Multitasking may be Achilles heel for hepatitis C

Saturday, November 21, 2009

Despite its tiny genome, the hepatitis C virus packs a mean punch. The virus is a microcosm of efficiency, and each of its amino acids plays multiple roles in its survival and ability to sidestep attack. But new research from Rockefeller University suggests that this fancy footwork and multitasking could be the key to bringing down the virus. The work, which focuses on a once-ignored protein, provides insights on how drug therapy for sufferers of the disease might be improved.

The protein, NS2, which is one of the 10 proteins that make up the hepatitis C virus, gained momentum as a plausible drug target in 2006, when Charles M. Rice, head of the Laboratory of Virology and Infectious Disease, and his team solved the structure of its protease domain. The domain spans the second half of NS2 and acts like a molecular scissor, cleaving itself from its neighbor, NS3. (At first, the 10 proteins that make up the virus are strung together in a continuous chain, which is later cleaved by various enzymes.) By that time, it's also known to aid in the production of infectious virus particles.

Now Rice and his team have dissected the nooks and crannies of this protease domain down to the amino acids that make them up, and have mapped which amino acids are responsible for churning out infectious particles, and distinguished them from those involved in the cleaving process. During the researchers' meticulous poking and prodding, deleting and replacing, one amino acid in particular caught their attention: the protein's very last one.

"When we changed or deleted the terminal leucine -- leucine 217 -- infectious virus production shut down," says graduate student Thomas Dentzer, who led the research. "But what really intrigued us was leucine 217's position."

After the protease makes its cut, leucine 217 remains in a protein fold that makes up the protease's active site. Although the active site isn't involved in making infectious virus particles, Dentzer and Rice -- who is also Maurice R. and Corinne P. Greenberg Professor in Virology and scientific director of the Center for the Study of Hepatitis C at Rockefeller -- showed that it is essential for the protease's cleaving activity. With both functions mapping to this tiny region of NS2, the researchers suggest that drugs targeting this area might be able to pack a double punch against the virus.

Since the hepatitis C virus has an uncanny ability to mutate and evade detection just when the body's immune forces are closing in, punching several phases of the virus's life cycle simultaneously may be a better approach than dealing one phase a forceful blow. "A double punch may give the immune system time to attack the virus before it mutates," says Dentzer. "So this is a good therapeutic target to explore."

The fact that this amino acid is exposed on the virus's surface makes the finding all the more exciting and suggests that it is involved in protein-protein interactions during the life cycle of the virus. "We not only have a target that can weaken the virus, but a target that is also accessible," says Rice. "It is a lead that can really help us move forward."

Source: Rockefeller University

Permalink: http://www.sflorg.com/comm_center/unv_medical/p950_230.html

Time Stamp: 11/21/2009 at 1:09:18 AM UTC

Lockheed Martin Receives $17.8 Million Contract Award for A-10 Software Upgrade

Saturday, November 21, 2009

Lockheed Martin [NYSE: LMT] has received a $17.8 million contract from the U.S. Air Force for a software upgrade that integrates critical communications and situational awareness capabilities into the A-10C close air support fighter.

The software upgrade will provide improved pilot vehicle interface and enhanced weapons delivery. Also included with the upgrade are software baselines for the helmet-mounted cueing system that increase situational awareness through improved visual cues for the pilot, and the lightweight airborne recovery system that integrates search and rescue capability.

"This software upgrade is another critical achievement in the continued modernization of a proven weapon system. Armed with these latest enhancements, A-10C pilots can more quickly access the information they need to prevail on the battlefield," said Roger Il Grande, A-10 program director at Lockheed Martin Systems Integration in Owego, NY.

The software upgrade is the third in an annual series planned for the A-10 and is scheduled for release in May 2011. The earlier two upgrades were also performed by Lockheed Martin; the first was fielded on schedule in May 2009 and the second is on target for release in May 2010.

