Mice And Humans Should Have More In Common In Clinical Trials

Purdue researcher Joseph Garner found that traditional testing methods in mice increase errors in lab results. His study suggests researchers vary the environmental conditions for mice during tests to lessen the possibility of false positives.

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Just as no two humans are the same, a Purdue University scientist has shown treating mice more as individuals in laboratory testing cuts down on erroneous results and could significantly reduce the cost of drug development.

Mice have long been used as test subjects for treatments and drugs before those products are approved for human testing. But new research shows that the customary practice of standardizing mice by trying to limit environmental variation in laboratories actually increases the chance of getting an incorrect result.
The study, done by Joseph Garner, a Purdue assistant professor of animal sciences, and professor Hanno Würbel of the Justus-Liebig University of Giessen in Germany, was published in the early online edition of Nature Methods on Monday (March 30). It suggests scientists should change their methods and test mice in deliberately varying environmental conditions. Garner said that will decrease the number of false positive test results and eliminate further costly testing of drugs or treatments destined to fail.
"In lab animals, we have this bizarre idea that we can control everything that happens," Garner said. "But we would never be able to do that with humans, and we wouldn't want to. You want to know if a drug is going to work in all people, so you test it on a wide range of different people. We should do the same thing with mice."
Garner said human testing uses a broad range of subjects, giving scientists an idea of how a drug or treatment might affect different types of people. But scientists often use mice that are basically genetically identical and try to limit internal and external environmental factors such as stress, diet and age to eliminate variables affecting the outcome.
Garner said there is no practical way to ensure that all environmental conditions are the same with mice, however, because they respond to cues humans cannot detect. For example, a researcher's odor in one lab might cause more stress for a mouse than another researcher's odor in a second lab with different mice, giving different results. But scientists, unaware of the odor difference, may believe a treatment worked when the mice were actually responding to an environmental cue, giving a false positive.
The study used three different strains of mice from previously published data and compared their behavioral characteristics against each other. The observations were done in three different labs, two different types of cages and at three different times to make 18 different replicates of the same experiment. Traditional testing theories say the results should have been the same in all those experiments.
Once the results were compared, however, the researchers found many false positives, or instances when one strain appeared to act differently from another when it actually should not.
"There were nearly 10 times more false positives than we would expect by chance," Garner said. "There had to be a gremlin causing these false positives."
The researchers suspected the problem was in the traditional lab experiment design. So they reevaluated the data, picking a mouse of each strain from each environment - similar to matching pairs in human clinical trials - and found only the same number of false positives as would be expected by chance.
When mouse testing creates a false positive, leading a researcher to believe a drug has worked, the drug could be sent to further animal testing and human clinical trials at a cost of millions of dollars. Drugs that fail in clinical trials cannot be marketed, and the money is wasted. To recoup those losses, drug companies must increase the costs of marketable drugs.
"Drugs aren't expensive because they're costly to make," Garner said. "They're expensive because the company has to recoup the costs of the other drugs that have failed in human clinical trials. Numbers are hard to estimate, but for every drug that reaches the marketplace, well over 100 have been abandoned at some point in their development."
Garner said giving mice varying environments also could be better for the animals because fewer could be used. Weeding out an unsuccessful drug would eliminate an unnecessary second round of animal testing.
"The really exciting message is that we have shown how the false positives in early drug discovery can be drastically reduced without costing anything more than a change in experimental design," Garner said. "These are positive results for pharmaceutical research, patients and for mice."
Garner and Würbel, along with Würbel's doctoral student Helene Richter, received research funding from the German Research Foundation. Their research will now focus on which environmental factors have the most impact on results.
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Adapted from materials provided by Purdue University.

Hollow Gold Nanospheres Show Promise For Biomedical And Other Applications

Partial view of a gold nanosphere (shown), magnified by a factor of one billion, as seen through an electron microscope. The darker ring shows the "wall" of the nanosphere, while the lighter area to the right of the ring shows the interior region of the shell.

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A new metal nanostructure developed by researchers at the University of California, Santa Cruz, has already shown promise in cancer therapy studies and could be used for chemical and biological sensors and other applications as well.
The hollow gold nanospheres developed in the laboratory of Jin Zhang, a professor of chemistry and biochemistry at UCSC, have a unique set of properties, including strong, narrow, and tunable absorption of light. Zhang is collaborating with researchers at the University of Texas M. D. Anderson Cancer Center, who have used the new nanostructures to target tumors for photothermal cancer therapy. They reported good results from preclinical studies earlier this year (Clinical Cancer Research, February 1, 2009).

Zhang will describe his lab's work on the hollow gold nanospheres in a talk on Sunday, March 22, at the annual meeting of the American Chemical Society in Salt Lake City.
"What makes this structure special is the combination of the spherical shape, the small size, and the strong absorption in visible and near infrared light," Zhang said. "The absorption is not only strong, it is also narrow and tunable. All of these properties are important for cancer treatment."
Zhang's lab is able to control the synthesis of the hollow gold nanospheres to produce particles with consistent size and optical properties. The hollow particles can be made in sizes ranging from 20 to 70 nanometers in diameter, which is an ideal range for biological applications that require particles to be incorporated into living cells. The optical properties can be tuned by varying the particle size and wall thickness.
In the cancer studies, led by Chun Li of the M. D. Anderson Cancer Center, researchers attached a short peptide to the nanospheres that enabled the particles to bind to tumor cells. After injecting the nanospheres into mice with melanoma, the researchers irradiated the animals' tumors with near-infrared light from a laser, heating the gold nanospheres and selectively killing the cancer cells to which the particles were bound.
Cancer therapy was not the goal, however, when Zhang's lab began working several years ago on the synthesis and characterization of hollow gold nanospheres. Zhang has studied a wide range of metal nanostructures to optimize their properties for surface-enhanced Raman scattering (SERS). SERS is a powerful optical technique that can be used for sensitive detection of biological molecules and other applications.
Adam Schwartzberg, then a graduate student in Zhang's lab at UCSC, initially set out to reproduce work reported by Chinese researchers in 2005. In the process, he perfected the synthesis of the hollow gold nanospheres, then demonstrated and characterized their SERS activity.
"This process is able to produce SERS-active nanoparticles that are significantly smaller than traditional nanoparticle structures used for SERS, providing a sensor element that can be more easily incorporated into cells for localized intracellular measurements," Schwartzberg, now at UC Berkeley, reported in a 2006 paper published in Analytical Chemistry.
The collaboration with Li began when Zhang heard him speak at a conference about using solid nanoparticles for photothermal cancer therapy. Zhang immediately saw the advantages of the hollow gold nanospheres for this technique. Li uses near-infrared light in the procedure because it provides good tissue penetration. But the solid gold nanoparticles he was using do not absorb near-infrared light efficiently. Zhang told Li he could synthesize hollow gold nanospheres that absorb light most efficiently at precisely the wavelength (800 nanometers) emitted by Li's near-infrared laser.
"The heat that kills the cancer cells depends on light absorption by the metal nanoparticles, so more efficient absorption of the light is better," Zhang said. "The hollow gold nanospheres were 50 times more effective than solid gold nanoparticles for light absorption in the near-infrared."
Zhang's group has been exploring other nanostructures that can be synthesized using the same techniques. For example, graduate student Tammy Olson has designed hollow double-nanoshell structures of gold and silver, which show enhanced SERS activities compared to the hollow gold nanospheres.
The ability to tune the optical properties of the hollow nanospheres makes them highly versatile, Zhang said. "It is a unique structure that offers true advantages over other nanostructures, so it has a lot of potential," he said.
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Adapted from materials provided by University of California - Santa Cruz, via EurekAlert!, a service of AAAS.

