OREGON STATE UNIVERSITY

college of science

Discovery opens door to new drug options for serious diseases

CORVALLIS, Ore. – Researchers have discovered how oxidative stress can turn to the dark side a cellular protein that’s usually benign, and make it become a powerful, unwanted accomplice in neuronal death.

This finding, reported today in Proceedings of the National Academy of Sciences, could ultimately lead to new therapeutic approaches to many of the world’s debilitating or fatal diseases.

The research explains how one form of oxidative stress called tyrosine nitration can lead to cell death. Through the common link of inflammation, this may relate to health problems ranging from heart disease to chronic pain, spinal injury, cancer, aging, and amyotrophic lateral sclerosis, or Lou Gehrig’s disease.

As part of the work, the scientists also identified a specific “chaperone” protein damaged by oxidants, which is getting activated in this spiral of cellular decline and death. This insight will provide a new approach to design therapeutic drugs.

The findings were published by scientists from the Linus Pauling Institute at Oregon State University; Maria Clara Franco and Alvaro Estevez, now at the University of Central Florida; and researchers from several other institutions. They culminate a decade of work.

“These are very exciting results and could begin a major shift in medicine,” said Joseph Beckman.

Beckman is an LPI principal investigator, distinguished professor of biochemistry, and director of the OSU Environmental Health Sciences Center. He also last year received the Discovery Award from the Medical Research Foundation of Oregon, given to the leading medical scientist in the state.

“Preventing this process of tyrosine nitration may protect against a wide range of degenerative diseases,” Beckman said. “The study shows that drugs could effectively target oxidatively damaged proteins.”

Scientists have known for decades about the general concept of oxidative damage to cells, resulting in neurodegeneration, inflammation and aging. But the latest findings prove that some molecules in a cell are thousands of times more sensitive to attack.

In this case, heat shock protein 90, or HSP90, helps monitor and chaperone as many as 200 necessary cell functions. But it can acquire a toxic function after nitration of a single tyrosine residue.

“It was difficult to believe that adding one nitro group to one protein will make it toxic enough to kill a motor neuron,” Beckman said. “But nitration of HSP90 was shown to activate a pro-inflammatory receptor called P2X7. This begins a dangerous spiral that eventually leads to the death of motor neurons.”

The very specificity of this attack, however, is part of what makes the new findings important. Drugs that could prevent or reduce oxidative attack on these most vulnerable sites in a cell might have value against a wide range of diseases.

“Most people think of things like heart disease, cancer, aging, liver disease, even the damage from spinal injury as completely different medical issues,” Beckman said. “To the extent they can often be traced back to inflammatory processes that are caused by oxidative attack and cellular damage, they can be more similar than different.

“It could be possible to develop therapies with value against many seemingly different health problems,” Beckman added.

Beckman has spent much of his career studying the causes of amyotrophic lateral sclerosis, and this study suggested the processes outlined in this study might be relevant both to that disease and spinal cord injury.

One key to this research involved new methods that allowed researchers to genetically engineer nitrotyrosine into HSP90. This allowed scientists to pin down the exact areas of damage, which may be important in the identification of drugs that could affect this process, the researchers said.

This work was supported by the National Institutes of Health, Burke Medical Research Institute, Weill Cornell Medical College, the ALS Association and other agencies.

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Death of a motor neuron

Tyrosine nitration

A war without end - with Earth’s carbon cycle held in the balance

CORVALLIS, Ore. – The greatest battle in Earth’s history has been going on for hundreds of millions of years - it isn’t over yet - and until now no one knew it existed, scientists reported today in the journal Nature.

In one corner is SAR11, a bacterium that’s the most abundant organism in the oceans, survives where most other cells would die and plays a major role in the planet’s carbon cycle. It had been theorized that SAR11 was so small and widespread that it must be invulnerable to attack.

