Kansas City Chiefs quarterback Matt Cassel (7) warms up before an NFL football game against the Pittsburgh Steelers, Monday, Nov. 12, 2012, in Pittsburgh. (AP Photo/Don Wright)
Kansas City Chiefs quarterback Matt Cassel (7) warms up before an NFL football game against the Pittsburgh Steelers, Monday, Nov. 12, 2012, in Pittsburgh. (AP Photo/Don Wright)
Kansas City Chiefs quarterback Matt Cassel (7) scrambles as Pittsburgh Steelers inside linebacker Larry Foote (50) pursues in the second quarter of an NFL football game in Pittsburgh, Monday, Nov. 12, 2012. (AP Photo/Gene J. Puskar)
Kansas City Chiefs quarterback Matt Cassel (7) talks with Pittsburgh Steelers strong safety Troy Polamalu after an NFL football game in Pittsburgh, Monday, Nov. 12, 2012. The Steelers won 16-13 in overtime. (AP Photo/Gene J. Puskar)
KANSAS CITY, Mo. (AP) ? Matt Cassel will start at quarterback for the Kansas City Chiefs on Sunday against Cincinnati because Brady Quinn still has not been cleared to play following a concussion.
Chiefs coach Romeo Crennel said that Quinn feels better and could be cleared by the end of the week. But the coach said he couldn't take the chance that Quinn wouldn't be ready for the Bengals.
"He's feeling a lot better, doing a lot better," Crennel said of Quinn, who has sustained two concussions this season. "He went to the doctor and he told him he's doing a lot better. The doctor also told him he was going to monitor him this week, and if he makes it through this week without incident, he could be cleared for the weekend. But he's got to make it through the week."
Cassel will start his third consecutive game. He was the starter earlier this year before sustaining his own concussion in a game against Baltimore. Quinn was the fill-in starter for a game, and then got the permanent job, only to be knocked out of his second start against the Raiders.
Quinn has been practicing, but Crennel said he's not been cleared for full contact.
"Brady does feel better. I'm glad he's feeling better. But he hasn't been cleared to play yet," Crennel said. "I can't take the chance on practicing the guy and not having him ready."
Quinn admitted last week that he tried to play through the latest concussion, which he believes happened when an Oakland defender's knee collided with the back of his helmet while he was scrambling early in the game. Quinn was later sacked, and then threw an interception during which he recalled having "tunnel vision," before he was removed from the game.
Quinn has been consulting with Dr. Micky Collins, the executive director of the UPMC Sports Medicine Concussion Program in Pittsburgh, one of the leading experts in the diagnosis, treatment and rehabilitation of athletes who have suffered concussions. Collins helped design the ImPACT test now used by many professional sports leagues, including the NFL, to assess concussions and determine when an injured athlete can safely return to play.
Crennel said that the Chiefs training staff has been relaying information to Collins, and together they'll make a determination by Sunday whether Quinn is available.
"If there are any complications, they will not clear him," Crennel said.
Cassel is on pace to have arguably the worst season of his career.
He's completing 58 percent of his throws with a quarterback rating of 66.6, and has only thrown six touchdown passes with 12 interceptions. The most recent pick, early in overtime Monday night, gave the Steelers a chip-shot field goal to win the game.
It was the Chiefs' sixth straight defeat.
"We need to build on the effort, energy and attitude we played with Monday night," Crennel said. "We have to show consistency in all areas going forward. Nobody is happy with our record."
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Last week was a very busy one for those of us on the Northern Meetups, TechCrunch's three-city tour through a few of North America's hottest (well, not literally) burgeoning tech hubs outside of the typical San Francisco/Silicon Valley/New York bubble that we in the media are too often caught up in covering.
Lincoln Middle School hopes to hold onto its domination this season in the championship round of the Alameda Education Foundation?s Middle School Sports Volleyball Championships this Tuesday, Nov. 13, beginning at 4 p.m. at the Boys and Girls Club. ?
Both the A (varsity) and B (junior varsity) Lincoln teams will be defending their No. 1 ranking Tuesday, but if the competitive matches seen in the playoffs are any indication, it won?t be a walk in the park.
In the A division, the Lions will face the Academy of Alameda, who edged out perennial favorite Wood in the playoffs in a third set nail-biter, 22 - 20. ?Wood will challenge in the B teams finals, however, having beaten out No. 3 ranked Nea/ACLC in two games.
The B team match begins at 4 p.m., followed by the A team match. ?All teams are co-ed.