Teenage Boys Who Eat Fish At Least Once A Week Achieve Higher Intelligence Scores

New research has found that 15-year-old males who ate fish at least once a week displayed higher cognitive skills at the age of 18 than those who it ate it less frequently.

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Fifteen-year-old males who ate fish at least once a week displayed higher cognitive skills at the age of 18 than those who it ate it less frequently, according to a study of nearly 4,000 teenagers published in the March issue of Acta Paediatrica.
Eating fish once a week was enough to increase combined, verbal and visuospatial intelligence scores by an average of six per cent, while eating fish more than once a week increased them by just under 11 per cent.
Swedish researchers compared the responses of 3,972 males who took part in the survey with the cognitive scores recorded in their Swedish Military Conscription records three years later.

"We found a clear link between frequent fish consumption and higher scores when the teenagers ate fish at least once a week" says Professor Kjell Torén from the Sahlgrenska Academy at the University of Gothenburg, one of the senior scientists involved in the study. "When they ate fish more than once a week the improvement almost doubled.
"These findings are significant because the study was carried out between the ages of 15 and 18 when educational achievements can help to shape the rest of a young man's life."
The research team found that:

• • 58 per cent of the boys who took part in the study ate fish at least once a week and a further 20 per cent ate fish more than once a week.
• • When male teenagers ate fish more than once a week their combined intelligence scores were on average 12 per cent higher than those who ate fish less than once a week. Teenagers who ate fish once a week scored seven per cent higher.
• • The verbal intelligence scores for teenagers who ate fish more than once a week were on average nine per cent higher than those who ate fish less than once a week. Those who ate fish once a week scored four per cent higher.
• • The same pattern was seen in the visuospatial intelligence scores, with teenagers who ate fish more than once a week scoring on average 11 per cent higher than those who ate fish less than once a week. Those who ate fish once a week scored seven per cent higher.

"A number of studies have already shown that fish can help neurodevelopment in infants, reduce the risk of impaired cognitive function from middle age onwards and benefit babies born to women who ate fish during pregnancy" says Professor Torén.

"However we believe that this is the first large-scale study to explore the effect on adolescents."
The exact mechanism that links fish consumption to improved cognitive performance is still not clear.
"The most widely held theory is that it is the long-chain polyunsaturated fatty acids found in fish that have positive effects on cognitive performance" explains Professor Torén.
"Fish contains both omega-3 and omega-6 fatty acids which are known to accumulate in the brain when the foetus is developing. Other theories have been put forward that highlight their vascular and anti-inflammatory properties and their role in suppressing cytokines, chemicals that can affect the immune system."
In order to isolate the effect of fish consumption on the study subjects, the research team looked at a wide range of variables, including ethnicity, where they lived, their parents' educational level, the teenagers' well-being, how frequently they exercised and their weight.
"Having looked very carefully at the wide range of variables explored by this study it was very clear that there was a significant association between regular fish consumption at 15 and improved cognitive performance at 18" concludes lead author Dr Maria Aberg from the Centre for Brain Repair and Rehabilitation at the University of Gothenburg.
"We also found the same association between fish and intelligence in the teenagers regardless of their parents' level of education."
The researchers are now keen to carry out further research to see if the kind of fish consumed - for example lean fish in fish fingers or fatty fish such as salmon - makes any difference to the results.
"But for the time being it appears that including fish in a diet can make a valuable contribution to cognitive performance in male teenagers" says Dr Aberg.
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Adapted from materials provided by Wiley-Blackwell, viaEurekAlert!, a service of AAAS.

Big-hearted Fish Reveals Genetics Of Cardiovascular Condition

Enlarged heart of a 48-hour-post-fertilization zebrafish embryo lacking the gene for ccm2. Nuclei from endothelial cells shown in red and junctions in between in green.

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Researchers at the University of Pennsylvania School of Medicine have unlocked the mystery of a puzzling human disease and gained insight into cardiovascular development, all thanks to a big-hearted fish.
Mark Kahn, MD, Associate Professor of Medicine, graduate student Benjamin Kleaveland, and colleagues report in the February issue of Nature Medicine that a human vascular condition called Cerebral Cavernous Malformation (CCM) is caused by leaky junctions between cells in the lining of blood vessels. By combining studies with zebrafish and mice, the researchers found that the aberrant junctions are the result of mutated or missing proteins in a novel biochemical process, the so-called Heart-of-glass (HEG)-CCM pathway.
The HEG-CCM pathway "is essential to regulate endothelial cell-cell interaction, both during the time that vertebrates make the cardiovascular system and later in life," says Kahn. "Its loss later in life confers this previously unexplained disease, cerebral cavernous malformation."
CCM proteins, along with the receptor HEG, are responsible for building properly formed blood and lymphatic vessels during embryonic development by sealing the cell-cell junctions in the walls of vessels; loss of any of these proteins disrupts those seals, causing leaky vasculature.

