Merry Christmas Eve to everyone who celebrates Christmas ? and Happy Holidays to everyone else! ?This morning I woke up with another great Note from the Universe, from Tom Dooley and TUT, the Adventurer?s Club:
?If it?s not yet obvious to you, the real reason for this, and all seasons, is you, Joe. A more perfect child of the Universe has never lived. Until now, only celebrations cloaked in myth and mystery could hint at your divine heritage and sacred destiny. You are life?s prayer of becoming and its answer. The first light at the dawn of eternity, drawn from the ether, so that I might know my own depth, discover new heights, and revel in seas of blessed emotion.
A pioneer into illusion, an adventurer into the unknown, and a lifter of veils. Courageous, heroic, and exalted by legions in the unseen.
To give beyond reason, to care beyond hope, to love without limit; to reach, stretch, and dream, in spite of your fears. These are the hallmarks of divinity ? traits of the immortal ? your badges of honor. May you wear them with a pride as great as what we feel for you.
Your light has illuminated darkened paths, your gaze has lifted broken spirits, and already your life has changed the course of history.
This is the time of year we celebrate Joe Kennedy.
Bowing before Greatness, The Universe?
As you can see, these notes can be extremely thoughtful and extra powerful ? although this ?Note from the Universe? is much longer than most of them are. ?You can sign up for Tom Dooley?s Notes from the Universe at?http://www.tut.com/account/register
What?s really cool is that Tom and his team are coming to the Seattle area for an Infinite Possibilities Train the Trainer Conference January 10-13. ?I really hope to see you there!
Today: Overcast with a chance of rain, then a chance of a thunderstorm and rain in the afternoon. Fog early. High of 72. Winds from the south-southwest at 10 to 15 mph. Chance of rain 40%.
Tonight: Mostly cloudy with a chance of a thunderstorm. Fog overnight. Low of 57. Winds from the south at 10 to 15 mph. Chance of rain 50%.
When you're trying to pick the right product to buy on Amazon, official descriptions and personal taste factor in, sure, but the deal-maker—or breaker—is often that review score, especially with books. The problem is, how do you know if they're legitimate or not? Well Amazon is trying to help you out with that by getting rid of the bogus ones, or at least the ones it thinks are bogus. More »
CHASE KOWALSKI, 7: Chase was always outside, playing in the backyard, riding his bicycle. A week earlier, he was visiting neighbor Kevin Grimes, telling him about completing ? and winning ? his first mini-triathlon. "You couldn't think of a better child," Grimes said. ---- Names of Connecticut school shooting victims, including Chase, are displayed on a makeshift memorial as people walk by on Friday, Dec. 21, 2012, in Newtown, Conn. (AP Photo/Julio Cortez)
CHASE KOWALSKI, 7: Chase was always outside, playing in the backyard, riding his bicycle. A week earlier, he was visiting neighbor Kevin Grimes, telling him about completing ? and winning ? his first mini-triathlon. "You couldn't think of a better child," Grimes said. ---- Names of Connecticut school shooting victims, including Chase, are displayed on a makeshift memorial as people walk by on Friday, Dec. 21, 2012, in Newtown, Conn. (AP Photo/Julio Cortez)
FILE - In this Wednesday, Dec. 19, 2012 file photo, Christmas stockings with the names of shooting victims hang from railing near a makeshift memorial near the town Christmas tree in the Sandy Hook village of Newtown, Conn. In the wake of the shooting, the grieving town is trying to find meaning in Christmas. (AP Photo/Julio Cortez, File)
FILE - In this Tuesday, Dec. 18, 2012 file photo, Addison Strychalsky, 2, of Newtown, Conn., pets Libby, a golden retriever therapy dog, during a visit from the dogs and their handlers to a memorial for the Sandy Hook Elementary School shooting victims in Newtown. As the shock of Newtown's horrific school shooting starts to wear off, as the headlines fade and the therapists leave, residents are seeking a way forward through faith, community and a determination to seize their future. (AP Photo/David Goldman, File)
FILE - In this Thursday, Dec. 20, 2012 file photo, a woman with flowers walks past a Christmas tree which has become a memorial to the Newtown shooting victims in Newtown, Conn. In the wake of the shooting, the grieving town is trying to find meaning in Christmas. (AP Photo/Seth Wenig, File)
Connecticut's Bria Hartley leaves a news conference holding two teddy bears given to her by children from the Newtown Youth Basketball Association after an NCAA women's college basketball game against Hartford at the University of Hartford in West Hartford, Conn., Saturday, Dec. 22, 2012. (AP Photo/Jessica Hill)
NEWTOWN, Conn. (AP) ? People drawn to Newtown to share in its mourning brought cards and handmade snowflakes to town Monday while residents prepared to observe Christmas less than two weeks after a gunman killed 20 children and six educators at an elementary school.