In the other corner, and so strange-looking that scientists previously didn’t even recognize what they were, are “Pelagiphages,” viruses now known to infect SAR11 and routinely kill millions of these cells every second. And how this fight turns out is of more than casual interest, because SAR11 has a huge effect on the amount of carbon dioxide that enters the atmosphere, and the overall biology of the oceans.

“There’s a war going on in our oceans, a huge war, and we never even saw it,” said Stephen Giovannoni, a professor of microbiology at Oregon State University. “This is an important piece of the puzzle in how carbon is stored or released in the sea.”

Researchers from OSU, the University of Arizona and other institutions today outlined the discovery of this ongoing conflict, and its implications for the biology and function of ocean processes. The findings disprove the theory that SAR11 cells are immune to viral predation, researchers said.

“In general, every living cell is vulnerable to viral infection,” said Giovannoni, who first discovered SAR11 in 1990. “What has been so puzzling about SAR11 was its sheer abundance; there was simply so much of it that some scientists believed it must not get attacked by viruses.”

What the new research shows, Giovannoni said, is that SAR11 is competitive, good at scavenging organic carbon, and effective at changing to avoid infection. Because of that, it thrives and persists in abundance even though it’s constantly being killed by the new viruses that have been discovered.

The discovery of the Pelagiphage viral families was made by Yanlin Zhao, Michael Schwalbach and Ben Temperton, OSU postdoctoral researchers working with Giovannoni. They used traditional research methods, growing cells and viruses from nature in a laboratory, instead of sequencing DNA from nature. The new viruses were so unique that computers could not recognize the virus DNA.

“The viruses themselves, of course, appear to be just as abundant as SAR11,” Giovannoni said. “Our colleagues at the University of Arizona demonstrated this with new technologies they developed for measuring viral diversity.”

SAR11 has several unique characteristics, including the smallest known genetic structure of any independent cell. Through sheer numbers, this microbe has a huge role in consuming organic carbon, which it uses to generate energy while producing carbon dioxide and water in the process. SAR11 recycles organic matter, providing the nutrients needed by algae to produce about half of the oxygen that enters Earth’s atmosphere every day.

This carbon cycle ultimately affects all plant and animal life on Earth.

Contributors to this research included scientists at OSU’s High Throughput Culturing Laboratory; the University of Arizona’s Tucson Marine Phage Lab; University of California/San Diego’s National Center for Microscopy and Imaging Research; and the Monterey Bay Aquarium Research Institute, which provided opportunity to sample viruses from nature. Funding was provided by the Gordon and Betty Moore Foundation Marine Microbiology Initiative.

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Infected bacteria

Infected SAR-11 bacterium

Respiratory infection strategy: get a flu shot, and get enough vitamin D

CORVALLIS, Ore. – Your best defense against influenza, by far, is to get the flu vaccine. Washing hands, a healthy diet and lifestyle are also important.

But after that, a growing body of research suggests the next best thing you should consider for the prevention of flu and other upper respiratory infections is to make sure you have adequate levels of vitamin D. Most Americans do not.

As one of the worst flu seasons in recent years spreads its misery across the nation, experts in the Linus Pauling Institute at Oregon State University say that more people may want to get their blood levels of vitamin D checked. If too low, they could consider supplements to reach optimal levels of this “sunshine vitamin” that both laboratory and epidemiological studies suggest can help reduce respiratory infection.

The winter cold and flu season corresponds – perhaps by coincidence, perhaps not – with the time of year when most people also get the least sun exposure and, as a result, drop to their lowest levels of vitamin D. It can be difficult in winter to get adequate vitamin D from diet alone.

“Vitamin D affects a wide range of immune functions, both innate and adaptive, that can help a person recognize and respond to both bacteria and viruses, not just the flu but many others,” said Adrian Gombart, an OSU associate professor of biochemistry and biophysics, principal investigator with the Linus Pauling Institute and international expert on vitamin D and the immune response.

