This image illustrates the new "colorimetric technique" developed by researchers at Florida Atlantic University to map four dimensions (4D) of brain data using EEG signals at once. Using this fourth dimension will dramatically change the way neuroscientists are able to understand how the brain operates, shedding insight on a number of psychiatric and neurological disorders and opening up new ways to study therapeutic interventions, in particular the effects of drugs.

Groundbreaking Technique Reveals Modus Operandi of the Intact Living Brain

Dynamical Theory and Novel 4D Colorimetric Method Reveal the Essential Modus Operandi of the Intact Living Brain--Study shows how areas in the brain integrate and segregate at the same time.

For the brain to achieve its intricate functions such as perception, action, attention and decision making, neural regions have to work together yet still retain their specialized roles. Excess or lack of timely coordination between brain areas lies at the core of a number of psychiatric and neurological disorders such as epilepsy, schizophrenia, autism, Parkinson’s disease, sleep disorders and depression. How the brain is coordinated is a complex and difficult problem in need of new theoretical insights as well as new methods of investigation. In groundbreaking research published in the January 2009 issue and featured on the cover of Progress in Neurobiology, researchers at Florida Atlantic University’s Center for Complex Systems and Brain Sciences in the Charles E. Schmidt College of Science propose a theoretical model of the brain’s coordination dynamics and apply a novel 4D colorimetric method to human neurophysiological data collected in the laboratory. The article, titled “Brain coordination dynamics: true and false faces of phase synchrony and metastability,” is co-authored by Drs. Emmanuelle Tognoli, an expert in neurophysiology and research assistant professor in the Center’s Human Brain and Behavior Laboratory, and J. A. Scott Kelso, the Glenwood and Martha Creech Eminent Scholar in Science and founder of the Center. The authors’ theory and data show that both tendencies co-occur in the brain and are essential for its normal function. Their research demonstrates that coordination involves a subtle kind of ballet in the brain, and like dancers, cortical areas are capable of coming together as an ensemble (integration) while still exhibiting a tendency to do their own thing (segregation).

“A lot of emphasis in neuroscience these days is on what the parts do,” said Kelso. “But understanding the coordination of multiple parts in a complex system such as the brain is a fundamental challenge. Using our approach, key predictions of cortical coordination dynamics can now be tested, thereby revealing the essential modus operandi of the intact living brain.”

Tognoli and Kelso developed a novel colorimetric technique that simultaneously maps four dimensions of brain data (magnitude, 2D of cortical surface and time) in order to capture true synchronization in electroencephalographic (EEG) signals. Because of the fourth dimension afforded by this colorimetric method, it is possible to observe and interpret oscillatory activity of the entire brain as it evolves in time, millisecond by millisecond. Moreover, the authors’ method applies to continuous non-averaged EEG data thereby de-emphasizing the notion of “an average brain.” The authors demonstrate that only in continuous EEG can real synchronization be sorted from false synchronization – a kind of synchronization that arises from the spread of electrical fields and volume conduction rather than from genuine interactions between brain areas.

Most of the time, activity from multiple brain areas look coordinated; however, in actuality, there is far less synchrony than what appears to be. With the support of mathematical models that reproduce the biases of real brain records in synthetic data, the authors show how to tell apart real and false episodes of synchronization. For the first time, true episodes of brain coordination can be spotted directly in EEG records and carefully analyzed.

In addition to shedding insight on the way the brain normally operates, Tognoli and Kelso’s research provides a much-needed framework to understand the coordination dynamics of brain areas in a variety of pathological conditions. Their approach allows a precise parsing of “brain states” and is likely to open up new ways to study therapeutic interventions, in particular the effects of drugs (pharmaco-dynamics). Their approach will also help improve the design of brain computer interfaces used to help people who are paralyzed.

“In the future, it may be possible to fluently read the processes of the brain from the EEG like one reads notes from a musical score,” said Tognoli. “Our technique is already providing a unique view on brain dynamics. It shows how activity grows and dies in individual brain areas and how multiple areas engage in and disengage from working together as a coordinated team.”

In addition to simple linear synchronization between brain areas, the authors describe more subtle modes of coordination during which areas may cooperate (integrate) and at the same time retain their functional specificity (segregation).

“This property of metastability falls out of our theory and is crucial for the brain,” said Kelso. “The brain is a complex nonlinear dynamical system, and it needs to coordinate the activity of diverse and remotely connected parts in order to extract and communicate meaningful information.”

Tognoli points out that subtle regimes of coordination are advantageous for the brain and are faster, more powerful and less energetically costly, thereby creating rich modes of interaction that surpass those of simple linear modes of coordination.