Middle School Volleyball is a program of the Alameda Education Foundation (AEF). ?The AEF Middle School Sports program also includes boys and girls basketball in the winter and track and field in the spring. Teams based at the Academy of Alameda, LIncoln, Wood and a combined Nea/ACLC team compete. ? Volleyball playoffs were last week. Results below:
November 6, 2012 Teams: 1st place vs teams 4th place
B Teams game 1- LMS 25 / AOA 7 game 2- LMS 25 / AOA 14
A Teams game 1- LMS 25 / ACLC/Nea 10 game 2- LMS 25 / ACLC/Nea 20
November 8, 2012 Teams: 2nd place vs teams 3rd place
B Teams game 1- Wood 25 / ACLC/Nea 6 game 2- Wood 25 / ACLC/Nea 23
A Teams game 1- AOA 25 / Wood 17 game 2- Wood 25 / AOA 21 game 3- AOA 22 / Wood 20
November 13, 2012 B Team Final - Lincoln vs Wood 4 PM B&G Club A Team Final - Lincoln vs AOA 5 PM G&G Club
The Note's Must-Reads are a round-up of today's political headlines and stories from ABC News and the top U.S. newspapers. Posted Monday through Friday right here at www.abcnews.com
Compiled by ABC News' Carrie Halperin, Jayce Henderson and Amanda VanAllen
GENERAL PETRAEUS:
ABC News' Reena Ninan and Alyssa Newcomb: " Veteran: Paula Broadwell 'Not the Type' to Have Affair" As a military expert with ties around the world, Paula Broadwell kept a busy schedule packed with writing, teaching and helping wounded soldiers, leaving little time for the married mother to commit "indiscretions," a friend told ABC News. "I have some serious questions about who is connecting these dots and how. ? Paula Broadwell is not the type ? she isn't," said David Bixler, an active duty double amputee who met Broadwell though a charity foundation in 2010. LINK
The Wall Street Journal's Evan Perez, Siobhan Gorman and Devlin Barrett: " FBI Scrutinized on Petraeus" A social planner's complaints about email stalking launched the monthslong criminal inquiry that led to a woman romantically linked to former Gen. David Petraeus and to his abrupt resignation Friday as Central Intelligence Agency chief. The emails began arriving in Jill Kelley's inbox in May, U.S. officials familiar with the probe said. Ms. Kelley, who helped organize social events at MacDill Air Force Base in Tampa, Fla., told the Federal Bureau of Investigation about the emails, which she viewed as harassing, the U.S. officials said. LINK
The New York Daily News' Bill Hutchinson: " Politicians to demand to know why they were left in the dark about Petraeus scandal" The political fallout from David Petraeus' stunning resignation intensified Sunday, as Capitol Hill lawmakers said they will demand the FBI explain why congressional bigs were kept in the dark until after the news broke. Sen. Dianne Feinstein, chairwoman of the Senate Intelligence Committee, said she was blindsided by reports Friday that Petraeus was leaving his post as head of the Central Intelligence Agency after the FBI uncovered his secret love affair - a major no-no for government spooks. LINK
NATIONAL DEBT
The New York Times' Jackie Calmes: " In Debt Talks, Obama Is Ready to Go Beyond Beltway" President Obama, emboldened by his decisive re-election and lessons learned over four years in office, is looking to the renewal of budget talks with Republicans this week as a second chance to take command of the nation's policy debates and finally fulfill his promise to end gridlock in Washington, associates say. As he prepares to meet with Congressional leaders at the White House on Friday, aides say, Mr. Obama will not simply hunker down there for weeks of closed-door negotiations as he did in mid-2011, when partisan brinkmanship over raising the nation's debt limit damaged the economy and his political standing. LINK
GOP PROBLEMS
The Washington Post's Eli Saslow: "GOP's Red America forced to rethink what it knows about the country" She arrived early to take apart the campaign office piece by piece, just as she felt so many other things about her life were being dismantled. Beth Cox wore a Mitt Romney T-shirt, a cross around her neck and fresh eyeliner, even though she had been crying on and off and knew her makeup was likely to run. A day after the election, she tuned the radio to Glenn Beck and began pulling posters and American flags off the wall. LINK
Politico's Jake Sherman: " Election causes angst for House GOP" Last week's Republican bloodbath is causing angst in a series of House leadership elections. The GOP's problems with women - laid bare by last week's elections - is the main undertone in the battle for head of the Homeland Security Committee between Reps. Mike Rogers of Alabama and Candice Miller of Michigan. LINK
OBAMACARE: The Boston Globe's Katie Johnston: " Mass. health law thrown a curve by Obamacare" Now that President Obama has been reelected, it appears that his health care plan is here to stay, but there is still a great deal of confusion over what the mandates entail and how they will be implemented. In Massachusetts, there is even more ambiguity because Obamacare has several regulations that don't line up with the state's 2006 state health care reform law, and it isn't clear how those disparities will be resolved. With all this uncertainty, it can be tough for employers to keep it all straight. LINK
LATINO DONORS: USA Today's Fredreka Shouten: " Latino donors to Obama gain political clout" As a resident of a U.S. territory, Andr?s Lopez could not vote for President Obama on Nov. 6, but the Puerto Rico-based lawyer found another way to help propel Obama to a second term - raising campaign money. Latinos overwhelmingly backed Obama at the polls, pushing him to victory in key states, such as Colorado and Florida. Nationally, Obama won 71% of the Latino vote to Republican Mitt Romney's 27%. But behind the scenes, Lopez and a cadre of wealthy Latino business owners, entertainers, lawyers and financiers tapped their connections to collect roughly $30 million in small and large donations for Obama's re-election, Lopez said. LINK
BOOKMARKS The Note: LINK The Must-Reads Online: LINK Top Line Webcast (12noon EST M-F): LINK ABC News Politics: LINK The Political Punch (Jake Tapper): LINK George's Bottom Line (George Stephanopoulos): LINK Follow ABC News on Twitter: LINK ABC News Mobile: LINK ABC News app on your iPhone/iPod Touch/iPad: LINK
INDIANAPOLIS (AP) ? Splintered beams and boards on a piece of charred earth were all that remained Sunday where three Indianapolis homes were leveled in a blast that killed two people and rendered homes for blocks uninhabitable.