“The number of people in the U.S. with insufficient levels of vitamin D is probably above 60 percent, especially in the northern states, most of Europe and all of Canada,” Gombart said. “This problem is critical in the elderly, who may get little of it in their diets, don’t get outside as much, and synthesize vitamin D from sunshine at a rate only about 20 percent that of younger adults.”

Vitamin D has anti-inflammatory effects, may improve vaccine response, and is important for the response of immune and epithelial or “barrier cells” in the lungs. Without adequate vitamin D, these cells don’t adequately express cathelicidin, an antimicrobial peptide gene. Laboratory studies have shown that this antimicrobial peptide reduced both infection and inflammation, and protected mice against an influenza challenge.

“Many studies have been done, both in the laboratory and in clinical trials, and some have conflicting results,” Gombart said. “One explanation may be that some study participants already had adequate levels of vitamin D. If you aren’t deficient in this nutrient, adding more to your diet isn’t going to offer much benefit. We still need more well-designed clinical trials with a vitamin D deficient population.”

Many scientists believe that at least 32 nanograms per milliliter of vitamin D in the blood is a reasonable minimum, Gombart said, and some research has found increased protection against upper respiratory infection in people with levels around 38 ng/ml. But the level now considered insufficient, based primarily on bone health rather than other health outcomes, is less than 20 ng/ml.

The official RDA for vitamin D was recently raised, and is now 600 IU daily for most adults, 800 IU for the elderly. An intake of 2,000 IU per day for all adults and 400 IU for children should get most people to a blood level of 32 ng/ml or higher. But this is difficult to achieve through diet alone – a cup of vitamin D fortified milk, for example, has about 100 IU.

Historically, studies about adequate vitamin D were focused on bone health, including overt deficiency diseases such as rickets. Scientists now understand this vitamin plays a much larger role in many physiologic functions, especially an appropriate immune response.

There are estimates that one billion people around the world may be deficient, mostly in the temperate zones and higher latitudes, and any population with darker skin color also faces higher risk. Some experts say that in the U.S. more than 90 percent of black, Hispanic and Asian populations have insufficient levels. The primary source of this fat-soluble nutrient is a metabolic response to UV-B radiation in sunshine.  Diet plays only a limited role.

The regulation of cathelicidin by vitamin D, which was discovered by Gombart, is a unique biological pathway that can help explain vitamin D’s multiple roles in immune function. This pathway exists only in two groups of animals – humans and non-human primates.  Its importance for their immune response against infection is highlighted by its conservation through millions of years of separate evolution.

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Adrian Gombart, 541-737-8018

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Adrian Gombart

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New electronics for a sustainable world

CORVALLIS, Ore. – New, more powerful solar energy technologies could help reduce carbon emissions, but it will take a revolution in advanced materials to achieve that goal. Fortunately, scientists are well on the way. Doug Keszler, Oregon State University chemist, will describe their progress at the Corvallis Science Pub on Monday, Jan. 14.

The presentation will begin at 6 p.m. at the Old World Deli, 341 S.W. Second St., in Corvallis. It is free and open to the public.

“We all know that water is essential to life,” said Keszler. “With energy from the sun, water is converted to the food that we eat and the oxygen that we breathe by the chemical factories that we call plants.”

Keszler and his colleagues are now developing water-based chemistries that can provide industrial factories with new ways to make solar cells, simultaneously curbing energy use, reducing waste and increasing power output.

Such developments are transforming environmentally-responsible manufacturing, he adds.

Sponsors of Science Pub include Terra magazine at OSU, the Downtown Corvallis Association and the Oregon Museum of Science and Industry.

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Doug Keszler, 541-737-6736

Fossil of ancient spider attack only one of its type ever discovered

CORVALLIS, Ore. – Researchers have found what they say is the only fossil ever discovered of a spider attack on prey caught in its web – a 100 million-year-old snapshot of an engagement frozen in time.