For a long time, scientists have strictly emphasized one kind of synchronization called ‘inphase’ or ‘zero-lag synchrony’ looking only at who is coordinated with whom and not observing the details of how they are coordinated. Through their research, Tognoli and Kelso have shown that the brain uses a much wider repertoire of synchronization patterns than just inphase. For example, brain areas may lock their oscillations together but keep a different phase.

This characteristic is also a key to the brain’s dynamic complexity. Areas may encode distinct information when they coordinate with one phase difference or another, and the brain may finely tune itself, such as in learning, by altering the lag at which its areas coordinate rather than just switching synchrony on and off. Such a brain would have a far greater combinatorial and computational power than the old model of the ‘inphase brain’. But to understand the principals at work, the lag or ‘relative phase’ between coupled oscillations in the brain needs to be systematically studied.

“This work lies at the intersection of neuroscience and complexity science,” said Dr. Gary Perry, dean of the Charles E. Schmidt College of Science. “Drs. Kelso and Tognoli have successfully developed the specific conceptual and methodological tools needed to capture and observe these important features in empirical data. Their unique approach and findings will help to shed light on some of world’s most debilitating and costly health disorders.”

The authors’ research is supported by the National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Science Foundation, U.S. Office of Naval Research and the Davimos Family Endowment for Excellence in Science.

- FAU -

Florida Atlantic University opened its doors in 1964 as the fifth public university in Florida. Today, the University serves more than 26,000 undergraduate and graduate students on seven campuses strategically located along 150 miles of Florida's southeastern coastline. Building on its rich tradition as a teaching university, with a world-class faculty, FAU hosts ten colleges: College of Architecture, Urban & Public Affairs, Dorothy F. Schmidt College of Arts & Letters, the Charles E. Schmidt College of Biomedical Science, the Barry Kaye College of Business, the College of Education, the College of Engineering & Computer Science, the Harriet L. Wilkes Honors College, the Graduate College, the Christine E. Lynn College of Nursing and the Charles E. Schmidt College of Science.

Frogs Are Being Eaten to Extinction

The global trade in frog legs for human consumption is threatening their extinction, according to a new study by an international team including University of Adelaide researchers.

The researchers say the global pattern of harvesting and decline of wild populations of frogs appears to be following the same path set by overexploitation of the seas and subsequent “chain reaction” of fisheries collapses around the world.

The researchers have called for mandatory certification of frog harvests to improve monitoring and help the development of sustainable harvest strategies.

University of Adelaide ecologist Associate Professor Corey Bradshaw says frogs legs are not just a French delicacy.

“Frogs legs are on the menu at school cafeterias in Europe, market stalls and dinner tables across Asia to high end restaurants throughout the world,” says Associate Professor Bradshaw, from the University’s School of Earth and Environmental Sciences and also employed as a Senior Scientist by the South Australian Research and Development Institute (SARDI).

“Amphibians are already the most threatened animal group yet assessed because of disease, habitat loss and climate change - man’s massive appetite for their legs is not helping.”

The annual global trade in frogs for human consumption has increased over the past 20 years with at least 200 million and maybe over 1 billion frogs consumed every year. Only a fraction of the total trade is assessed in world trade figures.

Indonesia is the largest exporter of frogs by far and its domestic market is 2-7 times that.

“The frogs’ legs global market has shifted from seasonal harvest for local consumption to year-round international trade,” says Associate Professor Bradshaw. “But harvesting seems to be following the same pattern for frogs as with marine fisheries - initial local collapses in Europe and North America followed by population declines in India and Bangladesh and now potentially in Indonesia.

“Absence of essential data to monitor and manage the wild harvest is a large concern.”

The study team also includes researchers from the Memorial University of Newfoundland in Canada, the National University of Singapore and Harvard University. A paper about the study is soon to be published online in the journal Conservation Biology.

Small Molecule Triggers Bacterial Community

While bacterial cells tend to be rather solitary individuals, they are also known to form intricately structured communities called biofilms. But until now, no one has known the mechanisms that cause isolated bacteria to suddenly aggregate into a social network. New insights from the lab of Harvard Medical School microbial geneticist Roberto Kolter reveal previously unknown communication pathways that cause such social phenomenon.

Using the non-pathogenic Bacillus subtilis as a model organism, Kolter and postdoctoral researcher Daniel Lopez discovered a group of natural, soil-based products that trigger communal behavior in bacteria. One molecule in particular, surfactin, is produced by B. subtilis. Biofilm formation begins when surfactin, and other similar molecules, cause bacteria to leak potassium. As potassium levels decline, a membrane protein on the bacterium stimulates a cascade of gene activity that signals neighboring cells to form a quorum. As a result, biofilms form.

