Monday, February 22, 2010

RESEARCHERS REVEAL 3-D STRUCTURE OF BULLET-SHAPED VIRUS WITH POTENTIAL TO FIGHT CANCER, HIV

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Vesicular stomatitis virus, or VSV, has long been a model system for studying and understanding the life cycle of negative-strand RNA viruses, which include viruses that cause influenza, measles and rabies.

More importantly, research has shown that VSV has the potential to be genetically modified to serve as an anti-cancer agent, exercising high selectivity in killing cancer cells while sparing healthy cells, and as a potent vaccine against HIV.

For such modifications to occur, however, scientists must have an accurate picture of the virus's structure. While three-dimensional structural information of VSV's characteristic bullet shape and its assembly process has been sought for decades, efforts have been hampered by technological and methodological limitations.

Now, researchers at UCLA's California NanoSystems Institute and the UCLA Department of Microbiology, Immunology and Molecular Genetics and colleagues have not only revealed the 3-D structure of the trunk section of VSV but have further deduced the architectural organization of the entire bullet-shaped virion through cryo-electron microscopy and an integrated use of image-processing methods.

Their research findings appear this month in the journal Science.

"Structures of individual rhabdovirus proteins have been reported in Science and other high-profile journals, but until now, how they are organized into a bullet shape has remained unclear," said study author Z. Hong Zhou, UCLA professor of microbiology, immunology and molecular genetics and a member of the CNSI. "The special shape of VSV-- a bullet head with a short, helical trunk-- has lent to its evasion from three-dimensional structural studies."

Based on their research into the structure of VSV, the team proposed a model for the assembly of the virus, with its origin at the bullet tip. Their data suggest that VSV assembles through the alternating use of several possible interaction interfaces coded in viral protein sequences to wind its protein and RNA chain into the characteristic bullet shape.

"Our structure provides the first direct visualization of the N and M proteins inside the VSV virion at 10.6-Å resolution. Surprisingly, our data clearly demonstrated that VSV is a highly ordered particle, with the nucleocapsid surrounded by, instead of surrounding, a matrix of M proteins," said lead study author Peng Ge, a visiting graduate student at UCLA from Baylor College of Medicine. "To our amusement, the sequence in assembling viral protein and RNA molecules into the virus appears to rhyme with the first several measures of Mozart's piano sonata in C-Major, K.545." (This musical correlation is illustrated in the paper's supplementary movie 2.)

The findings could help lead to advances in the development of VSV-based vaccines for HIV and other deadly viruses, according to the researchers.

"Our structure provides some of the first clues for understanding VSV-derived vaccine pseudotypes and for optimizing therapeutic VSV variants," Zhou said. "This work moves our understanding of the biology of this large and medically important class of viruses ahead in a dramatic way. The next stage of research for our team will be to reveal the details of molecular interactions at the atomic scale using advanced imaging instruments now available at CNSI."

The Electron Imaging Center for Nanomachines (EICN) lab at the CNSI has Cryo-EM instrumentation, including the Titan Krios microscope, which makes atomically precise 3-D computer reconstructions of biological samples and produces the highest-resolution images available of viruses, which may lead to better vaccines and new treatments for disease.

(Photo: UCLA)

University of California

CHILDHOOD OBESITY: IT'S NOT THE AMOUNT OF TV, IT'S THE NUMBER OF JUNK FOOD COMMERCIALS

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The association between television viewing and childhood obesity is directly related to children's exposure to commercials that advertise unhealthy foods, according to a new UCLA School of Public Health study published in the American Journal of Public Health.

The study, conducted by Frederick J. Zimmerman and Janice F. Bell, is the first to break down the types of television children watch to better determine whether different kinds of content may exert different effects on obesity.

The researchers gathered data from primary caregivers of 3,563 children, ranging from infants to 12-year-olds, in 1997. Through time-use diaries, study respondents reported their children's activities, including television viewing, throughout the course of an entire weekday and an entire weekend day.

Caregivers were also asked to report the format— television programs, DVDs or videos— and the names of the programs watched. This data was used to classify television viewing into either educational or entertainment programming and to determine whether or not it contained advertising or product placement. A follow-up was conducted in 2002.

The analysis controlled for the amount of physical activity and the children's gender, age, race/ethnicity, mother's body mass index (BMI), education and sleep time.

Among all children, commercial viewing was significantly associated with higher BMI, although the effect was stronger for children younger than 7 than for those older than 7, the study found.

