at so-called CpG sites, where C (cytosine) sits next to G (guanine) in the DNA alphabet. About 80 to 90 percent of CpG sites are methylated in human DNA. Salk researchers previously discovered that in human embryonic stem cells and induced pluripotent stem cells, a type of artificially derived stem cell, DNA methylation can also occur when G does not follow C, hence "non-CG methylation." Originally, they thought that this type of methylation disappeared when stem cells differentiate into specific tissue-types such as lung or fat cells. The current study finds this is not the case in the brain, where non-CG methylation appears after cells differentiate, usually during childhood and adolescence when the brain is maturing.
By sequencing the genomes of mouse and human brain tissue as well as neurons and glia (from the frontal cortex of the brain) during early postnatal, juvenile, adolescent and adult stages, the Salk team found that non-CG methylation accumulates in neurons through early childhood and adolescence, and becomes the dominant form of DNA methylation in mature human neurons. "This shows that the period during which the neural circuits of the brain mature is accompanied by a parallel process of large-scale reconfiguration of the neural epigenome," says Ecker, who is a Howard Hughes Medical Institute and Gordon and Betty Moore Foundation investigator.
The study provides the first comprehensive maps of how DNA methylation patterns change in the mouse and human brain during development, forming a critical foundation to now explore whether changes in methylation patterns may be linked to human diseases, including psychiatric disorders. Recent studies have demonstrated a possible role for DNA methylation in schizophrenia, depression, suicide and bipolar disorder. "Our work will let us begin to ask more detailed questions about how changes in the epigenome sculpt the complex identities of brain cells through life," says co-first author Eran Mukamel, from Salk's Computational Neurobiology Laboratory.
"The human brain has been called the most complex system that we know of in the universe," says Ryan Lister, co-corresponding author on the new paper, previously a postdoctoral fellow in Ecker's laboratory at Salk and now a group leader at The University of Western Australia. "So perhaps we shouldn't be so surprised that this complexity extends to the level of the brain epigenome. These unique features of DNA methylation that emerge during critical phases of brain development suggest the presence of previously unrecognized regulatory processes that may be critically involved in normal brain function and brain disorders."
At present, there is consensus among neuroscientists that many mental disorders have a neurodevelopmental origin and arise from an interaction between genetic predisposition and environmental influences (for example, early-life stress or drug abuse), the outcome of which is altered activity of brain networks. The building and shaping of these brain networks requires a long maturation process in which central nervous system cell types (neurons and glia) need to fine-tune the way they express their genetic code.
"DNA methylation fulfills this role," says study co-author Terrence J. Sejnowski, a Howard Hughes Medical Institute Investigator, holder of the Francis Crick Chair and head of Salk's Computational Neurobiology Laboratory. "We found that patterns of methylation are dynamic during brain development, in particular for non-CG methylation during early childhood and adolescence, which changes the way that we think about normal brain function and dysfunction."
By disrupting the transcriptional expression of neurons, adds co-corresponding author M. Margarita Behrens, a staff scientist in the Computational Neurobiology Laboratory, "the alterations of these methylation patterns will change the way in which networks are formed, which could, in turn, lead to the appearance of mental disorders later in life."
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Other researchers on the study were Joseph R. Nery, Mark Urich, Clare A. Puddifoot, Nicholas D. Johnson, Jacinto Lucero and Matthew D. Schultz from the Salk Institute; Julian Tonti-Filippini from the University of Western Australia; Yun Huang and Anjana Rao of the La Jolla Institute for Allergy and Immunology; Miao Yu and Chuan He of the University of Chicago; Andrew J. Dwork and Fatemeh G. Haghighi of Columbia University; Holger Heyn and Manel Esteller of Bellvigte Biomedical Research Institute; and Shijun Hu and Joseph C. Wu of the Stanford University School of Medicine.
The work was supported by the National Institute of Mental Health, the Howard Hughes Medical Institute, the Gordon and Betty Moore Foundation, the California Institute for Regenerative Medicine, the Leukemia and Lymphoma Society, the Australian Research Council, and the Center for Theoretical Biological Physics at the University of California, San Diego.
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