A backhoe raked through the rubble in the middle-class subdivision as clusters of firefighters and rescue workers weary from a long, chaotic day that began late the night before waited for their next assignment.
The two-story, brick-faced homes on either side of those demolished by the blast were ruins. One home's roof was gone, a blackened husk left behind. On the other side of the gap, the side of a home was sheared off. Across the street, garage doors had buckled from the heat.
It wasn't yet clear what caused the blast that shook the neighborhood at 11 p.m. Saturday. Residents described hearing a loud boom that blew out windows and collapsed ceilings. Some thought a plane had crashed or that it was an earthquake.
Alex Pflanzer, who was asleep when the nearby homes were leveled, said he heard his wife screaming and thought someone was breaking in his house. Grabbing his gun, he checked the house and saw the front door was standing open.
"I walked outside and all the houses were on fire," he said.
Pflanzer, his wife and two dogs were staying in a hotel room Sunday night. They were, however, without their cat, who refused to budge from the crawl space.
Deputy Code Enforcement Director Adam Collins said as many as 31 homes were damaged so badly that they may have to be demolished. The explosion damaged a total of 80 homes, he said. He estimated the damage at $3.6 million.
Some residents were allowed to return to their homes to retrieve a few belongings Sunday under police escort, officials said. Others whose homes weren't as badly damaged were allowed to go home, but officials said they would have to do without electricity overnight.
Officials did not identify the two people who were killed. However, a candlelight vigil was held at Greenwood's Southwest Elementary School on Sunday night for second-grade teacher Jennifer Longworth. She and her husband, John Dion Longworth, lived at a home destroyed in the blast. WTHR-TV reported that friends, family and colleagues of the teacher gathered at the school.
Deputy Fire Chief Kenny Bacon told reporters Sunday investigators haven't eliminated any possible causes for the blast. But U.S. Rep. Andre Carson, who represents the area, said he had been told a bomb or meth lab explosion had been ruled out.
Bacon said the crisis could have been much worse. "I know we're very fortunate that some of the people weren't home," he said.
Bryan and Trina McClellan were at home with their 23-year-old son, Eric, when the shock wave from the blast a block away shook their home. It knocked out the windows along one side of their house, and their first instinct was to check on their grandchildren, two toddlers who were in the basement. One held his ears and said, "Loud noise, loud noise."
Eric McClellan said he ran to the scene of the explosion and saw homes flat or nearly so.
"Somebody was trapped inside one of the houses, and the firefighters were trying to get to him. I don't know if he survived," he said, adding that firefighters ordered him to leave the area.
Once the flames were out, firefighters went through what was left of the neighborhood, one home at a time, in case people had been left behind, Fire Lt. Bonnie Hensley said. They used search lights until dawn as they peered into the ruined buildings.
Along with the two people killed, seven people were taken to a hospital with injuries, Bacon said. Everyone else was accounted for, he said.
Four of the seven who were injured had minor injuries, fire officials said.
Dan Considine, a spokesman for Citizens Energy, said the utility had not received any calls from people smelling natural gas in that area.
"Most of the time, when there's a gas leak, people smell it," he said. "But not always."
Carson said officials from the National Transportation Safety Board and the federal Department of Transportation, which have oversight over pipelines, were also sending investigators.
Dan Able, a 58-year-old state employee who lives across the street from the two homes that exploded, said his first thought was that a plane had hit his house.
The blast was "a sound I've never heard before, it was so loud," he said. His windows blew out and a bedroom ceiling collapsed on his wife, Jan. He pulled her out, and they went outside.
"Both houses across the street were on fire, basically, just rubble on fire," he said.
The Ables and about 200 other people evacuated from the neighborhood were taken to a nearby school. Some who had been sleeping arrived in their pajamas with pets they scooped up as they fled. Others had to leave their animals behind, and police said later in the day that they were trying to round up those wandering through the area and find their owners.
Most evacuees eventually left the school to stay with relatives, friends or at hotels.