The authors note that it’s still unclear how biofilm formation benefits the bacteria, and they hypothesize that it might be an antibacterial defense against competing species. Still, the notion that a single small molecule can induce multicellularity intrigues the researchers.

“Typically, scientists try to discover new antibiotics through some rather blunt means, like simply looking to see if one bacterium can kill another,” says Kolter. “This discovery of a single molecule causing such a dramatic response in bacteria hints at a new and potentially effective way to possibly discover antibiotics.”

These findings are published in the Proceedings of the National Academy of Sciences.

Spinning Spigots: 'Missing Link' in Spider Evolution Discovered

New interpretations of fossils have revealed an ancient missing link between today’s spiders and their long-extinct ancestors. The research by scientists at the University of Kansas and at Virginia’s Hampden-Sydney College may help explain how spiders came to weave webs.

The research focuses on fossil animals called Attercopus fimbriunguis. While modern spiders make silk threads with modified appendages called spinnerets, the fossil animals wove broad sheets of silk from spigots on plates attached to the underside of their bodies. Unlike spiders, they had long tails.

The research findings by Paul Selden, Gulf-Hedberg Distinguished Professor of Invertebrate Paleontology at KU and William Shear, Trinkle Professor of Biology at Hampden-Sydney College, were published this week in the Proceedings of the National Academy of Sciences.

Selden and Shear first discovered the fossils almost 20 years ago. At that time the specimens were thought to be the oldest spider fossils known, dating back to the Devonian Period, about 380 million years ago. Unearthed in upstate New York, the fossils were among the first animals to live on land in North America.

New finds near the same location, in Gilboa, New York, caused the paleontologists to reinterpret their original findings. The new fossils included silk-spinning organs, called spigots, arranged on the edges of broad plates making up the undersides of the animals. The researchers identified parts of a long, jointed tail not found in any previously known spider, but common among some of the spiders’ more primitive relatives.

“We think these ‘tailed spiders’ represent an entirely new kind of animal, not known before from living or fossil examples.” Shear said. “They were more primitive than spiders in many ways, and may be spider ancestors.” Besides having tails and spinning silk from broad plates, the animals also seem to lack poison glands.

Selden added, “This new information also allows us to reinterpret other fossils once thought to be spiders, and this evidence suggests these Uraraneida, or pre-spiders, existed for more than 100 million years, living alongside real spiders, which evolved later.”

The paleontologists think that Attercopus developed silk-spinning spigots in order to line burrows, make homing trails, and possibly to subdue prey, but were not capable of making webs because of the limited mobility of the spigots. True spiders may have arisen when the genetic information for certain appendages was “turned back on” and the spigots moved onto them. The appendages became the modern spiders’ spinnerets, which can move freely and create patterned webs.
Selden is director of the KU Paleontological Institute at the Biodiversity Institute, one of eight designated research centers on campus that report to the KU Office of Research and Graduate Studies.

Discovery: New Tooth Cavity Protection

Clarkson University Center for Advanced Materials Processing Professor Igor Sokolov and graduate student Ravi M. Gaikwad have discovered a new method of protecting teeth from cavities by ultrafine polishing with silica nanoparticles.

The researchers adopted polishing technology used in the semiconductor industry (chemical mechanical planarization) to polish the surface of human teeth down to nanoscale roughness. Roughness left on the tooth after the polishing is just a few nanometers, which is one-billionth of a meter or about 100,000 times smaller than a grain of sand.

Sokolov and Gaikwad showed that teeth polished in this way become too “slippery” for the "bad" bacteria that is responsible for the destruction of dental enamel. As a result the bacteria can be removed fairly easily before they cause damage to the enamel.

Although silica particles have been used before for tooth polishing, polishing with nanosized particles has not been reported. The researchers hypothesized that such polishing may protect tooth surfaces against the damage caused by cariogenic bacteria, because the bacteria can be removed easily from such polished surfaces.

The Clarkson researchers' findings were published in the October issue of the Journal of Dental Research, the dentistry journal with the top worldwide scientific impact index.

Sokolov is a professor of physics, professor of chemical and biomolecular science, and director of Clarkson's Nanoengineering and Biotechnology Laboratories Center (NABLAB). Gaikwad is a graduate student in physics.

Read more at http://jdr.iadrjournals.org/cgi/content/short/87/10/980.