The upgrades will be integrated in Lockheed Martin's A-10 Systems Integration Lab in Owego, NY. The lab is used by engineers and pilots to prototype software and hardware upgrades for operational validity before flight, to fully integrate aircraft avionics modifications to reduce development risk and cost, and to aid in pilot and maintainer familiarization of newly-deployed systems. Lockheed Martin leads an A-10 industry team that includes Southwest Research Institute, San Antonio, TX and Northrop Grumman, St. Augustine, FL.

Headquartered in Bethesda, Md., Lockheed Martin is a global security company that employs about 140,000 people worldwide and is principally engaged in the research, design, development, manufacture, integration and sustainment of advanced technology systems, products and services. The corporation reported 2008 sales of $42.7 billion.

Source: Lockheed Martin

Permalink: http://www.sflorg.com/comm_center/lockheed_martin/p949_28.html

Time Stamp: 11/21/2009 at 12:25:49 AM UTC

New Method to Measure Snow, Soil Moisture With GPS May Benefit Meteorologists, Farmers

Friday, November 20, 2009

A research team led by the University of Colorado at Boulder has found a clever way to use traditional GPS satellite signals to measure snow depth as well as soil and vegetation moisture, a technique expected to benefit meteorologists, water resource managers, climate modelers and farmers.

The researchers have developed a technique that uses interference patterns created when GPS signals that reflect off of the ground -- called "multipath" signals -- are combined with signals that arrive at the antenna directly from the satellite, said CU-Boulder aerospace engineering sciences Professor Kristine Larson, who is leading the study. Since such multipath signals arrive at GPS receivers "late," they have generally been viewed as noise by scientists and engineers and have largely been ignored, said Larson, who is leading a multi-institution research effort on the project.

In one recent demonstration, the team was able to correlate changes in the multipath signals to snow depth by using data collected at a field site in Marshall, Colo. just south of Boulder, which was hit by two large snowstorms over a three-week span in March and April of 2009. Published in the September issue of Geophysical Research Letters, the snowpack study built on a project Larson and her colleagues have been working on that is funded by the National Science Foundation to measure soil moisture using GPS receivers.

The new study on snow and vegetation moisture will be presented at the fall meeting of the American Geophysical Union being held in San Francisco Dec. 14 to 18.

Larson's group is the first to use traditional GPS receivers -- which were designed for use by surveyors and scientists to measure plate tectonics and geological processes -- to assess snowpack, soil moisture and vegetation moisture. The team hopes to apply the technique to data collected from an existing network of more than 1,000 GPS receivers in place around the West known as the Plate Boundary Observatory, a component of NSF's Earthscope science program.

"By using the Plate Boundary Observatory for double duty, so to speak, we hope this will be a relatively inexpensive and accurate method that can benefit climate modelers, atmospheric researchers and farmers throughout the West," said Larson.

Study collaborators, all from Boulder, include CU-Boulder's Eric Small and Mark Williams, John Braun from the University Corporation for Atmospheric Research, Ethan Gutmann from the National Center for Atmospheric Research and Valery Zavorotny and Andria Bilich from National Oceanic and Atmospheric Administration.

The most recent effort by the team has been conducted in cooperation with Munson Farms of Boulder. The new experiment is designed to analyze how the GPS signals traveling through alfalfa, corn and grass correlate with the amount of water in the vegetation. Small and CU-Boulder students have been cutting and weighing both wet and dry vegetation and matching the sample weights with comparative GPS multipath signal changes using a receiver set up at the farm.

The team is collaborating with Bob Munson, owner of Munson Farms and a former antenna engineer at Ball Aerospace & Technologies of Boulder. Munson holds more than 30 patents related to antenna design, including one of the most widely used antennas for GPS applications like vehicle navigation and recreational applications.

"With this system, the GPS antenna allows us to see across a whole field, unlike individual moisture sensors that are sometimes set up to measure only small, specific areas," Munson said. If a farmer relied on data from only a single soil moisture sensor that happened to be in a particularly dry pocket of his crop field, for example, it could have a negative effect on the timing and quality of the harvest, he said.

Originally developed in the 1970s for military use, GPS technology is in wide use today, telling drivers and hikers their exact position on the planet and providing directions to their destinations by gathering at least four signals simultaneously from the 31 GPS satellites now orbiting Earth.