On Christmas Eve, residents said they would light luminaries outside their homes in memory of the victims. Tiny empty Christmas stockings with the victims' names on them hung from trees in the neighborhood where the children were shot.
"We know that they'll feel loved. They'll feel that somebody actually cares," said Treyvon Smalls, a 15-year-old from a few towns away who arrived at town hall with hundreds of cards and paper snowflakes collected from around the state.
Organizers said they wanted to let the families of victims know they are not alone while also giving Connecticut children a chance to express their feelings about the shootings at Sandy Hook Elementary School.
At the Trinity Episcopal Church, less than 2 miles from the school, an overflow crowd of several hundred people attended Christmas Eve services. They were greeted by the sounds of a children's choir echoing throughout a sanctuary hall that had its walls decorated with green wreaths adorned with red bows.
The church program said flowers were donated in honor of Sandy Hook shooting victims, identified by name or as the "school angels" and "Sandy Hook families."
The service, which generally took on a celebratory tone, made only a few vague references to the shooting. Pastor Kathie Adams-Shepherd led the congregation in praying "that the joy and consolation of the wonderful counselor might enliven all who are touched by illness, danger, or grief, especially all those families affected by the shootings in Sandy Hook."
Police say the gunman killed his mother in her bed before his Dec. 14 rampage and committed suicide as he heard officers arriving. Authorities have yet to give a theory about his motive.
While the grief is still fresh, some residents are urging political activism in the wake of the tragedy. A grassroots group called Newtown United has been meeting at the library to talk about issues ranging from gun control, to increasing mental health services to the types of memorials that could be erected for the victims. Some clergy members have said they also intend to push for change.
"We seek not to be the town of tragedy," said Rabbi Shaul Praver of Congregation Adath Israel. "But, we seek to be the town where all the great changes started."
Since the shooting, messages similar to the ones delivered Monday have arrived from around the world. People have donated toys, books, money and more. A United Way fund, one of many, has collected $3 million. People have given nearly $500,000 to a memorial scholarship fund at the University of Connecticut. On Christmas Day, police from other towns have agreed to work so Newtown officers can have the time off.
In the center of Newtown's Sandy Hook section Monday, a steady stream of residents and out-of-towners snapped pictures, lit candles and dropped off children's gifts at an expansive memorial filled with stuffed animals, poems, flowers, posters and cards.
"All the families who lost those little kids, Christmas will never be the same," said Philippe Poncet, a Newtown resident originally from France. "Everybody across the world is trying to share the tragedy with our community here."
Richard Scinto, a deacon at St. Rose of Lima Roman Catholic Church, which was attended by eight children killed in the massacre, said the church's pastor, Rev. Robert Weiss, used several eulogies this week to tell his congregation to get angry and take action against what some consider is a culture of gun violence in the country.
Praver and Scinto said they are not opposed to hunting or to having police in schools, but both said something must be done to change what has become a culture of violence in the United States.
"These were his mother's guns," Scinto said. "Why would anyone want an assault rifle as part of a private citizen collection?"
A mediator who worked with gunman Adam Lanza's parents during their divorce has said Lanza, 20, was diagnosed with Asperger's syndrome, an autism-like disorder that is not associated with violence. It is not known whether he had other mental health issues. The guns used in the shooting had been purchased legally by his mother, Nancy Lanza, a gun enthusiast.
Gun control and mental health have also been topics at Newtown United meetings, along with what types of memorials would be most appropriate and any other action residents can take to feel like they are doing something.