Selenium, Vitamin E Do Not Prevent Prostate Cancer

Findings from one of the largest cancer chemoprevention trials ever conducted have concluded that selenium and vitamin E taken alone or in combination for an average of five and a half years did not prevent prostate cancer, according to a team of researchers coordinated by the Southwest Oncology Group (SWOG) and led by scientists at The University of Texas M. D. Anderson Cancer Center and Cleveland Clinic.

Data and analysis gathered through Oct. 23, 2008, from the Selenium and Vitamin E Cancer Prevention Trial (SELECT) were published in the Dec. 9 issue of the Journal of the American Medical Association (JAMA) by Scott M. Lippman, M.D., professor and chair of Thoracic/Head and Neck Medical Oncology at M. D. Anderson, Eric A. Klein, M.D., of the Cleveland Clinic Lerner College of Medicine, and 30 coauthors from the United States, Puerto Rico and Canada.

Funded by the National Cancer Institute (NCI) with some additional contribution from the National Center for Complementary and Alternative Medicine, the Phase III trial began recruitment in August 2001 and aimed to determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases in relatively healthy men. The study followed 35,533 participants from 427 sites in the United States, Canada and Puerto Rico. The randomized, placebo-controlled and double-blind trial divided the participants into four intervention groups: selenium, vitamin E, both selenium and vitamin E, and placebos.

Supplement Cases 5-year prostate cancer diagnosis
Placebo 416 4.43 percent
Selenium 432 4.56 percent
Vitamin E 473 4.93 percent
Selenium + Vitamin E 437 4.56 percent



The study found no evidence of benefit from selenium, vitamin E, or both. Additionally, the data showed two statistically non-significant findings of concern: slightly increased risks of prostate cancer in the vitamin E group and type two diabetes mellitus in the selenium group. Both trends may be due to chance and were not observed in the group taking selenium and vitamin E together.

An independent data and safety monitoring committee reached the same conclusion and recommended supplementation be discontinued Oct. 23 for lack of evidence of benefit.

"SELECT presented a unique opportunity to improve the lives of men from every social and ethnic background through chemoprevention," said Lippman, who serves as a national study coordinator. "Although supplementation has been discontinued, we will continue to follow these men and monitor their health for approximately three more years, conducting regular prostate screening tests and questioning them about diabetes and other health issues. Doing so is critical not only to determine any possible long-term effects of the selenium and vitamin E, but also in order to gain a better understanding of prostate and other cancers and age-related disease."

Prostate cancer is the most common male cancer in the U.S. and the second leading cause of cancer deaths overall. The American Cancer Society estimates that more than 180,000 American men will be diagnosed with prostate cancer this year and nearly 29,000 will die from the disease. African-American men have a 60 percent higher incidence rate of prostate cancer and are two times more likely to die from the disease compared with Caucasian men.

Elise Cook, M.D., an associate professor in M. D. Anderson's Department of Clinical Cancer Prevention and the location's principal investigator, served as the chair of SELECT's Minority and Medically Underserved Subcommittee. "Our site has placed a strong emphasis on recruiting African-American men to participate. Of the 387 men we follow, 101 of those are African-American. It is important we continue to follow these men to determine long-term effects and complete the ancillary studies in which many participate," said Cook.

SELECT was based upon the secondary outcomes from two previous cancer prevention trials. The first, a 1996 study of selenium versus placebo to prevent non-melanoma skin cancer, showed that although the supplement did not reduce the risk of skin cancer, selenium did reduce prostate cancer by two-thirds; and in the second, a 1998 study conducted by Finnish researchers determined that although vitamin E did not prevent lung cancer in more than 29,000 male smokers, it did result in 32 percent fewer prostate cancers in men taking the supplement.

"Preliminary data suggesting benefits - no matter how promising - cannot reliably result in new clinical recommendations until they've been tested in definitive trials," said Ernest T. Hawk, M.D., vice president and division head of M. D. Anderson's Cancer Prevention and Population Sciences.

Although the SELECT trial did not turn out as we'd hoped - identifying a new way to reduce men's risk of prostate cancer - it was nevertheless extremely valuable by generating definitive evidence. Cancer prevention advances by rigorous science."

Identity of SELECT participants will remain blinded to prevent the introduction of any unintentional bias, however, they may be unblinded upon request. The sub-studies, funded and conducted by the National Institutes of Health's National Heart, Lung and Blood Institute, the National Institute of Aging, the National Eye Institute and the NCI, will continue without the participants taking any supplementation. These ancillary studies were evaluating the effects of selenium and vitamin E on chronic obstructive pulmonary disease, the development of Alzheimer's disease, the development of age-related macular degeneration and cataracts, and the development of colon polyps.

