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Monday, June 24, 2013
La Jolla Institute discovers new player critical to unleashing T cells against disease
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Public release date: 23-Jun-2013[ | E-mail |
Share ] Contact: Bonnie Ward
contact@liai.org
619-991-0868
La Jolla Institute for Allergy and Immunology
Nature-published study reveals previously unknown role of septin proteins
SAN DIEGO (June 23, 2013) A major study from researchers at the La Jolla Institute for Allergy and Immunology provides new revelations about the intricate pathways involved in turning on T cells, the body's most important disease-fighting cells, and was published today in the prestigious scientific journal Nature.
The La Jolla Institute team is the first to prove that a certain type of protein, called septins, play a critical role in activating a calcium channel on the surface of the T cell. The channel is the portal through which calcium enters T cells from the blood stream, an action essential for the T cell's survival, activation, and ability to fight disease.
Patrick Hogan and Anjana Rao, Ph.D.s, are senior authors on the paper and Sonia Sharma and Ariel Quintana, Ph.D.s, are co-first authors. Drs. Sharma, Rao and Hogan are former researchers at Harvard Medical School with high-level genetics expertise who joined the La Jolla Institute in 2010. Dr. Quintana conducted advanced microscopy that was a major aspect of the study.
Dr. Hogan describes the discovery as another important step in understanding the overall functioning of T cells knowledge from which new, more precisely targeted drugs to treat diseases ranging from cancer to viral infections can emerge. "It's like working on an engine, you have to know what all the parts are doing to repair it," he says. "We want to understand the basic machinery inside a T cell. This will enable us to target the specific pressure points to turn up a T cell response against a tumor or virus or to turn it down in the case of autoimmune diseases."
The findings were published in a Nature paper entitled "An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca2+ entry."
"We have found that the septin protein is a very strong regulator of the calcium response, which is essential for activating immune cells," says Dr. Sharma, who was recently appointed to a faculty position, and now leads her own independent laboratory at the La Jolla Institute, in addition to serving as scientific director of the newly established RNAi screening center.
Dr. Hogan says the discovery took the research team by surprise. "We knew septins existed in the cellular plasma (surface) membrane, but we didn't know they had anything to do with calcium signaling," he says. Septins are known to build scaffolding to provide structural support during cell division.
This finding builds on Dr. Rao and Dr. Hogan's groundbreaking discovery in 2006 showing that the protein ORAI1 forms the pore of the calcium channel. The channel's entryway had been one of the most sought after mysteries in biomedical science because it is the gateway to T cell functioning and, consequently, to better understanding how the body uses these cells to fight disease.
To the research team's surprise, the septins were forming a ring around the calcium channel. "We aren't sure why, but we theorize that the septins are rearranging the cellular membrane's structure to "corral" the key proteins STIM and ORAI1, and maybe other factors needed for the calcium channel to operate," says Dr. Hogan.
Dr. Sharma adds that, "essentially we believe the septins are choreographing the interaction of these two proteins that are important in instigating the immune response." Without the septins' involvement, T cell activation does not occur.
In the study, the researchers devised a simple visual readout of activity in a main pathway responsible for activation of T cells the same pathway that is targeted by the immunosuppressive drug cyclosporin A that is used clinically and looked for impairment of the activity when individual genes were, in effect, deleted. After sorting through the roughly 20,000 human genes, they turned up 887 gene "hits," says Dr. Hogan.
With further experiments, they should be able to classify those hits into genes that affect the calcium channel itself and genes that act later in the pathway. "We are hopeful that one or more of these genes can be used as a clinical target for new drugs to treat transplant rejection and immune diseases, some of the same indications now treated with cyclosporine A," adds Dr. Hogan. He believes that a medication aimed at an early step of calcium entry through the ORAI channel could be more effective and have fewer side effects than cyclosporin A, which targets a later step in the pathway and can cause complications such as kidney disease.