"We don't want Newtown to go on the list with Columbine, Tucson and Virginia Tech and only have it associated with horrible acts," said Lee Shull, who moderated a Newton United meeting just days after the shootings. "We want to turn this into something positive. What can we do?"
A handful of people showed up to the group's first meeting at the town library two days after the Dec. 14 shooting. The next night, 35 attended, most scrawling ideas and notes on white paper covering the tables. A few days later there was barely room to maneuver around the meeting room when two guests showed up: Sen. Richard Blumenthal and Sen.-elect Chris Murphy, Connecticut Democrats who told the group they planned to push for gun control legislation and needed their constituents to help them press the issue in Washington.
The group sees itself as a way to spark a local and national dialogue and action in the aftermath of a tragedy. It's also a way to do something, anything, to cope with the sadness that has settled over Newtown.
Said resident John Neuhall: "Our hearts are broken wide open and we're here out of grief and out of love for those families."
___
Associated Press Writers Pat Eaton-Robb and John Christoffersen contributed to this report.
WASHINGTON?? Workers probably won't feel the full brunt of next year's tax increases in their January paychecks, but they shouldn't be fooled by the temporary reprieve.
No matter what Congress does to address the year-end fiscal cliff, it's already too late for employers to accurately withhold income taxes from January paychecks, unless all the current tax rates remain unchanged, which is an unlikely scenario.
Social Security payroll taxes are set to increase on Jan. 1, so workers should immediately feel the squeeze of a 2-percent cut in their take-home pay. But as talks drag on over how to address other year-end tax increases, the Internal Revenue Service has delayed releasing income tax withholding tables for 2013.
As a result, employers are planning to withhold income taxes at the 2012 rates, at least for the first one or two paychecks of the year, said Michael O'Toole of the American Payroll Association.
If employers don't withhold enough taxes in January, they will have to withhold even more taxes later in the year to make up the difference. Otherwise, taxpayers could get hit with big tax bills, and possibly penalties, when they file their 2013 returns.
Video: Breaking down the 'fiscal cliff'
The tax increases could be steep. If Congress fails to act, workers at every income level face significant tax increases next year as part of the year-end "fiscal cliff."
A taxpayer making between $50,000 and $75,000 would get an average tax increase of $2,400, according to the Tax Policy Center, a Washington research group. If the worker is paid every two weeks, that's about $92 a paycheck, on average.
Someone making between $75,000 and $100,000 would get a tax increase averaging nearly $3,700. If the worker is paid every two weeks, that's about $142 a paycheck.
O'Toole said it would take most employers two weeks to four weeks to update their payroll systems, once new tax withholding tables are released. For some small businesses, it could take longer.
"Employers can't really just come up with withholding tables on their own, depending on what the rates are," O'Toole said. "The smaller companies that do not use a payroll processing service probably would have more problems than anyone else."
On Friday, the IRS said it plans to issue guidance by the end the year, though it won't be early enough to affect paychecks in early January.
"We are aware that employers have questions with respect to 2013 withholding," the agency said in a written statement. "Since Congress is still considering changes to the tax law, we continue to closely monitor the situation. We intend to issue guidance by the end of the year on appropriate withholding for 2013."
About three-quarters of taxpayers received tax refunds this year, averaging $2,707, according to the IRS. That gives most taxpayers some leeway to manage their income tax withholding. However, many people rely on tax refunds to pay bills or make major purchases.
"The reality is, the vast majority of Americans do live paycheck to paycheck and that tax refund is their most significant payday of the year," said Bob Meighan, vice president of TurboTax, an online tax preparation service.
Most of the expiring tax breaks were first enacted under President George W. Bush and extended under President Barack Obama. Obama campaigned for re-election on extending the tax cuts on incomes below $200,000 for individuals and $250,000 for married couples. Obama would let the tax cuts expire on incomes above those amounts.
Video: ?Fiscal cliff? looms as lawmakers head home
In negotiations with House Speaker John Boehner, Obama offered to raise the income threshold, limiting tax increases to those making more than $400,000. Boehner, who has argued for years that the tax cuts should be made permanent for everyone, responded by trying to push a bill through the House that would have let many of the tax cuts expire on incomes above $1 million.