Braun, who received his doctorate from CU-Boulder in 2004, also is interested in observing water vapor in the atmosphere by measuring the delay of GPS signals as they propagate through the atmosphere. "Water scarcity is going to be a problem for the western United States in the coming century," he said. "Having improved observations of water in all of its phases is going to be an important step as we monitor changes in the environment, which is the most intriguing part of this project for me."

Larson helped to pioneer the use of GPS as a tool to measure the movement of tectonic plates and the crustal deformation associated with earthquakes as a graduate student at the University of California-San Diego in 1980s. "Even then we knew that the data were corrupted by ground reflection, which was really irritating," she said. "But it was only recently that we began to think maybe there was a way to use these ground reflections to our benefit."

All of the team's research efforts revolve around the water cycle, said Larson. "We want to know if the water is in the ground, in the snow or in the vegetation, and how much is evaporating into the atmosphere, since it will ultimately be returned to the Earth's surface through precipitation events."

Source: University of Colorado at Boulder

Permalink: http://www.sflorg.com/comm_center/unv_tech/p948_76.html

Time Stamp: 11/20/2009 at 8:57:27 PM UTC

Under Embargo Till: 19:00 UTC November 19, 2009
Posted: 19:00 UTC 11/19/2009

After Mastodons and Mammoths, a Transformed Landscape

Thursday, November 19, 2009

Roughly 15,000 years ago, at the end of the last ice age, North America's vast assemblage of large animals -- including such iconic creatures as mammoths, mastodons, camels, horses, ground sloths and giant beavers -- began their precipitous slide to extinction.

And when their populations crashed, emptying a land whose diversity of large animals equaled or surpassed Africa's wildlife-rich Serengeti plains then or now, an entirely novel ecosystem emerged as broadleaved trees once kept in check by huge numbers of big herbivores claimed the landscape. Soon after, the accumulation of woody debris sparked a dramatic increase in the prevalence of wildfire, another key shaper of landscapes.

This new picture of the ecological upheaval of the North American landscape just after the retreat of the ice sheets is detailed in a study published today (Nov. 19) in the journal Science. The study, led by researchers from the University of Wisconsin-Madison, uses fossil pollen, charcoal and dung fungus spores to paint a picture of a post-ice age terrain different from anything in the world today.

The work is important because it is "the clearest evidence to date that the extinction of a broad guild of animals had effects on other parts of these ancient ecosystems," says John W. Williams, a UW-Madison professor of geography and an expert on ancient climates and ecosystems who is the study's senior author. What's more, he says, the detailing of changes on the ice age landscape following the crash of keystone animal populations can provide critical insight into the broader effects of animals disappearing from modern landscapes.

The study was led by Jacquelyn Gill, a graduate student in Williams' lab. Other co-authors are Stephen T. Jackson of the University of Wyoming, Katherine B. Lininger of UW-Madison and Guy S. Robinson of Fordham University.

The new work, says Gill, informs but does not resolve the debate over what caused the extinction of 34 genera or groups of large animals, including icons of the ice age such as elephant like mastodons and ground sloths the size of sport utility vehicles. "Our data are not consistent with a rapid, 'blitzkrieg' overkill of large animals by humans," notes Gill, nor was their decline due to a loss of habitat.

However, the work does seem to rule out a recent hypothesis that a meteor or comet impact some 12.9 thousand years ago was responsible for the extinction of ice age North America's signature large animals.

The study was conducted using lake sediment cores obtained from Appleman Lake in Indiana, as well as data obtained previously by Robinson from sites in New York. Gill, Williams and their colleagues used pollen, charcoal and the spores of a dung fungus that requires passage through a mammalian intestinal tract to complete its life cycle to reconstruct a picture of sweeping change to the ice age environment. The decline of North America's signature ice age mammals was a gradual process, the Wisconsin researchers explain, taking about 1,000 years. The decline in the huge numbers of ice age animals is preserved in the fossil record when the fungal spores disappear from the record altogether: "About 13.8 thousand years ago, the number of spores drops dramatically. They're barely in the record anymore," Gill explains.