###
About La Jolla Institute
Founded in 1988, La Jolla Institute for Allergy and Immunology is a nonprofit, independent biomedical research institute focused on improving human health through increased understanding of the immune system. Its scientists carry out research seeking new knowledge leading to the prevention of disease through vaccines and the treatment and cure of infectious diseases, cancer, inflammatory, and autoimmune diseases such as rheumatoid arthritis, type 1 (juvenile) diabetes, Crohn's disease and asthma. La Jolla Institute's research staff includes more than 150 Ph.D.s and M.D.s. To learn more about the Institute's work, visit http://www.lji.org.
[ | 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.
Public release date: 23-Jun-2013[ | E-mail |
Share ] Contact: Bonnie Ward
contact@liai.org
619-991-0868
La Jolla Institute for Allergy and Immunology
Nature-published study reveals previously unknown role of septin proteins
SAN DIEGO (June 23, 2013) A major study from researchers at the La Jolla Institute for Allergy and Immunology provides new revelations about the intricate pathways involved in turning on T cells, the body's most important disease-fighting cells, and was published today in the prestigious scientific journal Nature.
The La Jolla Institute team is the first to prove that a certain type of protein, called septins, play a critical role in activating a calcium channel on the surface of the T cell. The channel is the portal through which calcium enters T cells from the blood stream, an action essential for the T cell's survival, activation, and ability to fight disease.
Patrick Hogan and Anjana Rao, Ph.D.s, are senior authors on the paper and Sonia Sharma and Ariel Quintana, Ph.D.s, are co-first authors. Drs. Sharma, Rao and Hogan are former researchers at Harvard Medical School with high-level genetics expertise who joined the La Jolla Institute in 2010. Dr. Quintana conducted advanced microscopy that was a major aspect of the study.
Dr. Hogan describes the discovery as another important step in understanding the overall functioning of T cells knowledge from which new, more precisely targeted drugs to treat diseases ranging from cancer to viral infections can emerge. "It's like working on an engine, you have to know what all the parts are doing to repair it," he says. "We want to understand the basic machinery inside a T cell. This will enable us to target the specific pressure points to turn up a T cell response against a tumor or virus or to turn it down in the case of autoimmune diseases."
The findings were published in a Nature paper entitled "An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca2+ entry."
"We have found that the septin protein is a very strong regulator of the calcium response, which is essential for activating immune cells," says Dr. Sharma, who was recently appointed to a faculty position, and now leads her own independent laboratory at the La Jolla Institute, in addition to serving as scientific director of the newly established RNAi screening center.
Dr. Hogan says the discovery took the research team by surprise. "We knew septins existed in the cellular plasma (surface) membrane, but we didn't know they had anything to do with calcium signaling," he says. Septins are known to build scaffolding to provide structural support during cell division.
This finding builds on Dr. Rao and Dr. Hogan's groundbreaking discovery in 2006 showing that the protein ORAI1 forms the pore of the calcium channel. The channel's entryway had been one of the most sought after mysteries in biomedical science because it is the gateway to T cell functioning and, consequently, to better understanding how the body uses these cells to fight disease.
To the research team's surprise, the septins were forming a ring around the calcium channel. "We aren't sure why, but we theorize that the septins are rearranging the cellular membrane's structure to "corral" the key proteins STIM and ORAI1, and maybe other factors needed for the calcium channel to operate," says Dr. Hogan.
Dr. Sharma adds that, "essentially we believe the septins are choreographing the interaction of these two proteins that are important in instigating the immune response." Without the septins' involvement, T cell activation does not occur.
In the study, the researchers devised a simple visual readout of activity in a main pathway responsible for activation of T cells the same pathway that is targeted by the immunosuppressive drug cyclosporin A that is used clinically and looked for impairment of the activity when individual genes were, in effect, deleted. After sorting through the roughly 20,000 human genes, they turned up 887 gene "hits," says Dr. Hogan.
With further experiments, they should be able to classify those hits into genes that affect the calcium channel itself and genes that act later in the pathway. "We are hopeful that one or more of these genes can be used as a clinical target for new drugs to treat transplant rejection and immune diseases, some of the same indications now treated with cyclosporine A," adds Dr. Hogan. He believes that a medication aimed at an early step of calcium entry through the ORAI channel could be more effective and have fewer side effects than cyclosporin A, which targets a later step in the pathway and can cause complications such as kidney disease.