Cerebral Cavernous Malformations are abnormal clusters of leaky blood vessels, typically in the brain, which can cause both seizures and strokes. The condition affects about 1 in 1,000 people, about 20% of whom carry a genetic predisposition for the condition. Researchers had already identified the genes responsible for the disease– indeed they were named CCM1, CCM2, and CCM3, in recognition of that fact – but not what those genes did.
That's where the big-hearted fish come in. Several years ago, another research team discovered that mutations in CCM1, CCM2, or HEG (which had not previously been linked to CCM) caused zebrafish to develop enlarged hearts. Sensing that this observation could help unlock the mystery of what CCM proteins do, Kleaveland decided to see if these results could be extended to mice.
"Our notion was to take the zebrafish developmental studies and use the mouse as a way of bridging between what appeared to be a role in heart development in fish and blood vessel disease in people," says Kahn.
Kleaveland genetically engineered mice that both completely lack the HEG protein and produce diminished amounts of CCM2. This combination of genetic defects is fatal for the mice; they die during embryonic development. But, examination of their cardiovascular system and that of genetically altered fish, as well revealed several key findings, Kleaveland says.
First, loss of HEG produces cardiovascular defects—mainly leakiness—in the heart, in blood vessels in the lung, and in the lymphatic system. Second, loss of HEG with partial loss of CCM2 produces a worse cardiovascular defect—failure to even form critical blood vessels. Third, all of these defects are characterized by malformed cell-cell junctions in the endothelial cells that line these organs. And finally, HEG actually physically interacts with CCM proteins.
"It looks like the disease is a reflection of a disruption in endothelial cell-cell junctions, and this pathway is required to regulate them," Kahn says.
These data underscore the evolutionary significance of the biochemical process underlying CCM. "With millions of years of evolution between fish and mammals, genes typically acquire new roles and lose old roles," Kahn explains. "When things are that conserved, it just tends to mean that it's a highly important and central process, and it probably also tells us that whatever it's doing is fundamental to blood vessels and the whole cardiovascular system."
The study, Kahn adds, addresses a debate in the field as to whether CCM is the result of defects that cause the disease present in the affected endothelial cells themselves, or in the cells that surround them, such as neurons in the brain?
"We think the developmental model has shown us that the requirement is in the endothelial cell," he says.
Now Kahn, Kleaveland, and their colleagues are working to determine just what it is that HEG is doing in endothelial cell-cell junctions – what proteins it "talks" to on adjacent endothelial cells – and also, to build a true mouse model of the CCM disease.
The mice in this study died in utero, but CCM disease tends to affect humans in their 30s and older. With a good model, however, "you could watch the progression of it, and you could try to change that progression, essentially to treat a mouse,” Kleaveland says.
The research was funded by the National Institutes of Health, the Swiss National Science Foundation, and the European Community, and involved researchers from the University of California, San Diego, Columbia University Medical Center, New York, and the University of Basel, Switzerland.
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Adapted from materials provided by University of Pennsylvania School of Medicine.

Molecular Motors In Cells Work Together, Study Shows

Jeneva Laib, Robert Bloodgood and William Guilford.

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Even within cells, the left hand knows what the right hand is doing. Molecular motors, the little engines that power cell mobility and the ability of cells to transport internal cargo, work together and in close coordination, according to a new finding by researchers at the University of Virginia. The work could have implications for the treatment of neurodegenerative disorders.
"We found that molecular motors operate in an amazingly coordinated manner when moving an algal cell one way or the other," said Jeneva Laib, the lead author and an undergraduate biomedical engineering student at the University of Virginia. "This provides a new understanding of the ways cells move."

The finding appears online in the current issue of The Proceedings of the National Academy of Sciences.
Laib, a second-year student from Lorton, Va., and her collaborators, U.Va. professors Robert Bloodgood and William Guilford, used the alga Chlamydomonas as a model to study how molecular motors in most types of cells work to move internal cargo, such as organelles associated with energy production and nutrient transport, or even the entire cell.
These motions are caused by a line of motors that pull the cell along, like the locomotive on a train. Previous studies had suggested that these motors pulled in opposite directions, like a game of tug of war. More recent studies indicated that the motors were working together rather than independently.
The new U.Va. study provides strong evidence that the motors are indeed working in coordination, all pulling in one direction, as if under command, or in the opposite direction — again, as if under strict instruction.
"We've found that large numbers of these molecular motors are turning on at the same time to generate large amounts of force, and then turning off at the same time to allow transport in the particular direction," said Guilford, Laib's adviser and lab director. "This insight opens up the possibility for us to begin to understand the mechanism that instructs the motors to pull one way or the other."
A greater understanding of cell motility and the ways in which cells move cargo within cells could eventually lead to therapies for neurodegenerative disorders such as amyotrophic lateral sclerosis (Lou Gehrig's Disease), diabetic neuropathy, and Usher syndrome, a progressive loss of hearing and vision. Neurodegenerative diseases can be caused by defects in the transport processes within neural cells.
"You basically get a logjam within the cell that prevents forward progress of these motors and their cargo," Guilford said. "So if we could understand how the motors are normally coordinated inside cells, we might be able to eventually realize therapeutic approaches to restoring transport for cell revival."
"There is some amazing cooperation going on among these motors," noted Bloodgood, a specialist in cell locomotion research. "When one set of as many as 10 motors turn on, another set turns off in unison. Understanding this process could help us to restore this locomotion when defects occur."
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Adapted from materials provided by University of Virginia.

Molecular Machine Turns Packaged Messenger RNA Into A Linear Transcript

Picking from the pack. A magnetically coupled helicase (green) and nuclear pore complex protein known as Nup214 (blue) play a key role in plucking individual messenger RNA proteins from a packaged ball.

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For RNA, the gateway to a productive life outside the nucleus is the nuclear pore complex, an amalgamation of 30 kinds of proteins that regulates all traffic passing through the nuclear membrane. New research from Rockefeller University shows that one of these proteins magnetically couples with a special molecule — a helicase — to form a machine that unpacks balled-up messenger RNA particles so that they can be translated.
The work illuminates a previously unknown stage in the process by which genetic information is read and converted to proteins. In humans and other higher organisms, the genetic information that is encoded in the DNA is stored inside the nucleus, while the factories that convert DNA instructions into proteins are located in the surrounding cytoplasm. As those instructions — messenger RNA particles — pass through the nuclear membrane, numerous proteins that cover and protect the delicate messenger RNA molecules must be stripped off.

André Hoelz, a research associate in John D. Rockefeller Jr. Professor Günter Blobel’s Laboratory of Cell Biology, and his colleagues solved the crystal structure of a complex located on the cytoplasmic side of the nuclear pore — nucleoportin Nup214 coupled with helicase Ddx19. They then performed a series of biochemical experiments to further parse the interactions between these two molecules and to elucidate their mechanism of action.
“We found that the messenger RNA protein package and Nup214 competitively bind to the helicase, one after the other,” Hoelz notes. Each time the helicase binds the ball of messenger RNA and protein, it strips one protein molecule off. “The process is akin to a ratchet mechanism for messenger RNA export.” The result, Hoelz speculates, is a linear messenger RNA transcript that travels on to the ribosome, where it delivers instructions for building proteins.
The work may also clarify a cause underlying acute myeloid leukemia, which is associated with mutations to Nup214. “Patients with mutations in Nup214 that remove the docking site for the helicase are likely to have a messenger RNA export defect,” Hoelz says.
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Adapted from materials provided by Rockefeller University.

New Reference Material Can Improve Testing Of Multivitamin Tablets

NIST has developed a new certified reference material that can be an important quality assurance tool for measuring the amounts of vitamins, carotenoids, and trace elements in dietary supplements. SRM 3280 is part of a larger ongoing effort the NIST group has undertaken to develop reference materials for fatty acids, caffeine and a whole host of other dietary supplements.