The extraordinarily rare fossils are in a piece of amber that preserved this event in remarkable detail, an action that took place in the Hukawng Valley of Myanmar in the Early Cretaceous between 97-110 million years ago, almost certainly with dinosaurs wandering nearby.

Aside from showing the first and only fossil evidence of a spider attacking prey in its web, the piece of amber also contains the body of a male spider in the same web. This provides the oldest evidence of social behavior in spiders, which still exists in some species but is fairly rare. Most spiders have solitary, often cannibalistic lives, and males will not hesitate to attack immature species in the same web.

“This juvenile spider was going to make a meal out of a tiny parasitic wasp, but never quite got to it,” said George Poinar, Jr., a professor emeritus of zoology at Oregon State University and world expert on insects trapped in amber. He outlined the findings in a new publication in the journal Historical Biology.

“This was a male wasp that suddenly found itself trapped in a spider web,” Poinar said. “This was the wasp’s worst nightmare, and it never ended. The wasp was watching the spider just as it was about to be attacked, when tree resin flowed over and captured both of them.”

Spiders are ancient invertebrates that researchers believe date back some 200 million years, but the oldest fossil evidence ever found of a spider web is only about 130 million years old. An actual attack such as this between a spider and its prey caught in the web has never before been documented as a fossil, the researchers said.

The tree resin that forms amber is renowned for its ability to flow over insects, small plants and other life forms, preserving them in near perfection before it later turns into a semi-precious stone. It often gives scientists a look into the biology of the distant past. This spider, which may have been waiting patiently for hours to capture some prey, was smothered in resin just a split second before its attack.

This type of wasp, Poinar said, belongs to a group that is known today to parasitize spider and insect eggs. In that context, the attack by the spider, an orb-weaver, might be considered payback.

Both the spider and the wasp belong to extinct genera and are described in the paper. At least 15 unbroken strands of spider silk run through the amber piece, and on some of these the wasp was ensnared.

Its large and probably terrified eyes now stare for eternity at its attacker, moving in for the kill.

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Ancient spider attack


Spider attack

The “slippery slope to slime”: Overgrown algae causing coral reef declines

The study this story is based on is available online: http://bit.ly/QkeZkp

CORVALLIS, Ore. – Researchers at Oregon State University for the first time have confirmed some of the mechanisms by which overfishing and nitrate pollution can help destroy coral reefs – it appears they allow an overgrowth of algae that can bring with it unwanted pathogens, choke off oxygen and disrupt helpful bacteria.

These “macroalgae,” or large algal species, are big enough to essentially smother corals. They can get out of control when sewage increases nitrate levels, feeds the algae, and some of the large fish that are most effective at reducing the algal buildup are removed by fishing.

Scientists found that macroalgal competition decreased coral growth rates by about 37 percent and had other detrimental effects. Other research has documented some persistent states of hypoxia.

Researchers call this process “the slippery slope to slime.”

Findings on the research were just published in PLoS One, a professional journal. The work was supported by the National Science Foundation.

“There is evidence that coral reefs around the world are becoming more and more dominated by algae,” said Rebecca Vega-Thurber, an OSU assistant professor of microbiology. “Some reefs are literally covered up in green slime, and we wanted to determine more precisely how this can affect coral health.”

The new study found that higher levels of algae cause both a decrease in coral growth rate and an altered bacterial community. The algae can introduce some detrimental pathogens to the coral and at the same time reduce levels of helpful bacteria. The useful bacteria are needed to feed the corals in a symbiotic relationship, and also produce antibiotics that can help protect the corals from other pathogens.

One algae in particular, Sargassum, was found to vector, or introduce a microbe to corals, a direct mechanism that might allow introduction of foreign pathogens.

There are thousands of species of algae, and coral reefs have evolved with them in a relationship that often benefits the entire tropical marine ecosystem. When in balance, some algae grow on the reefs, providing food to both small and large fish that nibble at the algal growth. But the algal growth is normally limited by the availability of certain nutrients, especially nitrogen and phosphorus, and some large fish such as parrot fish help eat substantial amounts of algae and keep it under control.