The relief operation was later moved to a church just a few blocks away, where residents could find supplies including blankets, shoes, diapers, canned goods and even a teddy bear.
ScienceDaily (Nov. 13, 2012) ? Scientists at Indiana University and international collaborators have found a way to link two hormones into a single molecule, producing a more effective therapy with fewer side effects for potential use as treatment for obesity and related medical conditions.
The studies were carried out in the laboratories of Richard DiMarchi, the Standiford H. Cox Distinguished Professor of Chemistry and the Linda & Jack Gill Chair in Biomolecular Sciences in the IU Bloomington College of Arts and Sciences, and of Matthias Tsch?p, professor of medicine and director of the Institute of Diabetes and Obesity, Helmholtz Center Munich, Germany.
Results were published online this week by the journal Nature Medicine.
Researchers combined a peptide hormone from the digestive system, GLP-1, with the hormone estrogen and administered it to obese laboratory mice. While both GLP-1 and estrogen have demonstrated efficacy as therapy for obesity and adult-onset diabetes, the combination was more effective in producing weight loss and other beneficial results than using either compound on its own. And it produced fewer adverse effects, such as excessive tissue growth linked to tumor formation.
"We find that combining the hormones as a single molecule dramatically enhanced their efficacy and their safety," DiMarchi said. "The combination improves the ability to lower body weight and the ability to manage glucose, and it does so without showing the hallmark toxicities associated with estrogen."
The researchers believe GLP-1 acts as a "medicinal chaperone," targeting estrogen to the hypothalamus and pancreas, which are involved with metabolic processes. The precise targeting reduces the likelihood that the estrogen will produce negative effects, such as cancer and stroke.
Brian Finan, a former doctoral student in DiMarchi's lab, is the lead author of the paper, "Targeted estrogen delivery reverses the metabolic syndrome." Co-authors include Bin Yang and Vasily Gelfanov, research scientists in the IU Bloomington Department of Chemistry, and DiMarchi. Finan is now a post-doctoral researcher at the Helmholtz Zentrum M?nchen in Germany, directed by Tsch?p, who is DiMarchi's longtime collaborator and a corresponding co-author. Affiliations of the other 20 co-authors include the University of Cincinnati where, also led by Tsch?p, many of the in vivo pharmacology and molecular mechanism studies were conducted; Northwestern University; and research laboratories in Germany and China.
Associated with what health authorities are calling a global epidemic of obesity, the metabolic syndrome consists of obesity associated with other factors such as high blood pressure, high triglycerides, hyperglycemia and low HDL cholesterol. The International Diabetes Federation estimates that as much as 20 percent of the world's adult population has some form of the metabolic syndrome and that they are three times as likely to have a heart attack or stroke and five times as likely to develop adult-onset diabetes as people without the syndrome.
DiMarchi said investigation continues in the optimization of the peptide-based hormone conjugates with an emphasis on determining the specific mechanism of biological action and identification of an optimal drug candidate suitable for human study. The combination of other peptides and nuclear hormones for targeting other medical conditions holds considerable promise and opportunity for future research.
Partial funding of the research was provided by Marcadia Biotech and more recently Roche Pharma. Marcadia is a company that DiMarchi co-founded and was acquired in 2010 by Roche Pharma, to which he remains a research consultant.
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The above story is reprinted from materials provided by Indiana University, via Newswise.
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Journal Reference:
Brian Finan, Bin Yang, Nickki Ottaway, Kerstin Stemmer, Timo D M?ller, Chun-Xia Yi, Kirk Habegger, Sonja C Schriever, Cristina Garc?a-C?ceres, Dhiraj G Kabra, Jazzminn Hembree, Jenna Holland, Christine Raver, Randy J Seeley, Wolfgang Hans, Martin Irmler, Johannes Beckers, Martin Hrab? de Angelis, Joseph P Tiano, Franck Mauvais-Jarvis, Diego Perez-Tilve, Paul Pfluger, Lianshan Zhang, Vasily Gelfanov, Richard D DiMarchi, Matthias H Tsch?p. Targeted estrogen delivery reverses the metabolic syndrome. Nature Medicine, 2012; DOI: 10.1038/nm.3009
Note: If no author is given, the source is cited instead.
Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.
Ask any barbecue lover, not just here but almost anywhere in the world, and they?ll tell you that Kansas City is the place to find the best barbecued bovine. But the city?s culinary palate is much richer and broader than its finger-licking ?cue, encompassing culinary adventures deeply rooted in its Midwestern food and drink culture. Ranging from simple, homemade comfort food fare at charming neighborhood caf?s, to high-end multi-course culinary indulgences, you are sure to find it here.
On more than one occasion the city has taken center stage on your favorite foodie programs like Food Network and Travel Channel. Two of the most well-known are seeker of the savory Guy Fieri?s Diners, Drive-Ins and Dives and jet setting restaurateur Anthony Bourdain?s No Reservations; when they visited KC they left no samples un-sampled and no plate unclean. But where do such refined palates find adventure? More places than you think!