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The National Institute of Standards and Technology (NIST) has developed a new certified reference material that can be an important quality assurance tool for measuring the amounts of vitamins, carotenoids, and trace elements in dietary supplements. The new Standard Reference Material (SRM) 3280 for multivitamin/multimineral tablets was created in collaboration with the Office of Dietary Supplements (ODS) at the National Institutes of Health (NIH).

Demand from a growing number of Americans concerned that they are not getting all the prescribed nutrients from their food has created a multibillion-dollar dietary supplement industry. Although manufacturers have their own testing methods and materials to ensure that their products contain the nutrients in the amounts listed on their labels, they have had no definitive, independently certified standard with which to verify their testing methods and calibrate their equipment. The new reference standard will help fill that gap.

A manufacturer of multivitamin/multimineral tablets prepared the source material for SRM 3280 as a non-commercial batch of tablets according to their normal procedures. NIST scientists tested and certified the concentrations of 24 elements and 17 vitamins and carotenoid compounds in the tablets.

“We are not saying what a product should contain, but what it does contain,” Sharpless said. “Our SRMs are intended for analytical chemists to use to make sure their methods are working properly, not a benchmark for what a good product should be.”

SRM 3280 is part of a larger ongoing effort the NIST group has undertaken to develop reference materials for fatty acids, caffeine, and a whole host of other dietary supplements including ginkgo, saw palmetto, and bitter orange, and others as they appear on store shelves.

The SRM will also be used to support the efforts of the ODS and the U.S. Department of Agriculture in developing accurate data for the Dietary Supplement Ingredient Database (DSID). Researchers in the academic community will also be able to use the SRM to benchmark their assays for vitamins and minerals just as other SRMs are used to standardize serum cholesterol measurements.

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Adapted from materials provided by National Institute of Standards and Technology.

New Method For Screening Thousands of Proteins: Major Step For Drug Discovery And Diagnostics

Antibody recognising a membrane protein dressed in an amphipol attached to a solid surface.

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Researchers from Nano-Science Center, University of Copenhagen and National Centre for Scientific Research, France have developed a general method to study membrane proteins. This method can be used to screen several thousand proteins, and it will reduce the way from development to useful drugs substantially.
Membrane proteins are located at the surface of cells and they have a very important role in the communication between the cells in our body. Defective membrane proteins are involved in diseases such as cancer, cardiovascular diseases and neurological diseases, just to mention at few. The researchers have developed a system, where they tie a tag to the protein that attach it to a surface and make it possible to investigate it in the laboratories.

Until now membrane proteins have been difficult to study when they are away from their natural environment in the cell, where there a belt of lipids surrounds them. This belt is essential for their survival and proper function.

Swimsuits for proteins with a tag
"With our new method we can study membrane proteins faster and more accurate using less material than before. We are using a kind of swimsuit for the proteins called amphipols. The amphipol substitute for the lipids, surround the membrane protein, and make it soluble in water while keeping its function intact. We attach a tag to the amphipol that will assemble to a surface like a key-lock system. When we have attached the proteins to a surface they can be adapted to several measuring instruments," says Associated Professor Karen Martinez, Department of Neuroscience and Pharmacology and Nano-Science Center at University of Copenhagen.
The researchers have tested their method on several different proteins and the results are very promising. When looking for new drugs, the researchers wants to study the interaction between membrane proteins and other molecules - e.g. potential drugs. It can also be used for the detection of virus, bacteria and parasites.
A European consortium that is currently under construction, involving approximately 15 different laboratories, including both private companies and universities, will exploit the perspectives of this promising method. The pharmaceutical industry is interested and participate in the European consortium.
The research results are published in the journal, PNAS.
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Adapted from materials provided by University of Copenhagen.

Antibacterial Plaster Could Put A Clean Sheen On Walls

Scientists report development of a novel plaster with excellent sterilizing abilities and properties similar to traditional gypsum plaster.

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Scientists in China are reporting development and testing of new self-sanitizing plaster with more powerful antibacterial effects than penicillin. The material could be used in wall coatings, paints, art works and other products.

Liang-jie Yuan and colleagues note that plaster has been used for centuries as building material and surfaces for great works of art, including Michelangelo’s famed Sistine Chapel ceiling in Vatican City. The new, first-of-its kind plaster —formed from different ingredients from traditional gypsum plaster — still retains similar mechanical properties while having added antibacterial effects.
Lab tests showed that the so-called “supramolecular” plaster has a “very broad” antibacterial spectrum, killing five types of disease-causing bacteria. When compared with penicillin, the plaster was more effective at controlling growth of four kinds of bacteria, including dangerous Staphylococcus aureus and Escherichia coli. “It can be expected that the supramolecular plaster can be used for building, painting, coating and carving, and the coat, brick, or art ware constructed by the plaster do not need additive antiseptic or sterilization,” the authors say.
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Adapted from materials provided by American Chemical Society.

Mixed Population Provides Insights Into Human Genetic Makeup

These are three-dimensional images of a face with location points indicated.

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Genetic diseases and genetically mixed populations can help researchers understand human diversity and human origins according to a Penn State physical anthropologist.
"We wanted to get to a strategy to predict what a face will look like," said Mark D. Shriver, associate professor of biological anthropology. "We want to understand the path of evolution that leads to that part of the selection process."
To pinpoint genes that influence the shape of the human face and head, Shriver began with an online database of genes linked to disease -- Online Mendelian Inheritance of Man. If the symptoms of the disease involved the face or skull the gene implicated in the disease became a candidate for those facial traits.

This approach works because although Shriver looked at genes implicated in disease, those same genes in a healthy person may also influence the same physical trait -- length, width, shape, size -- but within the range normal for healthy individuals. Facial traits vary among humans, but do tend to group by population. For example, in general, West Africans have wider faces than Europeans and Europeans have longer faces than West Africans.
"There is a strong relationship between genetic ancestry and facial traits," said Shriver. "Using individuals of combined ancestry, European and African, we can see how the target genes alter facial traits," he told attendees at the 2009 Annual Meeting of the American Association for the Advancement of Science.
The researchers looked at a combined sample of African Americans with West African and European ancestry whose genetic makeup was known through DNA testing. To make it simpler, anyone with Native American ancestry was eliminated so that only two genetic pools were represented -- West African and European. The researchers reported on a sample of 254 individuals using three-dimensional imaging and measured the distances between specific portions of the face. Each individual had provided a DNA sample.
"We started with 22 landmarks on the faces that could be accurately located in all the images," said Shriver.
These landmarks might be the tip of the nose, the tip of the chin, the outer corner of the eye or other repeatable locations. They then recorded the distances between all the points in all directions, so they had a distance map of each of the faces.
From their DNA profiles, Shriver could determine the admixture percentages of each individual, how much of their genetic make up came from each group. He could then compare the genetically determined admixture to the facial feature differences and determine the relative differences from the parental populations.
"This type of study, done on admixed populations shows that each person is a composite of their ancestors and that the range of facial features is a continuum," says Shriver.
Shriver found that there was a very strong statistical correlation between the amounts of admixture and the facial traits.
"We chose to look at African Americans because they were a large enough and available admixed population," said Shriver. "We are trying to solidify our understanding of the origins of humans and the evolutionary processes. Looking at admixed populations shows us the influence genes have and how they relate to physical features."
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Adapted from materials provided by Penn State.