Like detectives reconstructing a crime scene, the group's use of dung fungus spores helps establish a precise sequence of events, showing that the crash of ice age megafauna began before plant communities started to change and before fires appeared widely on the landscape.

"The data suggest that the megafaunal decline and extinction began at the Appleman Lake site sometime between 14.8 thousand and 13.7 thousand years ago and preceded major shifts in plant community composition and the frequency of fire," notes Williams.

Absent the large herbivores that kept them in check, such tree species as black ash, elm and ironwood began to colonize a landscape dominated by coniferous trees such as spruce and larch. The resulting mix of boreal and temperate trees formed a plant community unlike any observed today.

"As soon as herbivores drop off the landscape, we see different plant communities," Gill explains, noting that mastodon herds and other large animals occupied a parkland like landscape, typified by large open spaces and patches of forest and swamp. "Our data suggest that these trees would have been abundant sooner if the herbivores hadn't been there to eat them."

While both the extinction of North America's ice age megafauna and the sweeping change to the landscape are well-documented phenomena, there was, until now, no detailed chronology of the events that remade the continent's biological communities beginning about 14.8 thousand years ago. Establishing that the disappearance of mammoths, giant beavers, ground sloths and other large animals preceded the massive change in plant communities, promises scientists critical new insight into the dynamics of extinction and its pervasive influence on a given landscape.

The new study was funded by the Wisconsin Alumni Research Foundation, the UW-Madison Center for Climatic Research in the Nelson Institute for Environmental Studies, and the National Science Foundation.

Image Caption: Mastodons graze on black ash trees in a pleistocene swamp. A new study by researchers at the University of Wisconsin-Madison shows that the disappearance of North America's large herbivores not long after the retreat of the ice sheets that covered much of the continent triggered a dramatic reshaping of the landscape.

Image Credit: Barry Roal Carlsen / University of Wisconsin, Madison

Source: University of Wisconsin, Madison

Permalink: http://www.sflorg.com/comm_center/unv_science/p947_249.html

Time Stamp: 11/19/2009 at 19:00:00 UTC

Under Embargo Till: 19:00 November 19, 2009
Posted: 19:00 UTC 11/19/2009

Sweet Corn Story Begins in Lab

Thursday, November 19, 2009

This week, scientists are revealing the genetic instructions inside corn, one of the big three cereal crops. Corn, or maize, has one of the most complex sequences of DNA ever analyzed, says University of Wisconsin-Madison genomicist David Schwartz, who was one of more than 100 authors in the article in the journal Science.

"The maize genome is a true maze -- full of confusing repeats and dead-ends that have troubled would-be sequencers for years," says Schwartz.

Publication of the genome is expected to advance knowledge of corn's ancestry, and also guide breeders trying to extract even more productivity from a crop that is expected to produce more than 200 million tons of grain from more than 87 million acres in the United States this year.

Producing the genome sequence required input from a unique optical mapping facility in the Laboratory for Molecular and Computational Genomics at UW-Madison.

Unlike traditional gene sequencers, who examine DNA letter by letter, the optical mapping system looks at bigger pieces, and that has positioned the lab's research as a key complementary component for working with the data produced by gene sequencers.

The first step in optical mapping system is to stretch out long, string-like DNA molecules and stick them to electrically charged glass plates. These molecules are sliced up into a series of consecutive chunks, marking them in the same way as a grocery bar code, and then painted with a fluorescent dye.

When the bar-coded molecules are exposed to a blue laser, the amount of fluorescent light they emit reveals the length of each barcode feature. The microscopes in the optical mapping system are fully automated, so millions of bar-coded molecules can be pieced together to reveal the structure of a genome.

The optical map supplies a scaffold, or big-picture view, of the structure of the DNA under study, says Schwartz. "Traditional sequencing must work on small chunks at a time, but the maize genome is incredibly complex, full of repeats, and that's confusing. It's like buying a 10,000-piece jigsaw puzzle; from looking at one piece, it's hard to know if you are looking at the dwarf's foot, or Snow White's face. Our optical maps, just like the box cover, give the big picture that allows the sequencers to link up their smaller pieces into a complete genome."



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