Diners, Drive-Ins and Dives ? Grinders: Guy Fieri raved about the Bengal Tiger, a tandoori chicken pizza inspired by the flavors of Northwest India that he called ?funklicious.?
Diners, Drive-Ins and Dives ? Johnny?s Bar-B-Q: Smoked brisket, pulled pork, smoked sausage and ?one of the most righteous barbecue rubs I?ve ever had? as described by Fieri.
Diners, Drive-Ins and Dives ? YJ?s Snack Bar: For the show?s ?World of Flavors? episode, Guy Fieri sampled several items inspired by the chef?s worldly travels?including dirty rice, Thai-spiced chicken and fresh fish wrapped in banana leaves.
Diners, Drive-Ins and Dives ? The Brick: ?For the ?Wings, Dogs and Claws? episode, Guy Fieri stopped by this live music outpost to experience The Oklahoma?a hot dog battered with Boulevard Beer, deep fried and then wrapped in bacon.
Diners, Drive-Ins and Dives ? Happy Gillis Cafe: This visit to KC brought him to this soup ?n sandwich joint in Columbus Park. Here, he watched the husband-wife team put twists on authentic lunch and brunch favorites.
Diners, Drive-Ins and Dives ? Swagger: Guy was a fan of the Suribachi Burger (a tempura-fried burger with chili sauce and wasabi coleslaw) and the Dead Texan, a mammoth burger that uses two grilled cheese sandwiches in lieu of buns.?
Diners, Drive-Ins and Dives ? Woodyard Bar-B-Que: This no-frills joint was featured in an all-barbecue episode of ?Diners, Drive-Ins & Dives.? For something different, try the savory wings.
Anthony Bourdain: No Reservations - LC?s Bar-B-Q: With its barbecue pit positioned right behind the counter, Anthony Bourdain praised this joint for its laidback, no-frills vibe.
Anthony Bourdain: No Reservations- Fiorella?s Jack Stack Barbecue: He used words like ?family-friendly? and ?excellent? to describe this torchbearer of KC?s modern barbecue movement. If you?re real hungry, try the Flintstone-sized crown prime beef ribs.
Anthony Bourdain: No Reservations ? Savoy Grill: Anthony was a fan of the Savoy?s? turn-of-the-century decor and juicy steaks. Ask to sit in Harry Truman?s booth, just as Bourdain did in 2012.
Anthony Bourdain: No Reservations ? Oklahoma Joe?s Barbecue & Catering: One of Anthony Bourdain?s 13 Places to Eat at Before You Die, the flagship is located inside a gas station in Kansas City, Kan. Famous for its pulled pork, ribs, fries and spicy slaw!
Anthony Bourdain: No Reservations ? The Cigar Box: In his 2012 episode, this was Anthony Bourdain?s bar of choice for a nightcap of bourbon and entertaining karaoke.
Want to go on your own ?As Seen in KC? adventure? Here?s a map so you may systematically eat your way around Kansas City. Remember to bring extra napkins!
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Delaware State Police are searching for a man accused of manufacturing methamphetamine in his mother?s house.
On Sunday morning, a woman in Felton, Del., called the police reporting a toxic substance on her property. The woman told police that she had been collecting laundry to wash when she found a rag sticking out of a cooler in her son?s bedroom. She pulled the rag from the cooler, became overwhelmed by fumes and then quickly dragged the cooler outside onto a porch, she said.
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Detectives from the Delaware State Police Kent County Drug Unit found key ingredients involved in making methamphetamine at the house, according to investigators. Teams then safely dismantled and removed the lab from the home.
Police are currently searching for the woman?s son, John Bradley, 32, who was not home when they arrived. Warrants are on file for his arrest for manufacturing methamphetamine.
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On his show, Comedian Rodney Perry covers arts and entertainment, everything from comedy and politics to music and acting, with his signature comedic slant.
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The Bottom Line Sports Show is hosted by former NBA stars Penny Hardaway, Charles Oakley, Mateen Cleaves. Tune in to get the inside scoop on what's happening in sports today.
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Contact: Karin Eskenazi ket2116@columbia.edu 212-342-0508 Columbia University Medical Center
New computational analysis identifies gene networks affected in schizophrenia and shows that schizophrenia and autism share related genetic networks, each composed of hundreds of genes
New York, NY (November 11, 2012) Although schizophrenia is highly genetic in origin, the genes involved in the disorder have been difficult to identify. In the past few years, researchers have implicated several genes, but it is unclear how they act to produce the disorder. A new study by researchers at Columbia University Medical Center identifies affected gene networks and provides insight into the molecular causes of the disease.
The paper was published today in the online edition of the journal Nature Neuroscience.