Buying Experiences, Not Possessions, Leads To Greater Happiness

A new study demonstrates that experiential purchases, such as a meal out or theater tickets, result in increased well-being because they satisfy higher order needs, specifically the need for social connectedness and vitality -- a feeling of being alive.

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Can money make us happy if we spend it on the right purchases? A new psychology study suggests that buying life experiences rather than material possessions leads to greater happiness for both the consumer and those around them.
The study demonstrates that experiential purchases, such as a meal out or theater tickets, result in increased well-being because they satisfy higher order needs, specifically the need for social connectedness and vitality -- a feeling of being alive.

"These findings support an extension of basic need theory, where purchases that increase psychological need satisfaction will produce the greatest well-being," said Ryan Howell, assistant professor of psychology at San Francisco State University.
Participants in the study were asked to write reflections and answer questions about their recent purchases. Participants indicated that experiential purchases represented money better spent and greater happiness for both themselves and others. The results also indicate that experiences produce more happiness regardless of the amount spent or the income of the consumer.
Experiences also lead to longer-term satisfaction. "Purchased experiences provide memory capital," Howell said. "We don't tend to get bored of happy memories like we do with a material object.
"People still believe that more money will make them happy, even though 35 years of research has suggested the opposite," Howell said. "Maybe this belief has held because money is making some people happy some of the time, at least when they spend it on life experiences."
"The mediators of experiential purchases: Determining the impact of psychological need satisfaction" was conducted by Ryan Howell, assistant professor of psychology at San Francisco State University and SF State graduate Graham Hill.
These findings will be presented at the Society for Personality and Social Psychology annual meeting on Feb. 7.
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Adapted from materials provided by San Francisco State University, via EurekAlert!, a service of AAAS.

Growing Peppers: Does Hotter Mean Healthier?

Here, the relationship between chile peppers' heat level and plant disease resistance is studied.

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Phytophthora blight, caused by Phytophthora capsici, is a major plant disease that affects many crop species worldwide, including chile peppers in New Mexico. Farmers' observations suggested that Phytophthora capsici caused less damage in pepper crops of the hot pepper varieties than low-heat pepper varieties.
A study published in the October 2008 issue of HortScience by the research team of Mohammed B. Tahboub (postdoctoral researcher), Soumaila Sanogo (plant pathologist and team leader), Paul W. Bosland (chile pepper breeder), and Leigh Murray (statistician) set out to determine whether or not the severity of Phytophthora blight would be greater in low-heat than in hot chile peppers.

The most effective means for controlling Phytophthora blight are chile pepper cultivars that are genetically resistant to the disease. Some resistant lines have been identified, but currently there are no cultivars that are resistant to the blight in all environments.
Chile pepper fruit become infected during prolonged periods of heavy rain and high humidity in flooded and poorly drained fields. Prior to this study, there had been no systematic assessment of the relationship of chile pepper heat level to chile pepper response to Phytophthora capsici. If such a connection could be found, information might have been revealed that would assist breeding programs intended for developing disease-resistant cultivars of pepper.
Based on documented field observations in New Mexico, Arizona, and South Carolina, the researchers hypothesized that peppers that produce high-heat fruits would be more resistant to Phytophthora blight than low-heat varieties. The study was conducted by observing infection on both the root and fruit of different varieties of peppers included.
The results of the study concluded, however, that there was no relationship between the heat level of the pepper and the plant's resistance to Phytophthora blight. For example, while the disease was slowest to develop on the roots of one variety of jalapeño, it was quickest to develop on the fruit of the same plant.
Conversely, the disease was faster to develop on roots and slower on fruit of all other cultivars. As the root of the plant contains no heat-inducing agents but the fruit does, the slow development on the root and rapid development on the fruit of the jalapeño indicates that heat level is not a factor.
The results of this study indicate that factors other than heat level may be involved in fruit response to Phytophthora capsici. Genetic differences and cuticle thickness of the plants and fruits are among other issues that could be relevant, but further study is warranted.
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Adapted from materials provided by American Society for Horticultural Science, via EurekAlert!, a service of AAAS.

New Test May Help To Ensure That Dengue Vaccines Do No Harm

Mosquitoes spread dengue fever.

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As vaccines against a virus that infects 100 million people annually reach late-stage clinical trials this year, researchers have developed a test to better predict whether a given vaccine candidate should protect patients from the infection, or in some cases, make it more dangerous, according to an article just published in the journal Clinical and Vaccine Immunology.

Cases of tropical, mosquito-borne dengue fever have expanding globally for more than 50 years, with nearly a third of the human population in 100 countries now at risk of infection with the four types of dengue virus. Infection with the dengue flavivirus, which is related to West Nile Virus and Yellow Fever, results in an estimated 500,000 hospitalizations and 22,000 deaths, mostly among infants, each year, according to the World Health Organization. After decades of absence in the United States, experts say the disease is causing illness again along the Texas-Mexico border, and that widespread dengue infection in the continental United States is a real possibility.

A typical dengue infection confines a patient to bed for more than a week with fever and severe limb pains, but most recover. In less than five percent of cases, however, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), often deadly complications, develop just as the fever breaks. Mostly affecting babies between five and eight months of age, DHF causes victims to vomit and pass blood in their feces and urine. If diagnosed quickly, patients respond to intensive hospital treatment and fluids, but mortality can reach 15 percent when undiagnosed. DSS comes when the infection has caused so much fluid to leak out of capillaries that there is not enough blood to supply organs. As of 2008, there were no antiviral drugs designed to treat dengue and no drug candidates in late-stage development.
"Aggressive health education and mosquito abatement programs have saved lives, but hopes for a true solution lie with vaccine design," said Xia Jin, M.D., Ph.D., associate professor in the Department of Medicine, Division of Infectious Diseases, at the University of Rochester Medical Center. "Our study shows that the new test is likely superior to the standard test in its ability to tell whether a patient's response to a vaccine is safe," said Jin, an author for the CVI paper.