Other political news of note
Schumer non-committal on Hagel as defense secretary
Updated 97 minutes ago
12/23/2012 5:37:07 PM +00:00
The possibility of President Barack Obama nominating former Nebraska senator Chuck Hagel as defense secretary seemed to suffer some deflation Sunday when in an appearance on NBC?s Meet the Press, Sen. Charles Schumer, D- N.Y., passed up the chance to support Hagel.
LaPierre refuses to back new gun curbs
Obama on cliff deal: 'Still think we can get it done'
George H.W. Bush to stay in hospital longer
Boehner's fiscal path forward: 'God only knows'
Many Republicans revolted and Boehner, R-Ohio, shelved the bill, sending lawmakers home for the Christmas holiday and leaving the outcome of talks in doubt as the new year approaches.
If Congress and the White House cannot reach a deal, income tax rates would go up, estate taxes and investment taxes would increase and the alternative minimum tax would hit millions of middle-income people. A temporary payroll tax cut that has benefited nearly every wage earner in 2011 and 2012 expires, costing the average family an additional $1,000 a year by itself.
In addition, dozens of other tax breaks for businesses and individuals that are routinely renewed each year already expired at the end of 2011. Congress was expected to renew many of them by January, so taxpayers could still claim them on their 2012 tax returns.
If Congress doesn't act on those tax cuts, businesses would lose a popular tax credit for research and development as well as generous tax breaks for investing in new plants and equipment. Individuals would lose federal tax breaks for paying local sales taxes, buying energy efficient appliances and using mass transit.
In all, taxes would increase by about $536 billion next year.
Copyright 2012 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
That?s what Neil Patel of Quick Sprout told us when we asked him about the future of the internet. He went on to say:
?It?s going to be more tablet and mobile based in the next few years. We?re going to start seeing a lot less laptops and computers and more and more mobile phones for everything.?
?Want to buy something? Cool. Click a button and it?s charged to your mobile phone.?
Neil?s right:? we asked 20 of the world?s top online entrepreneurs about the trends that would define the future of online business and ?mobile? was the most common answer (online video was #2). If you have a website and you?re not thinking about mobile, then you?re missing out on the biggest thing to happen to the Internet since broadband.
There are now more than 1.2 billion mobile web users worldwide and 25% of US internet users are mobile only. Mobile searches have quadrupled in the last year and this phenomenon is not going away any time soon.
Below, I?ll explain what makes mobile users different based on research from Google Mobile. Then I?ll share the mobile content, design, email marketing, and sales copy strategies that I learned directly from experts like Syed Balkhi and Yanik Silver.
What You?ll Learn:
The browsing habits of mobile users
The simple secret to writing mobile content
Why responsive web design matters and how to get it
The trick to good good mobile sales copy
How mobile readers might change your email marketing tactics
All images courtesy of JD Hancock.
Understanding Why the Mobile Web is Different
Compact Interface
Mobile users experience the web differently. First of all, the screen is smaller. This can be a problem, as Shane Ketterman points out on CopyBlogger:
?What happens when readers feel cramped or have to work hard to navigate your site or read your content? They leave.?
In order to keep visitors around, keep your pages straightforward and your links ?thumb-sized? ? especially call-to-action buttons.
Objective Oriented Browsing
Mobile users are often accessing the web on the go and therefore they?re more likely to be using the web to meet an immediate, specific need.
According to a Google Mobile Ads study, Nine out 10 mobile searches result in an action and 88% of these users take action within the first day.
Slower Connection Speed
Smartphones and tablets are becoming more and more powerful with every iteration, but they still can?t compete with the big boys (laptops and desktops) in terms of speed.
So if you?re load times are lagging on those devices, you?ll definitely be turning mobile users away. Try removing unnecessary plugins, images, and eliminating any Flash or Javascript.
Multi-Tasking Mobile
Mobile devices are so convenient to use that they?re often used as a supplement to other activities. 72% of people use their smartphones while consuming other media, a third while watching TV.
So keep in mind that you likely won?t have the full attention of your mobile audience.
Location-Specific Searches
Mobile users can access the web from anywhere and that changes what they?re able to search for online. For instance, 70% use their smartphones while shopping in a store to help make purchasing decisions.