Using an unbiased collection of hundreds of mutations associated with schizophrenia, the Columbia researchers applied a sophisticated computational approach to uncover hidden relationships among seemingly unrelated genes. The analysis revealed that many of the genes mutated in schizophrenia are organized into two main networks, which take part in a few key processes, including axon guidance, synapse function, neuron mobility, and chromosomal modification.
The study also uncovered an intriguing connection between schizophrenia and autism. "If we hadn't known that these were two different diseases, and had put all the mutations into a single analysis, it would have come up with very similar networks," said the study's senior author, Dennis Vitkup, PhD, associate professor in the Department of Biomedical Informatics, the Center for Computational Biology and Bioinformatics, and the Columbia Initiative in Systems Biology at Columbia University Medical Center. "It shows how closely the autism and schizophrenia genetic networks are intertwined," he added.
Although it will take time to translate the findings into practical treatments, the study provides insight into the molecular causes of schizophrenia. It also suggests that mutations associated with schizophrenia, autism, and probably many other psychiatric disorders, are likely to converge on a set of interrelated molecular processes.
Computer analysis uncovers genetic networks
To discover potential connections among genes mutated in schizophrenia, Dr. Vitkup and colleagues developed a computational approach, called NETBAG+, to identify networks of genes likely to be responsible for the same genetic phenotype. They then gathered the strongest mutations that had been observed in schizophrenia by other researchersincluding a set of de novo mutations recently described by a team of Columbia researchers led by Maria Karayiorgou, MD, and Joseph A. Gogos, MD, PhDand fed them into the program.
The program uncovered two genetic networks. Genes in the first network are involved primarily in axon guidance, synapse function, and cell migration. Genes in the second network are involved in chromosomal organization and remodeling.
Parts of both networks are highly active during prenatal development, suggesting that changes in the brain that cause schizophrenia later in life are laid down very early in life.
Connection to autism
Dr. Vitkup also compared his schizophrenia networks with networks found in neurodevelopmental disorders such as autism. One schizophrenia network is strongly related to an autism network he described in a study published last year. Both networks contain genes involved in axon guidance, synapse function, and cell migration.
"Our recent mutational analysis showed that this overlap includes primarily genes that are important for early fetal development. This is not surprising, because some cases of schizophrenia and likely many cases of autism have neurodevelopmental origin," said Dr. Karayiorgou.
The close relationship between genetic networks involved in autism and schizophrenia raises an intriguing question: How can mutations in the same or related genes cause two different disorders?
"I like to use the analogy of car brakes," said Dr. Vitkup. "Different mechanical malfunctions of the brake mechanism can have very different functional consequences, from rapid acceleration to stalling."
Dr. Vitkup looked at large mutations called copy number variants (CNVs) that can lead to either schizophrenia or autism. CNVs involve long stretches of the genome containing several genes that have been either duplicated or deleted. Duplication of a region increases the "dosage" of its genes; deletion of a region decreases the dosage.
In CNVs involved in the growth of dendrites, or dendritic spines, at the ends of neurons, he found decrease in growth to be more common in schizophrenia and increase in growth more common in autism. "That's consistent with what's been found by postmortem brain studies," he said.
"Evidence of functional convergence among risk genes is consistent with the notion that schizophrenia and autism are both primarily diseases of neuronal communication. However, they have distinct clinical features and the challenge remains to identify the critical neural circuits and mechanisms that differentiate them," said Dr. Joseph A. Gogos. "This is a step in that direction."
Dr. Vitkup predicts that many more genes involved in schizophrenia and autism will eventually be foundpossibly up to 1000 genes for each disorderbut a significant fraction of them will likely fall into the networks and pathways identified in the current study.
"Until a few years ago, people were looking for just a handful of genes responsible for autism and schizophrenia, so the idea that many hundreds of genes are involved is a big change in thinking," Dr. Vitkup said. "Our study and the studies of our collaborators suggest that in the search for the causes of complex genetic disorders, it will be more productive to look for common pathways and gene circuits than for a handful of causal genes. This type of network analysis gives us a way to begin to make sense of what's happening."
Study points way to future approaches to gene discovery
"To uncover all of the processes and molecular pathways involved in schizophrenia and related disorders, more gene searches are clearly necessary," said Dr. Vitkup.
Until recently, the hunt for disease genes was focused primarily on analyses of common genetic mutations, using so-called genome-wide association studies (GWAS). But according to Drs. Vitkup, Karayiorgou, and Gogos, a complementary, possibly less expensive, approach may be more fruitful. "By looking at individuals with schizophrenia who are born into families with no history of the disorder," Dr. Vitkup said, "we can identify de novo mutations that are likely to have caused their disorder."
Drs. Karayiorgou and Gogos recently used this approach to uncover many dozens of new schizophrenia mutations from several hundred families; nearly every mutation was unique to one patient.
"Our study demonstrates that through network-based analyses of rare de novo mutations, it is possible to implicate relevant molecular processes," said Dr. Vitkup. "Applying similar methods to larger cohorts of patients, we should be able to delineate all of the pathways and molecular processes underlying complex psychiatric disorders such as schizophrenia."