Second Time Deadly
Most people, upon first exposure to any dengue virus, develop an immune response that protects them against that version of the virus for life. Unfortunately, the dengue virus, in its ancient relationship with humans, has evolved into four related but independent classes of virus called serotypes (DENV-1, DENV-2, DENV-3 and DENV-4). The frightening aspect of the disease comes with a person's second dengue infection with one of the other three dengue serotypes, which may place them at much greater risk for bleeding and shock.
In cases where simple dengue fever progresses to DHS, patients have about 100 times as much virus in their blood as seen in a mild infection. What makes the virus so much better at penetrating human cells and reproducing the second time around? Decades of research are just now providing the answer, which lies within the intricacies of the immune system designed to recognize and destroy invading organisms.
As patients attempt to fight off a dengue infection, their immune systems activate antibodies, immune proteins that lock onto certain identifying pieces of the virus to form antibody-virus complexes that flag the virus for destruction. Humans produce a vast variety of antibodies, each with a unique "business end" shaped to recognize one specific viral protein, which enables the system to react to most invaders encountered. Ideally, an infected patient produces a large amount of the type of antibody that binds most strongly to the virus and that covers the greatest amount of the viral surface area to "neutralize" the virus (takes away its ability to reproduce).
Complicating matters is a second feature of antibodies, one which is the same across all antibodies: the crystalizable fragment (Fc). The Fc is designed to bind to proteins called the Fc receptors on the surfaces of macrophages, immune cells that roam the bloodstream seeking to engulf and "dissolve" viruses and bacteria. Coated with Fc receptors, macrophages constantly stick to the Fc end of antibodies, which brings whatever the antibody has locked onto into close contact with the cells capable of destroying it. In most people infected with their first dengue serotype, antibodies bind tightly to the viral surface and escort the virus via the Fc/Fc receptor link to macrophages where the virus is destroyed. The immune system then stores away a few of the successful antibodies in case that same virus is ever encountered again. When the system encounters a second dengue serotype, however, the antibodies from the first infection do not attach as securely to the new version in many cases, enabling the virus to break away from its antibody partner and begin copying itself. In this scenario, the antibody's Fc/Fc receptor interaction has served only to deliver the virus into cells that it could not otherwise penetrate.
The latter phenomenon, called antibody-dependent enhancement (ADE), has delayed the development of dengue vaccines for decades. The threat of enhancement dictates that any dengue vaccine must raise protective immunity against all four dengue serotypes simultaneously and equally, and several vaccine candidates have generated unequal responses across serotypes. That creates the possibility that some of the antibodies created by such vaccines could raise the risk for hemorrhagic fever and shock, and calls for the development of tests that can precisely measure enhancement risk.
Different versions of dengue move around the globe, sometimes displacing each other. Asian serotype DENV-2 strains, for example, have been taking the place of relatively more benign American DENV-2. One important example of this was seen in 1981, when Asian DENV-2 struck Cuba with nearly 900 people hospitalized following an uneventful DENV-1 outbreak four years earlier. While the Cuba outbreak followed the standard pattern, with a spike in serious cases accompanying a second infection, another outbreak, in Iquitos, Peru, in 1995, was unusual. In an area infected with DENV-1 four years previously, the second infection in 1995 with DENV-2 outbreak did not cause fatal complications. The reasons why one DENV 2 strain caused fatal second infections, and another did not, remained a mystery for years.
The current study may have helped solve the mystery, while pointing out a weakness of the standard test of antibody responses. The assay used originally to analyze the blood of patients in Iquitos was the plaque-reduction neutralization test (PRNT), the recognized gold standard for determining how effectively the human immune system responds to dengue infection. PRNT starts with a sheet of cells chosen because they can be invaded by the virus, and because they share some qualities with the kind of cell targeted by the virus in the body, the macrophage.
When the viral strain being studied is introduced to this cell culture, it begins invading and killing the cells, and making copies of itself. By diluting these mixtures, scientists can identify and count "islands" (or plaques) in the culture where the virus has destroyed cells.
When serum (which contains antibodies) from an infected patient's blood is added to this mix, the number of spots over time reveals the degree to which the patient's antibodies can effectively neutralize the virus. In the case of dengue research, PRNT tests are used to measure how efficiently the antibodies from a natural infection protect the cultured cells from the experimental infection with a second dengue serotype.
According to past experiments on the standard PRNT test, it took on average about seven times as many antibodies created by DENV-1 infection to neutralize Asian DENV-2 vs. American DENV-2. Jin and colleagues added an important element to the PRNT test, and then retested the Iquitos samples. The new, more sensitive test found that it took up to 100 times as many DENV-1 antibodies to neutralize the Asian DENV-2 virus as it did to the American DENV-2 infection. The results suggest that, in the harmless Iquitos outbreak, the second dengue serotype to hit the region was the American version of DENV-2, was cross-neutralized with relative ease by antibodies created by the first infection. In Cuba, however, the people were unfortunate to be hit by the Asian DENV-2 upon second infection, which their antibodies from DENV-1 infection could not shut it down, and only helped to deliver the virus into their cells. By magnifying the differences in the ability of an antibody for a given dengue serotype to neutralize other serotypes, researchers believe the new test will capture enhancement that the older test misses.
To construct the new test of cross-neutralization, researchers took CV-1 fibroblast cells, which share some traits with macrophages, and genetically engineered them to include a gene that directs for the building of an FC receptor on their surfaces. They also constructed a CV-1 cell line for culture without Fc receptors for use as a control group that resembles standard PRNT cultures used in the past. Both sets of cultures were then subjected the blood taken from patients in the 1995 Peru outbreak, and the new test captured for the first time the contribution of antibodies to more severe disease via fc/fc receptor delivery of virus to target cells.
Along with Jin, the work in Rochester was led by corresponding author Jacob Schlesinger, M.D., and Robert Rose, Ph.D., as well as by graduate student W. W. Shanaka I. Rodrigo, who conducted the genetic engineering experiments on CV-1 cells. Also contributing in Rochester were Danielle Alcena and Zhihua Kou. Tadeusz Kochel contributed from at the Naval Medical Research Center Detachment, Lima, Peru, as did Kevin Porter at the US Naval Medical Research Center, Silver Spring, Maryland. Guillermo Comach led a team as well at the Laboratorio Regional de Diagnostico e Investigacion del Dengue y otras Enfermedades Virales in Maracay Estado Aragua, Venezuela.
"Beyond the Peruvian case, our test promises to have a profound effect on the design of vaccines because we can take the antibodies generated by two different candidate vaccines, and better compare which strongly neutralizes virus without threat of enhancement across all four serotypes," Jin said. "With experimental vaccines from companies like GlaxoSmithKline and Sanofi Aventis entering Phase II and Phase III clinical trials this year, we hope the new test will be adopted widely and soon because it is more likely to catch enhancement."
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Adapted from materials provided by University of Rochester Medical Center.

Threat To Cod Fisheries: Pathogenic Bacterium Identified In Cod

Colonies of Francisella in growth medium.

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Farmed cod have recently been hit by a serious disease caused by an unknown bacterium. In his doctorate, Jarle Mikalsen contributed to the identification of this bacterium, now called Francisella philomiragia noatunensis. The disease caused by the bacterium is now called francisellosis and is listed in the national disease register and regulated under the terms of the Norwegian Food Act.
Mikalsen's work with intracellular bacteria (bacteria living in body cells) of farmed cod and salmon has increased knowledge and improved the diagnostics of these bacteria. It has been an important contribution to the understanding of bacterial infections in the fish farming industry.