Your online audience is no longer guaranteed to be sitting at a desk. Think about your niche:? from what other locations and situations might your audience be accessing your site?
?
Mastering the Mobile Web from Content Writing to Copy Writing
Make Mobile Content Easy-to-Digest
Syed Balkhi is one of the world?s most forward-thinking bloggers, especially when it comes to content. His latest project, List25, has earned over 200,000 Facebook likes in just over a year.
He told us that ?easy to consume? content is the wave of the future, as more and more people spend their online hours casually browsing mobile devices:
?We?re seeing an emergence of infographics and motion graphics. We?re going towards an age of data consumption and we need to make it as easy to consume as possible, because people?s attention span is so low. To captivate that short attention span, you have to have very, very compelling content that?s very easy to consume.?
Income Diary is a strong proponent of writing long content because it ranks better (the average front-page search result is 2,000+ words) and because it?s more likely to be shared (as demonstrated by Neil Patel).
But Syed?s right too. As more and more people go mobile, more and more web users will be browsing your site while waiting in line, watching TV, and otherwise unable to engage with in-depth content. You can make your content more ?easy-to-consume? by putting an emphasis on visuals and videos ? and keeping text to a minimum.
Responsive & Mobile Web Design
Jacob Cass is a graphic designer at NYC-based firm Ammirati (clients include Nintendo, Zynga, and Jerry Seinfeld). When we asked him about the future of web design, he immediately start talking about mobile:
?Responsive design is at the top of my list. A responsive website is a website that adapts to the screen that you?re viewing it on. For example, a website will change its look when you?re viewing it on a mobile device, versus a large screen.?
Upgrading to a responsive web design may be the single most important thing you can do to make your website more mobile friendly.
If you?re wondering how to make the? switch over to responsive web design, Jacob gave us this advice, ?For my site, I used the Skeleton responsive boilerplate. There?s really no reason to redo everything if there are already frameworks in place. Another good one to explore is Bootstrap, by Twitter.?
Email Marketing and Mobile
?More and more people are going to be reading your email on little screens.? David Risley, from Web Domination 20
Nearly all mobile users are using their device to check their email.
According to Andigo New Media, your first priority should be to limit scrolling on the email:? ?left to right scrolling is an absolute no-no but even north/south scrolling should be limited whenever possible.?
David Risley earns a six-figure income through email marketing. In our interview, he told us that optimizing your emails for mobile devices mostly comes down to keeping it as simple as possible ? especially since some mobile devices aren?t so great at displaying email:
?The nice smart phones are pretty good at scaling the email up and down. But not everybody?s walking around with an iPhone, so you have to just keep things as simple as you can.?
If you?ve got an email list, then try opening your emails with a variety of different mobile devices to see how they look.
Writing Sales Copy for a Mobile Audience
?You?ve got to balance the device with the message.? Yanik Silver, from Web Domination 20
Yanik Silver is the creator of Instant Sales Letters and quite possibly the world?s leading expert in online copywriting. He?s also one of the first copywriters to recognize that online sales letters should adapt for mobile users.
His first advice is to keep it short:
?You?ve got to make sure that your copy is ideal for someone coming off of a mobile device. Maybe that means even shorter paragraphs. Maybe that means keeping it really tight and engaging.?
Silver also sees a sales video as a way to level the copywriting playing field across all devices:
?For someone to scroll through on their iPhones through a twenty page sales letter is going to be a lot tougher than watching a three minute video about it.?
These sales page videos don?t have to be flashy in order to be effective on mobile. Michael Dunlop uses a video that?s just voiceover and text for his Web Domination sales page. What matters it that mobile users can digest your entire message with just one touch of the screen.
The devices are small, but the mobile web is big? and only getting bigger.
The sooner you start running your website with a mobile audience in mind, the soon you?ll be able to benefit from this fast-growing demographic.
In this post, I reviewed mobile content, design, email marketing, and sales copy, but that?s really only scratching the surface. If you have any insights into mastering the mobile web ? or questions about it ? let us know in the comments.