###
The paper is titled, "Diverse types of genetic variation converge on functional gene networks involved in schizophrenia." The other contributors are Sarah R. Gilman, Jonathan Chang, Bin Xu, Tejdeep S. Bawa, Joseph A. Gogos, and Maria Karayiorgou (all at CUMC).
This work was supported in part by a grant from the Simons Foundation (SFARI award number SF51), US National Centers for Biomedical Computing (MAGNet) grant U54CA121852 to Columbia University, US National Institute of Mental Health grants MH061399 (to M.K.) and MH077235 (to J.A.G.) and the Lieber Center for Schizophrenia Research at Columbia University. S.R.G. was supported in part by US National Institute of General Medical Sciences training grant T32 GM082797. B.X. was partially supported by a US National Alliance for Research in Schizophrenia and Depression (NARSAD) Young Investigator Award.
The authors declare no financial or other conflict of interest.
Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest in the United States. www.cumc.columbia.edu
The Columbia University Department of Biomedical Informatics is the second-oldest in the nation and among the largest. Its 38 faculty members and 60 trainees work in a highly collaborative environment, applying informatics from the atomic level to global populations. Its goals are to discover new information methods, to augment the biomedical knowledge base, and to improve the health of the population. It is consistently identified as among the best programs in the field.
Columbia Psychiatry is ranked among the best departments and psychiatric research facilities in the Nation and has contributed greatly to the understanding of and current treatment for psychiatric disorders. Located at the New York State Psychiatric Institute on the NewYork-Presbyterian Hospital/Columbia University Medical Center campus in the Washington Heights community of Upper Manhattan, the department enjoys a rich and productive collaborative relationship with physicians in various disciplines at Columbia University's College of Physicians and Surgeons. Columbia Psychiatry is home to distinguished clinicians and researchers noted for their clinical and research advances in the diagnosis and treatment of depression, suicide, schizophrenia, bipolar and anxiety disorders, and childhood psychiatric disorders. http://columbiapsychiatry.org/
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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.
Contact: Karin Eskenazi ket2116@columbia.edu 212-342-0508 Columbia University Medical Center
New computational analysis identifies gene networks affected in schizophrenia and shows that schizophrenia and autism share related genetic networks, each composed of hundreds of genes
New York, NY (November 11, 2012) Although schizophrenia is highly genetic in origin, the genes involved in the disorder have been difficult to identify. In the past few years, researchers have implicated several genes, but it is unclear how they act to produce the disorder. A new study by researchers at Columbia University Medical Center identifies affected gene networks and provides insight into the molecular causes of the disease.
The paper was published today in the online edition of the journal Nature Neuroscience.
Using an unbiased collection of hundreds of mutations associated with schizophrenia, the Columbia researchers applied a sophisticated computational approach to uncover hidden relationships among seemingly unrelated genes. The analysis revealed that many of the genes mutated in schizophrenia are organized into two main networks, which take part in a few key processes, including axon guidance, synapse function, neuron mobility, and chromosomal modification.
The study also uncovered an intriguing connection between schizophrenia and autism. "If we hadn't known that these were two different diseases, and had put all the mutations into a single analysis, it would have come up with very similar networks," said the study's senior author, Dennis Vitkup, PhD, associate professor in the Department of Biomedical Informatics, the Center for Computational Biology and Bioinformatics, and the Columbia Initiative in Systems Biology at Columbia University Medical Center. "It shows how closely the autism and schizophrenia genetic networks are intertwined," he added.
Although it will take time to translate the findings into practical treatments, the study provides insight into the molecular causes of schizophrenia. It also suggests that mutations associated with schizophrenia, autism, and probably many other psychiatric disorders, are likely to converge on a set of interrelated molecular processes.
Computer analysis uncovers genetic networks
To discover potential connections among genes mutated in schizophrenia, Dr. Vitkup and colleagues developed a computational approach, called NETBAG+, to identify networks of genes likely to be responsible for the same genetic phenotype. They then gathered the strongest mutations that had been observed in schizophrenia by other researchersincluding a set of de novo mutations recently described by a team of Columbia researchers led by Maria Karayiorgou, MD, and Joseph A. Gogos, MD, PhDand fed them into the program.
The program uncovered two genetic networks. Genes in the first network are involved primarily in axon guidance, synapse function, and cell migration. Genes in the second network are involved in chromosomal organization and remodeling.
Parts of both networks are highly active during prenatal development, suggesting that changes in the brain that cause schizophrenia later in life are laid down very early in life.
Connection to autism
Dr. Vitkup also compared his schizophrenia networks with networks found in neurodevelopmental disorders such as autism. One schizophrenia network is strongly related to an autism network he described in a study published last year. Both networks contain genes involved in axon guidance, synapse function, and cell migration.