This thesis is the result of a collaboration by several Norwegian research environments. Its central goal was to increase our knowledge of bacterial infections of significance for health or economy in the farming industry. Mikalsen contributed to the development of new diagnostic methods for demonstrating pathogenic bacteria in Norwegian fish farming, and an important part of this work was the identification and characterisation of the bacterium Francisella philomiragia noatunensis.
This new bacterium has caused significant loss in the cod farming industry in recent years. However, it may also pose a threat to farmed salmon since it occurs naturally in coastal waters and is liable to cause disease in a range of marine species. The bacterium is not harmful to warm-blooded animals.
In addition to identifying Francisella, a breakthrough was achieved in the demonstration of the bacterium, Piscirickettsia salmonis. This is another intracellular bacterium that has caused significant loss in the fish farming industry both nationally and internationally, especially in Chile.
This doctorate produced six scientific articles and was carried out at the Norwegian Veterinary Institute in close collaboration with the research environment at the Norwegian School of Veterinary Science.
Cand. scient. Jarle Mikalsen defended his Ph. D. thesis, entitled "Diagnosis and characterisation of intracellular Gram-negative pathogens of marine and salmonid fish", at the Norwegian School of Veterinary Science, on November 21, 2008.
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Adapted from materials provided by Norwegian School of Veterinary Science.

Protective Shield Used By Hundreds Of Viruses Deciphered

High-energy X-ray diffraction was used to pinpoint some 5 million atoms in the protective protein coat used by hundreds of viruses.

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If a picture is worth a thousand words, then Rice University's precise new image of a virus' protective coat is seriously undervalued. More than three years in the making, the image contains some 5 million atoms -- each in precisely the right place -- and it could help scientists find better ways to both fight viral infections and design new gene therapies.

The stunning image, which appears online this week in the Proceedings of the National Academy of Sciences, reveals the structure of a type of protein coat shared by hundreds of known viruses containing double-stranded RNA genomes. The image was painstakingly created from hundreds of high-energy X-ray diffraction images and paints the clearest picture yet of the viruses' genome-encasing shell called a "capsid."
"When these viruses invade cells, the capsids get taken inside and never completely break apart," said lead researcher Jane Tao, assistant professor of biochemistry and cell biology at Rice.
Capsids come into play because viruses can reproduce themselves only by invading a host cell and highjacking its biochemical machinery. But when they invade, viruses need to seal off their genetic payload to prevent it from being destroyed by the cell's protective mechanisms.
Though there are more than 5,000 known viruses, including whole families that are marked by wide variations in genetic payload and other characteristics, most of them use either a helical or a spherical capsid.
In their attempt to map precisely the spherical variety, Tao and lead author Junhua Pan, a postdoctoral fellow at Rice, first had to create a crystalline form of the capsid that could be X-rayed. They chose the oft-studied Penicillium stoloniferum virus F, or PsV-F, a virus that infects the fungus that makes penicillin. PsV-F uses the spherical capsid; although it does not infect humans, it is similar to a rotavirus and others that do.
"Spherical viruses like this have symmetry like a soccer ball or geodesic dome," Pan said. "The whole capsid contains exactly 120 copies of a single protein."
Previous studies had shown that spherical capsids contain dozens of copies of the capsid protein, or CP, in an interlocking arrangement. The new research identified the sphere's basic building block, a four-piece arrangement of CP molecules called a tetramer, which could also be building blocks for other viruses' protein coats. By deciphering both the arrangement and the basic building block, the research team hopes to learn more about the capsid-forming process.
"Because many viruses use this type of capsid, understanding how it forms could lead to new approaches for antiviral therapies," Tao said. "It could also aid researchers who are trying to create designer viruses and other tools that can deliver therapeutic genes into cells."
The research team used X-ray crystallography to decipher the structure of the capsid. Pan first spent several months creating hundreds of crystal samples of PsV-F. He then collected hundreds of high-intensity, high-energy X-ray diffraction images at the Cornell High Energy Synchotron Source, or CHESS, in Ithaca, N.Y. By analyzing the way the X-rays scattered when they struck the crystals, Pan and the team created a precise three-dimensional image of the spherical capsid.
The research team included Rice postdoctoral researcher Li Lin and former graduate student Liping Dong; Max Nibert of Harvard Medical School; Timothy Baker, Wendy Ochoa and Robert Sinkovits, all of the University of California, San Diego; and Said Ghabrial and Wendy Havens, both of the University of Kentucky.
The research was supported by the National Institutes of Health, the USDA, the Welch Foundation, the Kresge Science Initiative Endowment Fund, the Agouron Foundation and the San Diego Supercomputer Center.
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Adapted from materials provided by Rice University, viaEurekAlert!, a service of AAAS.

Arginine Discovery Could Help Fight Human Obesity

A Texas AgriLife Research scientist and fellow researchers have discovered that arginine, an amino acid, reduces fat mass in diet-induced obese rats and could help fight human obesity.
"Given the current epidemic of obesity in the U.S. and worldwide, our finding is very important,” said Dr. Guoyao Wu, an AgriLife Research animal nutritionist in College Station and Senior Faculty Fellow in the department of animal science at Texas A&M University.
The research found dietary arginine supplementation shifts nutrient partitioning to promote skeletal-muscle gain, according to the researchers. The findings were published recently in the Journal of Nutrition.
In laboratory experiments, rats were fed both low-and high-fat diets. They found that arginine supplementation for a 12-week period decreased the body fat gains of low-fat and high-fat fed rats by 65 percent and 63 percent, respectively. The long-term arginine treatment did not have any adverse effects on either group.
“This finding could be directly translated into fighting human obesity,” Wu said. “At this time, arginine has not been incorporated into our food (but could in the future).”
Arginine-rich foods include seafood, watermelon juice, nuts, seeds, algae, meats, rice protein concentrate and soy protein isolate, he said.
The research suggests that arginine may increase lean tissue growth. In pigs, it was found that dietary arginine supplementation reduced fat accretion (growth) but increased muscle gain in growing/finishing pigs without affecting body weight.
Another important observation according to the research was that dietary arginine reduced serum concentrations of branched-chain amino acids.
“This metabolic change is likely beneficial because elevated concentrations of branched-chain amino acids may lead to insulin resistance in obesity. Additionally, arginine can stimulate muscle protein synthesis, a biochemical process that requires large amounts of energy,” Wu said. “Thus, dietary energy would be utilized for lean tissue rather than fat gain.”
The research, funded by the American Heart Association, will be presented in August at the 11 th International Symposium on Amino Acids in Vienna, Austria.
Follow-up research will include clinical studies with obese children and adults, Wu said.