###
About La Jolla Institute
Founded in 1988, La Jolla Institute for Allergy and Immunology is a nonprofit, independent biomedical research institute focused on improving human health through increased understanding of the immune system. Its scientists carry out research seeking new knowledge leading to the prevention of disease through vaccines and the treatment and cure of infectious diseases, cancer, inflammatory, and autoimmune diseases such as rheumatoid arthritis, type 1 (juvenile) diabetes, Crohn's disease and asthma. La Jolla Institute's research staff includes more than 150 Ph.D.s and M.D.s. To learn more about the Institute's work, visit http://www.lji.org.
[ | 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.
Source: http://www.eurekalert.org/pub_releases/2013-06/ljif-lji062113.php
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Deal of the Day ? Dell Optiplex 3010 Core i5 Quad-Core desktop with Windows 7 Pro and 3-year warranty
LogicBUY’s Deal for Sunday is the configurable Dell?Optiplex 3010 3rd Gen Core i5 Quad-core desktop, starting at?$539.00. ?Features: Core i5-3470 3.2GHz Quad-core CPU 4GB RAM 500GB Hard Drive, 16X DVD-ROM Keyboard and mouse Windows 7 Professional (64-bit) 3-year warranty $841.43 – 29% instant savings – $50 coupon code = $539.00 with free shipping. This deal [...]
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Rivers receding in Calgary, thousands return home
Residents look out from Scholten Hill as water floods an area of the River Flats in Medicine Hat, Alberta. on Sunday, June 23, 2013. (AP Photo/The Canadian Press, Medicine Hat News, Emma Bennett)
Residents look out from Scholten Hill as water floods an area of the River Flats in Medicine Hat, Alberta. on Sunday, June 23, 2013. (AP Photo/The Canadian Press, Medicine Hat News, Emma Bennett)
Cpl. Brett Martens from CFB Edmonton helps a resident clear out damaged debris from their home near downtown Calgary, Alberta, on Sunday, June 23, 2013. About 65,000 residents of Calgary were being allowed to return to their homes Sunday to assess the damage from flooding that has left Alberta's largest city awash in debris and dirty water. (AP Photo/The Canadian Press, Jonathan Hayward)
Homeowner Glenn Tibbles looks at the damage done by floodwaters to his home near downtown Calgary, Alberta, on Sunday, June 23, 2013. About 65,000 residents of Calgary were being allowed to return to their homes Sunday to assess the damage from flooding that has left Alberta's largest city awash in debris and dirty water. (AP Photo/The Canadian Press, Jonathan Hayward)
A flooded downtown Calgary, Alberta is seen from a aerial view of the city Saturday, June 22, 2013. The two rivers that converge on the western Canadian city of Calgary are receding Saturday after floods devastated much of southern Alberta province, causing at least three deaths and forcing thousands to evacuate. (AP Photo/The Canadian Press, Jonathan Hayward)
A flooded downtown Calgary, Alberta is seen from a aerial view of the city Saturday, June 22, 2013. The two rivers that converge on the western Canadian city of Calgary are receding Saturday after floods devastated much of southern Alberta province, causing at least three deaths and forcing thousands to evacuate. (AP Photo/The Canadian Press, Jonathan Hayward)
CALGARY, Alberta (AP) ? About 65,000 residents of Calgary were being allowed to return to their homes Sunday to assess the damage from flooding that has left Alberta's largest city awash in debris and dirty water.
Some were returning to properties spared by flooding, but others were facing extensive repairs to homes and businesses.
About 75,000 people had to leave at the height of the crisis as the Elbow and Bow rivers surged over their banks Thursday night. Three bodies have been recovered since the flooding began in southern Alberta and a fourth person was still missing.
"We've turned a corner, but we are still in a state of emergency," Calgary Mayor Naheed Nenshi said. "Our hearts and thought and prayers are with our colleagues downstream."
People in the eastern part of the province headed for higher ground as the flood threat remained. In Medicine Hat, Alberta, thousands of people have left their homes as water levels rose on the South Saskatchewan River. The river was not expected to crest until Monday, but by Sunday morning it was lapping over its banks in low-lying areas and people were busy laying down thousands of sandbags.