"Our recent mutational analysis showed that this overlap includes primarily genes that are important for early fetal development. This is not surprising, because some cases of schizophrenia and likely many cases of autism have neurodevelopmental origin," said Dr. Karayiorgou.
The close relationship between genetic networks involved in autism and schizophrenia raises an intriguing question: How can mutations in the same or related genes cause two different disorders?
"I like to use the analogy of car brakes," said Dr. Vitkup. "Different mechanical malfunctions of the brake mechanism can have very different functional consequences, from rapid acceleration to stalling."
Dr. Vitkup looked at large mutations called copy number variants (CNVs) that can lead to either schizophrenia or autism. CNVs involve long stretches of the genome containing several genes that have been either duplicated or deleted. Duplication of a region increases the "dosage" of its genes; deletion of a region decreases the dosage.
In CNVs involved in the growth of dendrites, or dendritic spines, at the ends of neurons, he found decrease in growth to be more common in schizophrenia and increase in growth more common in autism. "That's consistent with what's been found by postmortem brain studies," he said.
"Evidence of functional convergence among risk genes is consistent with the notion that schizophrenia and autism are both primarily diseases of neuronal communication. However, they have distinct clinical features and the challenge remains to identify the critical neural circuits and mechanisms that differentiate them," said Dr. Joseph A. Gogos. "This is a step in that direction."
Dr. Vitkup predicts that many more genes involved in schizophrenia and autism will eventually be foundpossibly up to 1000 genes for each disorderbut a significant fraction of them will likely fall into the networks and pathways identified in the current study.
"Until a few years ago, people were looking for just a handful of genes responsible for autism and schizophrenia, so the idea that many hundreds of genes are involved is a big change in thinking," Dr. Vitkup said. "Our study and the studies of our collaborators suggest that in the search for the causes of complex genetic disorders, it will be more productive to look for common pathways and gene circuits than for a handful of causal genes. This type of network analysis gives us a way to begin to make sense of what's happening."
Study points way to future approaches to gene discovery
"To uncover all of the processes and molecular pathways involved in schizophrenia and related disorders, more gene searches are clearly necessary," said Dr. Vitkup.
Until recently, the hunt for disease genes was focused primarily on analyses of common genetic mutations, using so-called genome-wide association studies (GWAS). But according to Drs. Vitkup, Karayiorgou, and Gogos, a complementary, possibly less expensive, approach may be more fruitful. "By looking at individuals with schizophrenia who are born into families with no history of the disorder," Dr. Vitkup said, "we can identify de novo mutations that are likely to have caused their disorder."
Drs. Karayiorgou and Gogos recently used this approach to uncover many dozens of new schizophrenia mutations from several hundred families; nearly every mutation was unique to one patient.
"Our study demonstrates that through network-based analyses of rare de novo mutations, it is possible to implicate relevant molecular processes," said Dr. Vitkup. "Applying similar methods to larger cohorts of patients, we should be able to delineate all of the pathways and molecular processes underlying complex psychiatric disorders such as schizophrenia."
###
The paper is titled, "Diverse types of genetic variation converge on functional gene networks involved in schizophrenia." The other contributors are Sarah R. Gilman, Jonathan Chang, Bin Xu, Tejdeep S. Bawa, Joseph A. Gogos, and Maria Karayiorgou (all at CUMC).
This work was supported in part by a grant from the Simons Foundation (SFARI award number SF51), US National Centers for Biomedical Computing (MAGNet) grant U54CA121852 to Columbia University, US National Institute of Mental Health grants MH061399 (to M.K.) and MH077235 (to J.A.G.) and the Lieber Center for Schizophrenia Research at Columbia University. S.R.G. was supported in part by US National Institute of General Medical Sciences training grant T32 GM082797. B.X. was partially supported by a US National Alliance for Research in Schizophrenia and Depression (NARSAD) Young Investigator Award.
The authors declare no financial or other conflict of interest.
Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest in the United States. www.cumc.columbia.edu
The Columbia University Department of Biomedical Informatics is the second-oldest in the nation and among the largest. Its 38 faculty members and 60 trainees work in a highly collaborative environment, applying informatics from the atomic level to global populations. Its goals are to discover new information methods, to augment the biomedical knowledge base, and to improve the health of the population. It is consistently identified as among the best programs in the field.
Columbia Psychiatry is ranked among the best departments and psychiatric research facilities in the Nation and has contributed greatly to the understanding of and current treatment for psychiatric disorders. Located at the New York State Psychiatric Institute on the NewYork-Presbyterian Hospital/Columbia University Medical Center campus in the Washington Heights community of Upper Manhattan, the department enjoys a rich and productive collaborative relationship with physicians in various disciplines at Columbia University's College of Physicians and Surgeons. Columbia Psychiatry is home to distinguished clinicians and researchers noted for their clinical and research advances in the diagnosis and treatment of depression, suicide, schizophrenia, bipolar and anxiety disorders, and childhood psychiatric disorders. http://columbiapsychiatry.org/
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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.
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