All of those processes can be disrupted when algal growth is significantly increased by the nutrients and pollution from coastal waste water, and overfishing reduces algae consumption at the same time.

“This shows that some human actions, such as terrestrial pollution or overfishing, can affect everything in marine ecosystems right down to the microbes found on corals,” Vega-Thurber said. “We’ve suspected before that increased algal growth can bring new diseases to corals, and now for the first time have demonstrated in experiments these shifts in microbial communities.”

Some mitigation of the problem is already being done on high-value coral reefs by mechanically removing algae, Vega-Thurber said, but the best long-term solution is to reduce pollution and overfishing so that a natural balance can restore itself.

Corals are one of Earth’s oldest animal life forms, evolving around 500 million years ago. They host thousands of species of fish and other animals, are a major component of marine biodiversity in the tropics, and are now in decline around the world. Reefs in the Caribbean Sea have declined more than 80 percent in recent decades.

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Rebecca Vega-Thurber, 541-737-1851

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Healthy coral reef

Healthy corals

 

Algae covered corals

Algae on coral reef

Vitamin B3 may help in fight against staph infections, “superbugs”

CORVALLIS, Ore. – A new study suggests that nicotinamide, more commonly known as vitamin B3, may be able to combat some of the antibiotic-resistance staph infections that are increasingly common around the world, have killed thousands and can pose a significant threat to public health.

The research found that high doses of this vitamin increased by 1,000 times the ability of immune cells to kill staph bacteria. The work was done both in laboratory animals and with human blood.

The findings were published today in the Journal of Clinical Investigation by researchers from Cedars-Sinai Medical Center, the Linus Pauling Institute at Oregon State University, UCLA, and other institutions. The research was supported by several grants from the National Institutes of Health.

The work may offer a new avenue of attack against the growing number of “superbugs.”

“This is potentially very significant, although we still need to do human studies,” said Adrian Gombart, an associate professor in OSU’s Linus Pauling Institute. “Antibiotics are wonder drugs, but they face increasing problems with resistance by various types of bacteria, especially Staphylococcus aureus.

“This could give us a new way to treat staph infections that can be deadly, and might be used in combination with current antibiotics,” Gombart said. “It’s a way to tap into the power of the innate immune system and stimulate it to provide a more powerful and natural immune response.”

The scientists found that clinical doses of nicotinamide increased the numbers and efficacy of “neutrophils,” a specialized type of white blood cell that can kill and eat harmful bacteria.

The nicotinamide was given at megadose, or therapeutic levels, far beyond what any normal diet would provide - but nonetheless in amounts that have already been used safely in humans, as a drug, for other medical purposes.

However, there is no evidence yet that normal diets or conventional-strength supplements of vitamin B3 would have any beneficial effect in preventing or treating bacterial infection, Gombart said, and people should not start taking high doses of the vitamin.

Gombart has been studying some of these issues for more than a decade, and discovered 10 years ago a human genetic mutation that makes people more vulnerable to bacterial infections. In continued work on the genetic underpinnings of this problem, researchers found that nicotinamide had the ability to “turn on” certain antimicrobial genes that greatly increase the ability of immune cells to kill bacteria.

One of the most common and serious of the staph infections, called methicillin-resistant S. aureus, or MRSA, was part of this study. It can cause serious and life-threatening illness, and researchers say the widespread use of antibiotics has helped increase the emergence and spread of this bacterial pathogen.

Dr. George Liu, an infectious disease expert at Cedars-Sinai and co-senior author on the study, said that “this vitamin is surprisingly effective in fighting off and protecting against one of today’s most concerning public health threats.” Such approaches could help reduce dependence on antibiotics, he said.