"The persistence of these results, even when the child's baseline weight status was controlled, suggests that the association between commercial television viewing and obesity does not arise solely or even primarily because heavier children prefer commercial television," said Zimmerman, professor and chair of health services at the School of Public Health and the lead author of the study.

Non-commercial viewing, including watching DVDs or educational television programming, had no significant association with obesity.

According to the authors, the findings strongly suggest that steering children away from commercial television may be effective in reducing childhood obesity, given that food is the most commonly advertised product on children's television and the fact that almost 90 percent of children begin watching television regularly before the age of 2.

By the time they are 5 years old, children have seen an average of more than 4,000 television commercials for food annually. During Saturday morning cartoons, children see an average of one food ad every five minutes. The vast majority of these ads— up to 95 percent— are for foods with poor nutritional value, the researchers say.

"Commercial television pushes children to eat a large quantity of those foods they should consume least: sugary cereals, snacks, fast food and soda pop," Zimmerman said.

The authors conclude that the availability of high-quality, enjoyable and educational programs for all ages on DVD should make it relatively easy for health educators and care providers to nudge children's viewing toward content that does not contain unhealthy messages about food and eating.

"Just as there are far better and more nutritious foods than those advertised on television, there are also far better and more interesting shows on television than those supported by advertising," Zimmerman said. "Educational television has come a long way since today's parents were children, and there are now many fantastic shows on commercial-free television and, of course, wonderful content available on DVD."

University of California

FLOWER POWER CAN STILL CALM THE MASSES

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Feeling stressed? Try chamomile! This 'traditional' remedy has been around for years, but how much truth is there behind this old wives' tale?

In an evaluation for Faculty of 1000, Michael Van Ameringen and Beth Patterson draw attention to the first randomized controlled trial of chamomile for the treatment of generalized anxiety disorder (GAD).

The study, recently published in the Journal of Clinical Psychopharmacology, reports that "chamomile extract therapy was found to be efficacious for mild-moderate GAD".

Patients with mild-moderate GAD were included in the study and received either chamomile or placebo. Those that received the chamomile treatment were found to have a significant change in the severity of their GAD.

Van Amerigen and Patterson comment on the results of the study, saying that they "suggest that chamomile may have modest [anti-panic] activity in patients with mild-moderate GAD and may potentially be used in those who are averse to traditional pharmacotherapy".

These findings are important "because many individuals who suffer from GAD do not view their anxiety as a medical condition, [and, therefore,] self-diagnosis and self-medicating with alternative, over-the-counter remedies is common".

Van Amerigen and Patterson said "a big strength of this paper is that the authors took a herbal remedy and subjected it to scientific rigor unlike many 'natural' remedies which have associated claims of efficacy with no supportive data."

Faculty of 1000 Medicine

STUDY CHALLENGES BIRD-FROM-DINOSAUR THEORY OF EVOLUTION - WAS IT THE OTHER WAY AROUND?

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Ancient human teeth are telling secrets that may relate to modern-day health: Some stressful events that occurred early in development are linked to shorter life spans.

A new study just published in the Proceedings of the National Academy of Sciences provides yet more evidence that birds did not descend from ground-dwelling theropod dinosaurs, experts say, and continues to challenge decades of accepted theories about the evolution of flight.

A new analysis was done of an unusual fossil specimen discovered in 2003 called "microraptor," in which three-dimensional models were used to study its possible flight potential, and it concluded this small, feathered species must have been a "glider" that came down from trees. The research is well done and consistent with a string of studies in recent years that pose increasing challenge to the birds-from-dinosaurs theory, said John Ruben, a professor of zoology at Oregon State University who authored a commentary in PNAS on the new research.

The weight of the evidence is now suggesting that not only did birds not descend from dinosaurs, Ruben said, but that some species now believed to be dinosaurs may have descended from birds.

"We're finally breaking out of the conventional wisdom of the last 20 years, which insisted that birds evolved from dinosaurs and that the debate is all over and done with," Ruben said. "This issue isn't resolved at all. There are just too many inconsistencies with the idea that birds had dinosaur ancestors, and this newest study adds to that."

Almost 20 years of research at OSU on the morphology of birds and dinosaurs, along with other studies and the newest PNAS research, Ruben said, are actually much more consistent with a different premise – that birds may have had an ancient common ancestor with dinosaurs, but they evolved separately on their own path, and after millions of years of separate evolution birds also gave rise to the raptors. Small animals such as velociraptor that have generally been thought to be dinosaurs are more likely flightless birds, he said.