In Calgary, Nenshi said crews were working hard to restore services and he thanked residents for heeding the call to conserve drinking water.
He had already warned that recovery will be a matter of "weeks and months" and the damage costs will be "lots and lots."
While pockets of the city's core were drying out, other areas were still submerged. The mayor didn't anticipate that anyone could return to work downtown until at least the middle of the week. The downtown area was evacuated Friday.
The city's public schools were also to remain closed Monday.
Nathan MacBey and his wife found muddy water had risen to about kitchen counter level in their Calgary home at the peak of the flooding. His basement was still swamped and the main floor of the home was covered in wet mud.
"This is unprecedented," said the father of two, his voice cracking with emotion. "Not being able to give our kids a home, that's tough. ... We can survive, it's just the instability for the kids."
Alberta Municipal Affairs Minister Doug Griffiths said that 27 communities in Alberta were under states of emergency ? with some areas slowly starting to emerge from the watery onslaught and others still bracing for it
Griffiths said no place has been hit harder than the town of High River south of Calgary and it will be some time before residents there will be allowed back.
The waiting and worrying were causing tensions and emotions to run high, but Griffiths said virtually every home in the town of 18,000 would need to be inspected.
More than 2,200 military personnel were involved in flood relief efforts, along with nine helicopters. Soldiers were helping evacuate an area around the mountain town of Canmore, laying down sandbags in Medicine Hat and assisting in road repairs in Kananaskis Country, west of Calgary.
In High River, about 350 members of the Princess Patricia's Canadian Light Infantry from Edmonton have been assisting police in reaching homes that still haven't been checked. Armored vehicles have been churning through submerged streets and Zodiac watercraft have been used to reach the hardest-hit areas.
High River Mayor Emile Blokland said the town's infrastructure has been dealt a critical blow and there is no timeline for when citizens can return.
Royal Canadian Mounted Police Staff Sgt. Brian Jones said the atmosphere was "surreal."
"We're finding a great deal of mud, a great deal of sludge on the streets. The homes are secure. It's almost like time stopped," he said.
Back in Calgary, the water has taken a toll outside residential neighborhoods as well. The Saddledome hockey arena, home of the National Hockey League's Calgary Flames, was extensively damaged. The team said boards, dressing rooms, player equipment and several rows of seats were a total loss.
The rodeo and fair grounds of the world-famous Calgary Stampede were also swamped, although Nenshi was optimistic that things would be cleared up in time for the show to open July 5.
Nenshi said Sunday that all the major hotels in the downtown were closed and advised visitors to plan accordingly.
The federal Conservative party had planned to hold a policy convention in Calgary next weekend, but that's been postponed and a new date hasn't yet been set.
Canmore was one of the first communities hit when the flooding began on Thursday. Residents there have been allowed to return to 260 evacuated homes, but the Royal Canadian Mounted Police says 40 more are too damaged to allow people back.
In Saskatchewan, efforts are under way to move more than 2,000 people from their homes in a flood-prone part of the province's northeast.
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Sunday, June 23, 2013
Today in History
Today is Sunday, June 23, the 174th day of 2013. There are 191 days left in the year.
Today's Highlight in History:
On June 23, 1888, abolitionist Frederick Douglass received one vote from the Kentucky delegation at the Republican convention in Chicago, effectively making him the first black candidate to have his name placed in nomination for U.S. president. (The nomination went to Benjamin Harrison.)
On this date:
In 1757, forces of the East India Company led by Robert Clive won the Battle of Plassey, which effectively marked the beginning of British colonial rule in India.
In 1812, Britain, unaware that America had declared war against it five days earlier, rescinded its policy on neutral shipping, a major issue of contention between the two countries.
In 1860, a congressional resolution authorized creation of the United States Government Printing Office, which opened the following year.
In 1931, aviators Wiley Post and Harold Gatty took off from New York on a round-the-world flight that lasted eight days and 15 hours.
In 1938, the Civil Aeronautics Authority was established.
In 1947, the Senate joined the House in overriding President Harry S. Truman's veto of the Taft-Hartley Act, designed to limit the power of organized labor.
In 1956, Gamal Abdel Nasser was elected president of Egypt.