Lippman commented, "We are grateful to each of the 387 Houston-area men who committed to participating in this study through M. D. Anderson. Prevention trials are an important direction for the future of cancer research. SELECT played an important role in the study of the prevention of prostate cancer and we hope to learn more about why these supplements didn't do more to prevent prostate cancer as the study continues."

Co-authors with Lippman, Klein and Cook include 30 colleagues from the Southwest Oncology Group.



About M. D. Anderson
The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 41 Comprehensive Cancer Centers designated by the National Cancer Institute. For four of the past six years, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News and World Report.

Researchers Test Mobile Alert System for Cell Phones
In the first field trial of its kind, Georgia Tech’s Wireless Emergency Communications project tested the Federal Communications Commission’s (FCC) Commercial Mobil Alert System to see how well it met the needs of people with vision and hearing impairments. They found three areas where they will recommend changes to the FCC.

• Although 90 percent of participants who are blind or have low vision found the alert attention signal to be loud enough and long enough to get their attention, only 70 percent of deaf and hard of hearing participants indicated the same regarding the vibrating cadence. Comments regarding the vibrating cadence suggested that it would only be effective if the individual were holding the phone in their hand, but easily missed if in a purse or even in one’s pocket.

• All hearing participants expressed concern that the early part of the message was missed because the tone went too quickly into the 90-character spoken alert, causing the first few words of the message to be missed. The required Commercial Mobile Alert System message format places the event type first (i.e., tornado, flood, etc.) so crucial information may not be heard by blind consumers using text-to-speech software on their mobile phones to access the alerts. Many suggested the need for a header such as “This is a…” to allow for more clarity. Such a header is currently employed by the Emergency Alert System (EAS) messages broadcast on television, radio and cable systems.

• Deaf and hard of hearing participants commented that they would like to see enhancements such as strobe lights, screen flashes and stronger vibrating cadences. While these enhancements can be addressed by cell phone manufacturers, they aren’t required to do so by the FCC.

The tests were conducted on November 12, 2008, with 30 subjects. The results will be presented to the FCC and others during the State of Technology conference in September.

The FCC established the Commercial Mobile Alert System in 2008 to provide a framework for commercial mobile service providers to voluntarily transmit emergency alerts to their subscribers. The Rehabilitation Engineering Research Center for Wireless Technologies’ Wireless Emergency Communications project has been developing software and conducting field tests on how to make the emergency alert system accessible for people with sensory disabilities who use mobile devices.

Tech’s Wireless Emergency Communications project received additional federal funding to field test the provisions of Commercial Mobile Alert System that affect accessibility, such as the limitation of 90 characters, not permitting URLs, and volume limits including specific vibrating cadences and alert tones. By conducting this field test, they will provide the FCC and the wireless industry with concrete evidence from the perspective of end-users on how the Commercial Mobile Alert System would be better able to serve the specific needs of people with sensory disabilities. Most recommendations, however, would render the system more effective for all consumers. For example, participants suggested repeating the attention signal and vibrating cadences in intervals until they are shut off by the user to ensure the receipt of the alert by an individual who is away from their phone, asleep, driving or unable to hear or see.

The field test recruited participants from the Atlanta Area School for the Deaf, Atlanta Public School System, the Wireless Rehabilitation Engineering Research Center Consumer Advisory Network and the Georgia Radio Reading Service (GaRRS). Subjects were as diverse in their sensory limitations as they were in their technical skill level, ranging from those who were fully deaf or fully blind to those with enhanced hearing (hearing aid/cochlear implants) or enhanced vision (glasses/contacts).

Though field test participant’s names are usually held in the strictest confidence, one participant agreed to go on the record.

“I applaud PBA and Georgia Tech for their effort in bringing this very important issue to the public,” said Georgia State Representative Bob Smith. “We must continue to make this a priority, to seek innovative and creative ways to notify people with disabilities and tirelessly work to improve and perfect the notification system. It is paramount that Georgians are aware that people with various disabilities, more than any time in our history, need to be informed of catastrophic events.”

This is the second field test hosted by project partner Public Broadcasting Atlanta. PBA recognized the importance of this community project and how it aligned with its vision of implementing a Local Education Network System (LENS) capable of convening individuals, organizations and communities. MetroCast Atlanta, a component of LENS, would serve as an emergency information network for schools, city officials and citizens in the event of natural or terrorist disaster.

The mobile devices and cellular service used in this field test were the result of a generous donation from WEC industry partner AT&T. For more information on WEC, go to www.wirelessrerc.org. Funding for the CMAS parameter field test was made possible by the U.S. Department of Education’s National Institute on Disability and Rehabilitation Research, grant # H133E060061.