"Raptors look quite a bit like dinosaurs but they have much more in common with birds than they do with other theropod dinosaurs such as Tyrannosaurus," Ruben said. "We think the evidence is finally showing that these animals which are usually considered dinosaurs were actually descended from birds, not the other way around."

Another study last year from Florida State University raised similar doubts, Ruben said.

In the newest PNAS study, scientists examined a remarkable fossil specimen that had feathers on all four limbs, somewhat resembling a bi-plane. Glide tests based on its structure concluded it would not have been practical for it to have flown from the ground up, but it could have glided from the trees down, somewhat like a modern-day flying squirrel. Many researchers have long believed that gliders such as this were the ancestors of modern birds.

"This model was not consistent with successful flight from the ground up, and that makes it pretty difficult to make a case for a ground-dwelling theropod dinosaur to have developed wings and flown away," Ruben said. "On the other hand, it would have been quite possible for birds to have evolved and then, at some point, have various species lose their flight capabilities and become ground-dwelling, flightless animals – the raptors. This may be hugely upsetting to a lot of people, but it makes perfect sense."

In their own research, including one study just last year in the Journal of Morphology, OSU scientists found that the position of the thigh bone and muscles in birds is critical to their ability to have adequate lung capacity for sustained long-distance flight, a fundamental aspect of bird biology. Theropod dinosaurs did not share this feature. Other morphological features have also been identified that are inconsistent with a bird-from-dinosaur theory. And perhaps most significant, birds were already found in the fossil record before the elaboration of the dinosaurs they supposedly descended from. That would be consistent with raptors descending from birds, Ruben said, but not the reverse.

OSU research on avian biology and physiology has been raising questions on this issue since the 1990s, often in isolation. More scientists and other studies are now challenging the same premise, Ruben said. The old theories were popular, had public appeal and "many people saw what they wanted to see" instead of carefully interpreting the data, he said.

"Pesky new fossils...sharply at odds with conventional wisdom never seem to cease popping up," Ruben wrote in his PNAS commentary. "Given the vagaries of the fossil record, current notions of near resolution of many of the most basic questions about long-extinct forms should probably be regarded with caution."

(Photo: Oregon State University)

Oregon State University

BROWN BIOLOGIST SOLVES MYSTERY OF TROPICAL GRASSES' ORIGIN

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Around 30 to 40 million years ago, grasses on Earth underwent an epic evolutionary upheaval. An assemblage capitalized on falling levels of atmospheric carbon dioxide by engineering an internal mechanism to concentrate the dwindling CO2 supply that, like a fuel-injection system in a car, could more efficiently convert sunlight and nutrients into energy.

The rise of C4 grasses is not disputed. They dominate in hot, tropical climes and now make up to 20 percent of our planet's vegetational covering. Scientists have pinned the rise of C4 plants primarily to dwindling concentrations of CO2. But C4 grasses have been closely linked with warmer temperatures. Indeed, on a map, C4 grasses are found along tropical gradients, while C3 grasses occupy the northern, or colder, end of the temperature gradient. Considering knowledge of their past and their current distribution, what was left to question?

Everything, apparently, according to Erika Edwards, an evolutionary biologist at Brown University. In a paper published online in the Proceedings of the National Academy of Sciences, Edwards and Stephen Smith, a postdoctoral researcher at the National Evolutionary Synthesis Center in North Carolina, have found that rainfall — not temperature — was the primary trigger for C4 grasses' evolutionary beginnings. Moreover, the pair say C4 grasses were already in tropical forests before moving out of the shade of the taller trees and into drier, sunnier environments.

"We've kind of changed the story a bit," said Edwards, assistant professor of biology.

The paper is important, Smith said, because it "demonstrates the importance of precipitation in the evolution of grasses and particularly in the evolution of C4 grasses — specifically, their movement into drier, not necessarily warmer climates."

To arrive at their findings, the biologists compiled a database of roughly 1.1 million specimens of grasses collected by botanists worldwide. They mapped the locations for these species and then added global precipitation and temperature charts.

"By combining all these data," Edwards said, "we could get individual climate profiles for each grass species."

The pair then went a step further. They whittled the list to approximately 1,230 species for which the plants' genes had been sequenced and from there built a phylogenetic profile for the collection, the most comprehensive evolutionary tree to date for grasses. The reason for building the phylogeny, Edwards said, was to tease out the junctures at which C3 and C4 grasses diverged over time. The scientists zeroed in on 21 such "transition nodes" and examined the climatic conditions during those branching periods.

They found that in 18 of the 21 instances, precipitation, rather than temperature, had changed. "That was the clincher," Edwards said.