In 1967, President Lyndon B. Johnson and Soviet Premier Alexei Kosygin (ah-LEK'-say koh-SEE'-gihn) held the first of two meetings at Glassboro State College in New Jersey.
In 1969, Warren E. Burger was sworn in as chief justice of the United States by the man he was succeeding, Earl Warren.
In 1972, President Richard Nixon and White House chief of staff H.R. Haldeman discussed a plan to use the CIA to obstruct the FBI's Watergate investigation. (Revelation of the tape recording of this conversation sparked Nixon's resignation.) President Nixon signed into law Title IX, which barred discrimination on the basis of sex for "any education program or activity receiving federal financial assistance."
In 1988, James E. Hansen, a climatologist at the Goddard Institute for Space Studies, told a Senate panel that global warming of the earth caused by the "greenhouse effect" was a reality.
In 1993, in a case that drew widespread attention, Lorena Bobbitt of Prince William County, Va., sexually mutilated her husband, John, after he'd allegedly raped her. (John Bobbitt was later acquitted of marital sexual assault; Lorena Bobbitt was later acquitted of malicious wounding by reason of insanity.) Canada's Senate ratified the North American Free Trade Agreement.
Ten years ago: A divided Supreme Court, in a 5-4 decision, allowed the nation's colleges and universities to select students based in part on race, as long as race was not the determining factor. The Supreme Court said the government could require public libraries to equip computers with anti-pornography filters. Democrat Howard Dean formally announced his presidential campaign. Maynard Jackson Jr., the first black mayor of Atlanta, died in Arlington, Va., at age 65.
Five years ago: Outraged at the turmoil in Zimbabwe, the U.N. Security Council declared that a fair presidential vote was impossible because of a "campaign of violence" waged by President Robert Mugabe's government. Seattle's Felix Hernandez hit the first grand slam by an American League pitcher in 37 years, then departed with a sprained ankle before he could qualify for a win in the Mariners' 5-2 victory over the New York Mets.
One year ago: Syria and Turkey desperately sought to ease tensions following an incident in which Syria shot down a Turkish reconnaissance plane, saying the plane had entered its airspace. Ashton Eaton broke the world record in the decathlon, finishing with 9,039 points at the U.S. Olympic trials in Eugene, Ore. The Daytime Emmys showered "General Hospital" with five trophies, including best drama; NBC's "Today" show won as best morning show and the syndicated "Jeopardy!" was named best game show.
Today's Birthdays: Singer Diana Trask is 73. Musical conductor James Levine (luh-VYN') is 70. Rhythm-and-blues singer Rosetta Hightower (The Orlons) is 69. Actor Ted Shackelford is 67. Actor Bryan Brown is 66. Supreme Court Justice Clarence Thomas is 65. Actor Jim Metzler is 62. "American Idol" ex-judge Randy Jackson is 57. Actress Frances McDormand is 56. Rock musician Steve Shelley (Sonic Youth) is 51. Actor Paul La Greca is 51. Rhythm-and-blues singer Chico DeBarge is 43. Actress Selma Blair is 41. Rock singer KT Tunstall is 38. Rhythm-and-blues singer Virgo Williams (Ghostowns DJs) is 38. Singer-songwriter Jason Mraz is 36. Actress Melissa Rauch is 33. Rock singer Duffy is 29. Country singer Katie Armiger is 22.
Thought for Today: "Suffering without understanding in this life is a heap worse than suffering when you have at least the grain of an idea what it's all for." ? Mary Ellen Chase, American author (1887-1973).
(Above Advance for Use Sunday, June 23)
Copyright 2013, The Associated Press. All rights reserved.
Source: http://news.yahoo.com/today-history-050206767.html
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'Mad Men' stars in not-so-'60s roles
TV 
8 hours ago
They look sleek, sexy and dapper in their 1960s finery, but the cast of "Mad Men" isn't always so polished. In fact, sometimes when the stars who bring Don Draper, Roger Sterling and the rest of the characters to life aren't playing the roles they're most famous for, they're barely recognizable.
Before you say "so long" to the Sterling Cooper & Partners gang for the season on Sunday night, take a look at our roundup of some of the (not-so-) familiar faces.