A balancing act : Aging and Alzheimer’s disease

Cognitive decline may occur during aging, or due to genetic mutations that predispose individuals to develop Alzheimer’s disease. Now, a team of scientists, led by Akihiko Takashima at the RIKEN Brain Science Institute in Wako, has found support for their hypothesis that a similar molecular abnormality could account for cognitive dysfunction during both Alzheimer’s disease and aging. They report their findings in a recent issue of PLoS ONE (1).

The researchers subjected aged mice (19–25 months) and adult mice (9–15 months) harboring genetic mutations associated with Alzheimer’s disease to a test of spatial memory—the Morris water maze. Both groups of mice were trained to find a platform submerged in a pool of water based on visual cues around the pool (Fig. 1). When this training period was complete, the researchers could assess how well the mice remembered the platform location by determining how much time the mouse spends near the platform during a ‘probe trial’. They found that both the aged mice and the mice with the Alzheimer’s disease mutations had spatial memory deficits.

The neurotransmitter GABA (γ-aminobutyric acid) controls inhibitory signaling in the brain, and GABA receptor blockers have previously been shown to improve cognition in aging rats. To see if this was also true in Alzheimer mutant mice, the researchers administered a GABA receptor blocker, and saw restoration of normal spatial memory in the Morris water maze. The treated mice were also better at recognizing a new object placed into their cage, which is a measure of ‘declarative memory’.

The researchers then examined synaptic plasticity in a part of the brain that plays a role in spatial memory—the hippocampus. They found deficits in synaptic plasticity in hippocampal slices from both aging and Alzheimer mutant mice. However, normal synaptic plasticity could be restored by adding a GABA receptor blocker. This suggests that both aging and Alzheimer’s disease mutations may affect memory by increasing GABA-mediated inhibitory signaling in the hippocampus.

These findings show that GABA receptor blockers may be an effective therapeutic strategy to enhance cognitive function during both aging and Alzheimer’s disease. This work also indicates that an imbalance between excitatory and inhibitory signaling in the brain may result in memory dysfunction. Yuji Yoshiike, the study’s first author, says the findings suggest that “even when memory declines because of the accumulation of neurotoxic molecules during aging, memory may be improved by restoring the balance between synaptic excitation and inhibition.”

Reference

1. Yoshiike, Y., Kimura, T., Yamashita, S., Furudate, H., Mizoroki, T., Murayama, M. & Takashima, A. GABAA receptor-mediated acceleration of aging-associated memory decline in APP/PS1 mice and its pharmacological treatment by picrotoxin. PLoS ONE 3, e3029 (2008).

Bringing Galatea to life

Inflammation is a key step in the progression of heterotopic ossification – where soft tissue turns into bone – according to research. The study shows that an inhibitor of the disease gene’s protein product is partially therapeutic, and therefore offers hope for this devastating condition.

In a reverse of the ancient myth of Pygmalion, where a statue comes to life, sufferers of heterotopic ossification have their fibrous tissue ‘ossified’ — in effect, turning the patients into statues. A major form of heterotopic ossification is fibrodysplasia ossificans progressiva (FOP), which in about 98% of cases results from a mutation in a specific bone morphogenetic protein receptor.

A mouse model of FOP involving the same mutation found in people has yet to be made, but Paul Yu and colleagues have now developed a mouse model of the general phenomenon by expressing a related version of the mutated receptor. They found that just expressing the mutant version of the protein receptor was not sufficient to cause the disease – an inflammatory stimulus was also needed. Yu’s team also show that inhibiting inflammation with glucocorticoids—a treatment commonly used in the clinic—helps reduce the incidence of heterotopic ossification in their model.

Importantly, the authors also show that a small molecule inhibitor of the protein receptor likewise reduced the incidence of disease progression. This form of treatment represents a potential breakthrough, as long-term use of glucocorticoids causes severe side-effects. The authors caution, however, that much more research is needed before the drug could be considered for human trials.

Author contact:
Paul Yu (Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA)
Tel: +1 617 643 3493; E-mail: pbyu@partners.org

Cell Phone/Brain Tumor Connection Remains Inconclusive – But They Pose Neurological Health Risks
There has been much speculation over the last few years about whether cell phones increase the risk of developing a brain tumor. Research has not conclusively answered this question, which has left consumers confused. The majority of studies that have been published in scientific journals do not have sufficient evidence to show that cell phones increase the risk of brain tumors. The problem is that cell phone technology is in its infancy, so none of these studies could analyze long-term risks. This unknown is a particular issue for children, who will face a lifetime of cell phone usage. While the cell phone/brain tumor connection remains inconclusive, the American Association of Neurological Surgeons (AANS) cautions that cell phones present plenty of other risks to people’s neurological health.