Members of the research team are: Wu, Wenjuan Jobgen, Scott Jobgen, Peng Li, Stephen Smith, Thomas Spencer, all with the department of animal science at Texas A&M; Cynthia Meininger of Texas A&M Health Science Center; and Mi-Jeong Lee and Susan Fried, department of medicine at University of Maryland School of Medicine.
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Adapted from materials provided by Texas A&M.

New Prostate Cancer Marker In Urine Indicates Whether Cancer Is Spreading

Histological slide showing prostate cancer. (Credit: Otis Brawley / Courtesy of National Cancer Institute)

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Howard Hughes Medical Institute researchers have identified a new biological marker present in the urine of patients with prostate cancer that indicates whether the cancer is progressing and spreading.

In experiments reported in the journal Nature, the scientists identified 10 metabolites that become more abundant in prostate cells as cancer progresses. Their studies showed that one of these chemicals, sarcosine, helps prostate cancer cells invade surrounding tissue.
"One of the biggest challenges we face in prostate cancer is determining if the cancer is aggressive. We end up overtreating our patients because physicians don't know which tumors will be slow-growing. With this research, we have identified a potential marker for the aggressive tumors," says senior study author Arul Chinnaiyan, M.D., Ph.D. director of the Michigan Center for Translational Pathology and S.P. Hicks Endowed Professor of Pathology at the U-M Medical School.

HHMI investigator Arul Chinnaiyan and colleagues at the University of Michigan showed that as prostate cancer develops and progresses, sarcosine levels increase in both tumor cells and urine samples, suggesting that measurements of the metabolite could aid in non-invasively diagnosing the disease. Researchers might also be able to inhibit prostate cancer's spread by designing drugs that manipulate the sarcosine pathway.

The study is the first to analyze the levels of more than 1,000 different metabolites in human tumors. Scientists know that cells undergo complex changes as cancer develops and progresses to metastatic disease. Chinnaiyan's lab, which has extensively analyzed how genes and proteins in prostate cancer cells reflect these changes, thought that profiling cells' metabolites would offer an even more "holistic picture of the molecular alterations that occur," he said.

"This allows us to have more of a systems perspective of cancer development," he noted. "We are also looking at gene and protein markers, for therapeutic consideration, biomarker consideration, and just understanding the biology. We are not sure yet how it's going to sort out, so we're being non-discriminatory with what types of technologies we use."

In the experiments reported in Nature, the scientists used mass spectrometry, a technique that identifies chemicals based on the size and electrical charge of their components, to compare the levels of 1,126 metabolites in healthy prostate tissue, clinically localized prostate cancer, and metastatic prostate cancer. Sixty metabolites were present in tumor cells, but not in benign tissue. Of these, there were about 10 molecules whose levels increased dramatically during cancer progression. "This is proof-of-principle that we can identify metabolites, or panels of metabolites, that might be correlated with aggressive prostate cancer versus slower-growing prostate cancer," Chinnaiyan said.

Having demonstrated that "metabolomic" profiles change in predictable ways as cancer progresses, the group began more focused analyses. "We began to mine the data to look for metabolites that might serve as biomarkers or as therapeutic targets," Chinnaiyan explained. They chose to focus on sarcosine because it was elevated in clinically localized disease and very highly elevated in metastatic cancer.

They confirmed these dramatic increases in a new set of tissue samples, and also found that there was more sarcosine in the urine of patients with prostate cancer than in healthy individuals.

The team went on to test how sarcosine affected the behavior of cancer cells grown in the laboratory. Adding the chemical to prostate cells or manipulating cells' biochemical pathways so they produced more sarcosine on their own caused benign prostate cells to become cancerous and invasive. Conversely, shutting down sarcosine production in cancer cells blocked invasion.

"This really told us that sarcosine is involved biologically in some of the processes of a cancer cell," Chinnaiyan said. The results suggest that drugs that alter sarcosine metabolism might be useful in treating prostate cancer, but Chinnaiyan cautions that these Petri-dish findings still need further validation in animal models.

An important next step, he says, will be to do similar experiments on the other nine potential biomarkers they identified in this study. For reliable diagnosis of aggressive disease, he said, "we need to have panels, not just rely on a single metabolite."
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Adapted from materials provided by Howard Hughes Medical Institute.
Feb. 12, 2009

How Ebola Virus Avoids The Immune System

"Scanning electron microscope image of Ebola virions (spaghetti-like filaments) on the surface of a tetherin-expressing cell (center)."

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Researchers at the University of Pennsylvania School of Medicine have likely found one reason why the Ebola virus is such a powerful, deadly, and effective virus. Using a cell culture model for Ebola virus infection, they have discovered that the virus disables a cellular protein called tetherin that normally can block the spread of virus from cell to cell.

“Tetherin represents a new class of cellular factors that possess a very different means of inhibiting viral replication,” says study author Paul Bates, PhD, Associate Professor of Microbiology at the University of Pennsylvania School of Medicine. “Tetherin is the first example of a protein that affects the virus replication cycle after the virus is fully made and prevents the virus from being able to go off and infect the next cell.” These findings appear online this week in the Proceedings of the National Academy of Sciences.
When a cell is infected with a virus like Ebola, which is deadly to 90 percent of people infected, the cell is pirated by the virus and turned into a production factory that makes massive quantities on new virions. These virions are then released from that cell to infect other cells and promote the spreading infection.
Tetherin is one of the immune system's responses to a viral infection. If working properly, tetherin stops the infected cell from releasing the newly made virus, thus shutting down spread to other cells. However, this study shows that the Ebola virus has developed a way to disable tetherin, thus blocking the body's response and allowing the virus to spread.
“This information gives us a new way to study how tetherin works,” says Bates. "Binding of a protein produced by Ebola to tetherin apparently inactivates this cellular factor. Understanding how the Ebola protein blocks the activity of tetherin may facilitate the design of therapeutics to inhibit this interaction, allowing the cell's natural defense systems to slow down viral replication and give the animal or person a chance to mount an effective antiviral response and recover.”
Previous research had found that tetherin plays a role in the immune system's response to HIV-1, a retrovirus, and that tetherin is also disabled by HIV. These new studies reveal that human cells also use this defense against other types of viruses, such as Ebola, that are not closely related to HIV-1. “Because we see such broad classes of viruses that are affected by tetherin, it's possible that all enveloped viruses are targets of this antiviral system,” says Bates. “If so, then understanding how tetherin works and how viruses escape from the effect of tetherin will be very important.”
Rachel L. Kaletsky, Joseph R. Francica and Caroline Agrawal-Gamse of the University of Pennsylvania School of Medicine are co-authors of this study. This work was funded by the Public Health Service Grants and the Philip Morris External Research Foundation.
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Adapted from materials provided by University of Pennsylvania School of Medicine.