AMC / NBC
Jon Hamm as Don Draper on "Mad Men" and Abner on "30 Rock."
Don Draper's made some serious mistakes on "Mad Men" this season, but thankfully, the look on the right isn't one of them. No, that's just John Hamm spoofing old-timey, distasteful comedies in an "Alfie and Abner" skit from a live episode of "30 Rock."
AMC / Netflix
John Slattery as Roger Sterling on "Mad Men" and Dr. Norman on "Arrested Development."
If it looks like Roger Sterling has seen better days in the second shot, that's because the actor who plays him, John Slattery, took on the part of a washed up, dirty doctor in the recent return of "Arrested Development."
AMC / CBS
Elisabeth Moss as Peggy Olson on "Mad Men" and Cynthia Parks on "Picket Fences."
Peggy Olson's grown into quite the copywriter at Sterling Cooper & Partners, but way before that, actress Elisabeth Moss hit the small screen when she was still small. She made her first appearance in the quirky dramedy "Picket Fences" in 1992.
AMC / 20th Century Television
Vincent Kartheiser as Pete Campbell on "Mad Men" and Connor on "Angel."
Even Pete Campbell -- or rather Vincent Kartheiser -- had a fresh-faced look on TV back in the day. Long before joining "Mad Men," Kartheiser played Connor, the non-vamp son of the fang-bearing lead, on "Angel."
AMC / FOX
Christina Hendricks as Joan Harris on "Mad Men" and Saffron on "Firefly."
If you're a fan of Joan Harris' just-so hair, tailored dresses and crimson lipstick, then Christina Hendricks' turn on "Firefly" might not interest you. But if you want to see Hendricks' range (and don't mind seeing her in far fewer clothes), then be sure to catch both of her decade-old episodes.
AMC / Capri Films
Jessica Pare as Megan Draper on "Mad Men" and Jennifer on "Suck."
Yikes! Megan Draper goes from Don's secretary to wife on "Mad Men," but actress Jessica Pare went from alive to undead in the movie "Suck."
AMC / NBC
Alison Brie as Trudy Campbell on "Mad Men" and Annie Edison on "Community."
When actress Alison Brie isn't playing the part of Pete's long-suffering wife, Trudy Campbell, she's laughing it up as the brainy and beautiful Annie on the sitcom "Community."
AMC / Warner Bros. Pictures
Jared Harris as Lane Pryce on "Mad Men" and Moriarty in "Sherlock Holmes: A Game of Shadows."
Rest in peace, Lane Pryce. Fans of the fallen character can see actor Jared Harris back in action in the 2011 film "Sherlock Holmes: A Game of Shadows," playing the ultimate match for the sleuth -- the devious Professor Moriarty.
The season six finale of "Mad Men" airs Sunday at 10 p.m. on AMC.
Source: http://www.today.com/entertainment/mad-men-stars-not-so-60s-roles-6C10411625
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Meredith Melnick: HuffPost Workouts: First Run Of The Summer
Get Healthy Living Alerts:
Friday was the Summer solstice, although it's hard to imagine that fact escaped anyone's notice. And if you're as lazy on Friday mornings as I am, chances are this very day marks your first workout of summer.
Though extra precautions must be taken for this more strenuous season, summer workouts -- especially outdoors -- are a true pleasure: It's light later, the weather calls for little more than some running shorts and a tank top and everyone is in a better mood. That's a recipe for added energy and just the thing to get you moving.
Which means it's time for a summer playlist. The best thing to happen to my headphones this season has been the late spring arrival of Bleached's joyful garage pop album, dreamy tunes from Phoenix and Vampire Weekend's predictable but pleasing new record. For a short weekend run, this is what I'm queuing up:
A Tout A L'Heure -- Biblio
Entertainment -- Phoenix
Diamond -- Lightening Dust
East Coast Girl -- Cayucos
Dead Boy -- Bleached
Finger Back -- Vampire Weekend
Falling -- Haim
Wheel of Fortune -- The Virgins
Tell us in the comments -- what are you listening to this week?
?
Follow Meredith Melnick on Twitter: www.twitter.com/meredithcm
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