Several studies show cell phones are a leading cause of automobile crashes. It is estimated that drivers distracted by cell phones are four times more likely to be in a motor vehicle accident. The following are some sobering statistics:

~According to a Harvard University study, an estimated 2,600 people die and 12,000 suffer serious to moderate injuries each year in cell phone-related accidents.
~A Canadian study analysis of 26,798 cell phone calls made during the 14-month study period showed that the risk of an automobile accident was four times higher when using a cell phone.
~National statistics indicate that an estimated 50,000 traumatic brain injury-related deaths occur annually in the United States, 25,000-35,000 of which are attributed to motor vehicle accidents.

A few recent cases treated in U.S. hospital emergency rooms:

~A 29-year-old male was talking on his cell phone while on an escalator, fell backwards, and lacerated his head.
~A 25-year-old male was talking on his cell phone and walked into a street sign, lacerating his head.
~A 43-year-old female fell down 13-14 steps while talking on her cell phone, after drinking alcohol. She suffered a neck sprain and contusions to her head, back, shoulder, and leg.
~A 50-year-old female suffered nerve damage which was related to extensive cell phone usage. She felt pain in her fingers and the length of her arm while holding her cell phone, and was diagnosed with cervical radiculopathy.
~A 39-year-old man suffered a head injury after crashing into a tree on his bicycle while texting
~A 16-year-old boy suffered a concussion because he was texting and walked into a telephone pole.

Cell Phone Injury Prevention Tips

~Talk hands free by using an earpiece or on speaker mode whenever possible.
~Follow all cell phone laws applicable to your city and state – these vary greatly.
~Use your cell phone only when safely parked, or have a passenger use it.
~Do not dial the phone or take notes while driving, cycling, skateboarding, rollerblading, etc.
~Never text message while driving, walking, cycling, skateboarding, rollerblading, etc.
~Never text message or use a cell phone while performing any physical activities that require attention.
~If your phone rings while driving, let the call go into voice mail and respond later when you are safely parked.

Mathematics Students Make Prime Discovery
Westfield State College senior mathematics majors Jeffrey P. Vanasse and Michael E. Guenette, working under the direction of Mathematics Department faculty members Marcus Jaiclin and Julian F. Fleron, have made a significant new discovery in the mathematical field of number theory. They have discovered the first known example of a 3 by 3 by 3 generalized arithmetic progression (GAP).

Most easily thought of as a 3 by 3 by 3 cube (similar to a Rubik’s cube puzzle) made up of 27 primes, their discovery begins with 929 as its smallest prime ends with 27917 as its largest prime. The intervening 25 primes are constructed by adding combinations of the numbers 2904, 3150, and 7440 in an appropriately structured method.

“Such an object was known to exist and its approximate size had been loosely estimated,” Fleron said. “However, a blind search would require checking more cases than can be feasibly checked by all existing modern computers each running for the next million years. Instead, the group used knowledge of the structural relationships between the potential candidates to greatly reduce the potential candidates to be checked.”

An algorithm to check the necessary cases – still easily hundreds of trillions of cases – was programmed using a Linux version of the computer language C++.

“This breakthrough is another indication that our Mathematics Department is working on a world-class level,” said Evan S. Dobelle, president of Westfield State College. “The college is very proud of these students and their professors for taking the initiative to practice cutting-edge mathematics.”

“We were worried that it might take months to run based on our estimates,” Guenette said. “Yet initial tests showed the algorithm running at a hopeful speed.”

“We were always optimistic, but the first tests got us really excited that our method would be successful,” Vanasse said.

The team broke the search up into groups of cases for each of the researchers to run on separate computers. Within days the first known example of a 3 by 3 by 3 GAP was found – one with largest prime of 197,957.

Having succeeded in finding the first known example, and now having a strict bound on the size of the largest prime, the group set to work finding other 3 by 3 by 3 GAPs – in particular, the smallest such. They were successful, showing there are exactly three 3 by 3 by 3 GAPs of primes with largest prime less than 50,000, the smallest example being that described above.

The students and faculty members are hopeful that their work will aid number theorists who continue to work on elusive patterns that lurk within the mystery of the prime numbers.

With estimates for the largest prime in a 4 by 4 by 4 or 3 by 3 by 3 by 3 GAP being near 5 quadrillion (that’s a 5 followed by 15 zeroes) the group is fairly certain that their record for finding the highest dimensional GAP will stand for quite some time, Fleron said.