Looking more closely at the differences in rainfall, Edwards and Smith noticed the shifts in the amount of rainfall between C3 and C4 grasses in the tropics dictated in sharp relief how the different lineages evolved. Generally speaking, C3 grasses flourished in areas that received, on average, 1,800 millimeters (71 inches) of rain annually; C4 grasses took root in areas that received, on average, 1,200 millimeters (47 inches) of rain annually.

"Twelve-hundred millimeters isn't a desert," Edwards noted. "It's still a fairly mesic place. And so when you start looking at climate profiles, these closely related C3 and C4 lineages are straddling this transition zone between tropical forests and tropical woodlands and savanna."

So, did C4 grasses evolve in the tropical forest and then move out from the canopy or did they move out first and then adopt a different photosynthetic pathway? Edwards isn't sure, but she thinks the pathway may have begun to form with C3 grasses on the forest margins, where those plants would have been subjected to greater fluctuations in precipitation, sunlight, temperature and other environmental stresses, spurring the photosynthetic innovation.

What that all means for the future of C4 grasses and climate change is an open question. While the grasses would presumably benefit from projections of lower mean rainfall in some areas of the tropics, they may be less competitive with rising levels of atmospheric CO2. Also, the effects of changes in land through deforestation and other practices would need to be considered, Edwards said.

In a related finding, the scientists attempt to explain the dominance of a lineage of C3 grasses, called Pooideae, in northern, cold areas of the globe, such as the Mongolian steppes. "The global latitudinal gradients of C3 and C4 always has been explained by the physiological advantages that C4 grasses have under high temperatures," Edwards explained. "No one has considered that the evolution of cold tolerance might have been equally important in setting up that latitudinal gradient. Climatically speaking, the cool-climate Pooideae are really the grasses that are doing something very different."

"It highlights the apparently important role that cold tolerance has played for the evolution of non-C4 grasses and especially the group Pooideae, which includes rye, barley, and wheat and many of the other grasses in the temperate and boreal habitats," Smith said.

(Photo: Brown U.)

Brown University

RESEARCH REVEALS LINK BETWEEN BEER AND BONE HEALTH

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A new study suggests that beer is a significant source of dietary silicon, a key ingredient for increasing bone mineral density. Researchers from the Department of Food Science & Technology at the University of California, Davis studied commercial beer production to determine the relationship between beer production methods and the resulting silicon content, concluding that beer is a rich source of dietary silicon.

Details of this study are available in the February issue of the Journal of the Science of Food and Agriculture, published by Wiley-Blackwell on behalf of the Society of Chemical Industry.

"The factors in brewing that influence silicon levels in beer have not been extensively studied" said Charles Bamforth, lead author of the study. "We have examined a wide range of beer styles for their silicon content and have also studied the impact of raw materials and the brewing process on the quantities of silicon that enter wort and beer."

Silicon is present in beer in the soluble form of orthosilicic acid (OSA), which yields 50% bioavailability, making beer a major contributor to silicon intake in the Western diet. According to the National Institutes of Health (NIH), dietary silicon (Si), as soluble OSA, may be important for the growth and development of bone and connective tissue, and beer appears to be a major contributor to Si intake. Based on these findings, some studies suggest moderate beer consumption may help fight osteoporosis, a disease of the skeletal system characterized by low bone mass and deterioration of bone tissue.

The researchers examined a variety of raw material samples and found little change in the silicon content of barley during the malting process. The majority of the silicon in barley is in the husk, which is not affected greatly during malting. The malts with the higher silicon contents are pale colored which have less heat stress during the malting process. The darker products, such as the chocolate, roasted barley and black malt, all have substantial roasting and much lower silicon contents than the other malts for reasons that are not yet known. The hop samples analyzed showed surprisingly high levels of silicon with as much as four times more silicon than is found in malt. However, hops are invariably used in a much smaller quantity than is grain. Highly hopped beers, however, would be expected to contain higher silicon levels.

No silicon was picked up from silica hydrogel used to stabilize beer, even after a period of 24 hours and neither is there pick up from diatomaceous earth filter aid.

The study also tested 100 commercial beers for silicon content and categorized the data according to beer style and source. The average silicon content of the beers sampled was 6.4 to 56.5 mg/L.

"Beers containing high levels of malted barley and hops are richest in silicon," concludes Dr. Bamforth. "Wheat contains less silicon than barley because it is the husk of the barley that is rich in this element. While most of the silicon remains in the husk during brewing, significant quantities of silicon nonetheless are extracted into wort and much of this survives into beer."

Wiley-Blackwell

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