Nutrient-sensing enzymes key to starvation response and survival in newborn mammalsPublic release date: 23-Dec-2012 [ | E-mail | Share ]
Contact: Nicole Rura rura@wi.mit.edu 617-258-6851 Whitehead Institute for Biomedical Research
CAMBRIDGE, Mass. (December 23, 2012) In the perilous hours immediately after birth, a newborn mammal must survive the sudden loss of food supply from its mother. Under normal circumstances, newborns mount a metabolic response to ward off starvation until feeding occurs. This survival response involves a process of controlled breakdown of internal energetic sources known as autophagy. Although autophagy has been well documented, the key mechanistic regulators of autophagy in vivo have remained poorly understood.
Whitehead Institute researchers have discovered that a family of nutrient-sensing enzymes, dubbed Rag GTPases, modulates the activity of the mTORC1 protein complex, whose inhibition is essential for autophagy and survival in newborns. The finding, reported this week in the journal Nature, emerges from the lab of Whitehead Member David Sabatini, whose earlier in vitro studies showed that mTORC1 (for "mechanistic target of rapamycin complex 1") senses the presence of vital amino acids via interactions with Rag GTPases.
To assess the impact of this Rag GTPase-mTORC1 relationship in mammals, the lab generated mice genetically altered to continually express an active form of the GTPase RagA and compared them with wild-type mice. In normal mice, RagA is activated in the presence of nutrients, and turns on the mTORC1 pathway, which regulates organismal growth in response to nutrient availability. If the mice are deprived of nutrients, RagA is switched off, deactivating mTORC1 and initiating autophagy to tide the animal over until the next feeding. However, in the altered mice, RagA's continuous activity keeps mTORC1 active, despite a dearth of available nutrients. Instead of mTORC1 triggering autophagy, the animals' metabolisms remain unchanged, resulting in nutritional crisis and death.
"What happens to a newborn animal with the RagA enzyme always on is pretty shocking," says Sabatini, who is also a professor of biology at MIT and a Howard Hughes Medical Institute (HHMI) investigator. "A normal neonate animal within an hour after birth responds to that condition, but one with its RagA stuck 'on' doesn't, and it dies. It basically has a huge energetic and nutritional crisis because it can't make the adaption."
These striking results stunned Alejo Efeyan, a postdoctoral researcher in the Sabatini lab, and first author of the Nature that describes this work.
"We were surprised that there was no inhibition of this pathway independent of RagAthat there is no backup system," says Efeyan. "And that RagA is a more global nutrient sensor that goes beyond its known function as an amino acid sensor."
RagA's role as an amino acid sensor had been established in cultured cells by the Sabatini lab. Yet when Efeyan compared nutrient levels in fasting newborn RagA-active mice with those of fasting pups with normal RagA, not only amino acids were reduced in RagA-active animals, also glucose levels were dangerously low. The animals were unable to "sense" either of these reductions, so autophagy failed to initiate in the RagA-active pups, which all died within hours of birth.
This newly identified function for RagA suggests much remains unknown about the cell biology of nutrient sensing, an area of research that Sabatini and his lab continue to investigate.
###
This work was supported by National Institutes of Health (R01CA129105, R01 CA103866 and R37 AI047389), the American Federation for Aging, Starr Foundation, Koch Institute Frontier Research Program, the Ellison Medical Foundation, the Human Frontiers Science Program, the Jane Coffin Childs Memorial Fund for Medical Research, and the LAM Foundation.
Written by Nicole Giese Rura
David Sabatini's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.
Full Citation:
"Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival"
Nature, online on December 23, 2012.
Alejo Efeyan (1,2,3,4,5), Roberto Zoncu (1,2,3,4,5), Steven Chang (1,2,3,4,5), Iwona Gumper (6), Harriet Snitkin (6), Rachel L. Wolfson (1,2,3,4,5), Oktay Kirak (1,7), David D. Sabatini (6) and David M. Sabatini (1,2,3,4,5).
1. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
2. Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
3. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
4. David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
5. Howard Hughes Medical Institute, MIT, Cambridge, MA, 02139.
6. Department of Cell Biology, New York University School of Medicine, New York, NY 10016-6497, USA.
7. Present address: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.
[ | 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.