Co-first authors Pierre Kyme and Nils Thoennissen found that when used in human blood, clinical doses of vitamin B3 appeared to wipe out the staph infection in only a few hours.

Serious staph infections, such as those caused by MRSA, are increasingly prevalent in hospitals and nursing homes, but are also on the rise in prisons, the military, among athletes, and in other settings where many people come into close contact.

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Adrian Gombart, 541-737-8018

Rating of ocean health shows “room for improvement”

CORVALLIS, Ore. – An international group of more than 30 researchers today gave a score to every coastal nation on their contribution to the health of the world’s oceans, which showed the United States as being slightly above average, and identified food provision, tourism and recreation as leading concerns.

The analysis, published in the journal Nature, scored each nation on a 0-100 scale in 10 separate categories such as clean water, biodiversity, food provision, carbon storage, coastal protection, coastal economies and others.

In this “Ocean Health Index,” the world received an average score of 60. The U.S. was at 63.

This is one of the first comprehensive analyses to evaluate the global oceans in so many critical aspects, including natural health and the human dimensions of sustainability. But it’s meant less to be a conclusion, the authors said, and more a baseline that can help track either improvements or declines in ocean health going into the future.

“When we conclude that the health of the oceans is 60 on a scale of 100, that doesn’t mean we’re failing,” said Karen McLeod, an ecologist at Oregon State University, director of science at COMPASS, and one of several lead authors on the study.

“Instead, it shows there’s room for improvement, suggests where strategic actions can make the biggest difference, and gives us a benchmark against which to evaluate progress over time,” she said. “The index allows us to track what’s happening to the whole of ocean health instead of just the parts.”

The scores ranged from 36 to 86, with the highest ratings going to Jarvis Island, an uninhabited and relatively pristine coral atoll in the South Pacific Ocean. Many countries in West Africa, the Middle East and Central America scored poorly, while higher ratings went to parts of Northern Europe, Canada, Australia and Japan.

Human activities such as overfishing, coastal development and pollution have altered marine ecosystems and eroded their capacity to provide benefits, the researchers noted in their report.

Among the findings of the study:

  • Developed countries generally, but not always, scored higher than developing countries, usually due to better economies and regulation.
  • Only 5 percent of countries scored higher than 70, and 32 percent were below 50.
  • Biodiversity scores were surprisingly high, in part because few known marine species face outright extinction.
  • The U.S. received some of its best ratings for coastal protection and strong coastal livelihoods and economies.
  • Global food provision is far below its potential, and could be improved if wild-caught fisheries were more sustainably harvested, and sustainable marine aquaculture was increased.
  • Restoration of mangroves, salt marshes, coral reefs and seagrass beds could significantly improve ocean health by addressing multiple goals at once.
  • About half of the goals are getting worse, and this assessment could be overly optimistic if existing regulations are not effectively implemented.

Other primary authors of the report were from the University of California at Santa Barbara, Conservation International, the Union of Concerned Scientists, and the U.S. Commission on Ocean Policy. The work was led by the National Center for Ecological Analysis and Synthesis, and Conservation International.

The researchers said they hope the analysis will help inform public policy and management.

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“Selfish” DNA in animal mitochondria offers possible tool to study aging

The study this story is based on is available online: http://bit.ly/OLw6YY

CORVALLIS, Ore. – Researchers at Oregon State University have discovered, for the first time in any animal species, a type of “selfish” mitochondrial DNA that is actually hurting the organism and lessening its chance to survive – and bears a strong similarity to some damage done to human cells as they age.

The findings, just published in the journal PLoS One, are a biological oddity previously unknown in animals. But they may also provide an important new tool to study human aging, scientists said.

Such selfish mitochondrial DNA has been found before in plants, but not animals. In this case, the discovery was made almost by accident during some genetic research being done on a nematode, Caenorhabditis briggsaea type of small roundworm.

“We weren’t even looking for this when we found it, at first we thought it must be a laboratory error,” said Dee Denver, an OSU associate professor of zoology. “Selfish DNA is not supposed to be found in animals. But it could turn out to be fairly important as a new genetic model to study the type of mitochondrial decay that is associated with human aging.”

DNA is the material that holds the basic genetic code for living organisms, and through complex biological processes guides beneficial cellular functions. Some of it is also found in the mitochondria, or energy-producing “powerhouse” of cells, which at one point in evolution was separate from the other DNA.

The mitochondria generally act for the benefit of the cell, even though it is somewhat separate. But the “selfish” DNA found in some plant mitochondria – and now in animals – has major differences. It tends to copy itself faster than other DNA, has no function useful to the cell, and in some cases actually harms the cell. In plants, for instance, it can affect flowering and sometimes cause sterility.

“We had seen this DNA before in this nematode and knew it was harmful, but didn’t realize it was selfish,” said Katie Clark, an OSU postdoctoral fellow. “Worms with it had less offspring than those without, they had less muscle activity. It might suggest that natural selection doesn’t work very well in this species.”

That’s part of the general quandary of selfish DNA in general, the scientists said. If it doesn’t help the organism survive and reproduce, why hasn’t it disappeared as a result of evolutionary pressure? Its persistence, they say, is an example of how natural selection doesn’t always work, either at the organism or cellular level. Biological progress is not perfect.

In this case, the population sizes of the nematode may be too small to eliminate the selfish DNA, researchers said.

What’s also interesting, they say, is that the defects this selfish DNA cause in this roundworm are surprisingly similar to the decayed mitochondrial DNA that accumulates as one aspect of human aging. More of the selfish DNA is also found in the worms as they age.

Further study of these biological differences may help shed light on what can cause the mitochondrial dysfunction, Denver said, and give researchers a new tool with which to study the aging process.

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Roundworm with "selfish" DNA

Roundworm

Mechanism discovered for regulation of cell division

CORVALLIS, Ore. — Oregon State University scientists have revealed a new mechanism in the process of cell division. Their findings, reported today in the Journal of Biological Chemistry, add vital new details to one of the critical events in the life of a cell and could lead to novel treatments for human diseases from Alzheimer’s to cancer.

The study focused on three proteins that affect one of the central features of cell division, the mitotic spindle. One of the proteins, dynein, is a molecular motor that transports molecules during the development of the mitotic spindle and other structures in the cell. Two other proteins regulate dynein: dynactin, which is essential for linking dynein to other molecules; and NudE, whose depletion in experiments performed on mice produces a small brain and mental retardation.

“Protein molecules require a unique specific shape to recognize other proteins and do their biological function,” said Elisar Barbar, professor of biophysics at Oregon State and leader of the team that performed the research. “What is intriguing about the interplay of these three proteins is that the dynein segment that recognizes both dynactin and NudE does not have a specific shape. It belongs to a special class of proteins referred to as intrinsically disordered proteins. These proteins have multiple shapes and fluctuate quickly among them depending on alterations in environmental or cellular conditions.”

In work supported by the National Science Foundation and National Institutes of Health, the Barbar lab used a powerful tool ideally suited to reveal protein shapes, nuclear magnetic resonance spectroscopy, which can show multiple protein forms. The researchers used it to show that a segment of dynein changes shape depending on cellular conditions.

The shift in protein shapes has implications for the regulation of dynein and the formation of the mitotic spindle. The Barbar group found that the two dynein regulators bind to the same segment of dynein. However, dynactin binds to an additional disordered segment. By manipulating the length and chemical modification of this segment, one protein regulator can be selected over the other even when both are present in the same cellular compartment.

These results “offer a novel role for protein disorder in controlling cellular processes,” said Barbar.

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Elisar Barbar, 33 6 12 31 53 60 (in France until July 24), 49-6221-547102 (in Germany July 24 to August 4), 541-737-4143 (in Corvallis after August 4)

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