Nutrient-sensing enzymes key to starvation response and survival in newborn mammalsPublic release date: 23-Dec-2012 [ | E-mail | Share ]
Contact: Nicole Rura rura@wi.mit.edu 617-258-6851 Whitehead Institute for Biomedical Research
CAMBRIDGE, Mass. (December 23, 2012) In the perilous hours immediately after birth, a newborn mammal must survive the sudden loss of food supply from its mother. Under normal circumstances, newborns mount a metabolic response to ward off starvation until feeding occurs. This survival response involves a process of controlled breakdown of internal energetic sources known as autophagy. Although autophagy has been well documented, the key mechanistic regulators of autophagy in vivo have remained poorly understood.
Whitehead Institute researchers have discovered that a family of nutrient-sensing enzymes, dubbed Rag GTPases, modulates the activity of the mTORC1 protein complex, whose inhibition is essential for autophagy and survival in newborns. The finding, reported this week in the journal Nature, emerges from the lab of Whitehead Member David Sabatini, whose earlier in vitro studies showed that mTORC1 (for "mechanistic target of rapamycin complex 1") senses the presence of vital amino acids via interactions with Rag GTPases.
To assess the impact of this Rag GTPase-mTORC1 relationship in mammals, the lab generated mice genetically altered to continually express an active form of the GTPase RagA and compared them with wild-type mice. In normal mice, RagA is activated in the presence of nutrients, and turns on the mTORC1 pathway, which regulates organismal growth in response to nutrient availability. If the mice are deprived of nutrients, RagA is switched off, deactivating mTORC1 and initiating autophagy to tide the animal over until the next feeding. However, in the altered mice, RagA's continuous activity keeps mTORC1 active, despite a dearth of available nutrients. Instead of mTORC1 triggering autophagy, the animals' metabolisms remain unchanged, resulting in nutritional crisis and death.
"What happens to a newborn animal with the RagA enzyme always on is pretty shocking," says Sabatini, who is also a professor of biology at MIT and a Howard Hughes Medical Institute (HHMI) investigator. "A normal neonate animal within an hour after birth responds to that condition, but one with its RagA stuck 'on' doesn't, and it dies. It basically has a huge energetic and nutritional crisis because it can't make the adaption."
These striking results stunned Alejo Efeyan, a postdoctoral researcher in the Sabatini lab, and first author of the Nature that describes this work.
"We were surprised that there was no inhibition of this pathway independent of RagAthat there is no backup system," says Efeyan. "And that RagA is a more global nutrient sensor that goes beyond its known function as an amino acid sensor."
RagA's role as an amino acid sensor had been established in cultured cells by the Sabatini lab. Yet when Efeyan compared nutrient levels in fasting newborn RagA-active mice with those of fasting pups with normal RagA, not only amino acids were reduced in RagA-active animals, also glucose levels were dangerously low. The animals were unable to "sense" either of these reductions, so autophagy failed to initiate in the RagA-active pups, which all died within hours of birth.
This newly identified function for RagA suggests much remains unknown about the cell biology of nutrient sensing, an area of research that Sabatini and his lab continue to investigate.
###
This work was supported by National Institutes of Health (R01CA129105, R01 CA103866 and R37 AI047389), the American Federation for Aging, Starr Foundation, Koch Institute Frontier Research Program, the Ellison Medical Foundation, the Human Frontiers Science Program, the Jane Coffin Childs Memorial Fund for Medical Research, and the LAM Foundation.
Written by Nicole Giese Rura
David Sabatini's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.
Full Citation:
"Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival"
Nature, online on December 23, 2012.
Alejo Efeyan (1,2,3,4,5), Roberto Zoncu (1,2,3,4,5), Steven Chang (1,2,3,4,5), Iwona Gumper (6), Harriet Snitkin (6), Rachel L. Wolfson (1,2,3,4,5), Oktay Kirak (1,7), David D. Sabatini (6) and David M. Sabatini (1,2,3,4,5).
1. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
2. Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
3. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
4. David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
5. Howard Hughes Medical Institute, MIT, Cambridge, MA, 02139.
6. Department of Cell Biology, New York University School of Medicine, New York, NY 10016-6497, USA.
7. Present address: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.
[ | E-mail | Share ]
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Public release date: 23-Dec-2012
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