Guenette of Easthampton, Mass., and Vanasse of Chicopee, Mass., both plan on attending graduate school in mathematics following graduation. Their work on this problem has provided them with a valuable introduction to the efforts of a working research mathematician.

For Jaiclin and Fleron, and the rest of the Westfield State Mathematics Department, it is another opportunity to share with and involve undergraduates what they love best: doing significant mathematics and advancing the frontier of human knowledge.

Fleron said the team’s work was inspired by the recent discoveries of the young Australian mathematician Terence Chi-Shen Tao, now a professor at the University of California, Los Angeles. “Many prominent number theorists are working simply to understand the implications of these discoveries,” he said. “Now Westfield State College students are playing a role, as well.”

British mathematician Andrew Granville, now on the faculty of the Université de Montréal, also inspired the group. Granville’s paper, “Prime Number Patterns,” was published in the April edition of American Mathematical Monthly.

Ironically, Granville just gave a lecture on “Patterns in the Primes” as part of the Distinguished Lecture Series of the Mathematical Association of America (MAA). This series, sponsored by the National Security Agency, took place at the MAA Carriage House Conference Center in Washington D.C. on Thursday, Nov. 13. This was the day before the Westfield State group’s discovery.

Simple Chemical Procedure Augments Therapeutic Potential of Stem Cells

Adult stem cells resemble couch potatoes if they hang out and divide in a dish for too long. They get fat and lose key surface proteins, which interferes with their movement and reduces their therapeutic potential. Now, via a simple chemical procedure, researchers have found a way to get these cells off the couch and over to their therapeutic target.

To do this, they simply added a molecule called SLeX to the surface of the cells. The procedure took just 45 minutes and restored an important biological function.

“Delivery remains one of the biggest hurdles to stem cell therapy,” explains senior author Jeffrey Karp, an instructor at the Harvard-MIT Division of Health Sciences and Technology. “The blood stream offers a natural delivery vehicle, but stem cells don’t move through blood vessels normally after being expanded in culture. Our procedure promises to overcome this obstacle.”

These findings will be published online in the journal Bioconjugate Chemistry on Oct. 31.

In order for cells injected into the blood stream to be therapeutically useful, they need to take initiative to reach target tissues. But instead, cultured stem cells go with the flow. They move through the body quickly, carried by the current, which means they seldom contact the sides of blood vessels. Thus, they have fewer opportunities to escape into the surrounding tissue by squeezing between cells of the vessel wall. Adult stem cells must escape before they can colonize surrounding tissue and rebuild damaged structures.

In February of 2008, HMS associate professor Robert Sackstein (at Brigham and Women’s Hospital) and colleagues showed they could correct this problem by adding a particular molecule to the surface of adult stem cells. This molecule—a cousin of SLeX—formed temporary connections with proteins on the blood vessel wall, serving as a kind of weak tape. But Sackstein’s method involved enzymes, which made the chemistry complicated. Karp’s team achieved the same result without enzymes.

Karp lab postdoc Debanjan Sarkar simply flooded a dish of cells with three molecules—biotin, streptavidin, and SLeX—one after the other. The biotin and streptavidin anchored SLeX to the cell surface. Sarkar tweaked the concentrations of each molecule to maximize the cell’s ability to roll along the interior of the blood vessel, rather than getting lost in the flow. He also confirmed that the altered cells were still viable.

“The method is very simple,” says Sarkar, who is first author on the paper. “Plus, biotin and streptavidin work with many molecules, so labs can use this universal anchor we discovered to tackle other problems. They’re not limited to sticking SLeX on cells.”

The team worked with human cells extracted from the bone marrow. The cultures included mesenchymal stem cells (MSCs), which can form fat cells, cartilage, bone, tendon and ligaments, muscle cells, and even nerve cells. When injected into the bloodstream of patients, MSCs can home to the site of an injury and replace damaged tissue. But just a fraction of cultured MSCs currently reach their target in clinical trials. Karp’s procedure might improve their homing abilities.

Karp cautions that his lab’s discovery must be validated in animals, before doctors can apply it in the clinic. He’s collaborating with another lab to test the homing ability of the SLeX-dotted cells in mice.

“We need to confirm that this rolling behavior translates into increased homing and tissue repair,” explains Karp. “We may need to tweak the cells further.”

“This is definitely an approach that should be tried,” adds Pamela Robey, chief of the Craniofacial and Skeletal Diseases Branch of the National Institute of Dental and Craniofacial Research. Robey is working to reconstruct three-dimensional tissues with MSCs. “Jeff hasn’t tested the altered MSCs inside animals, and that’s really the gold-standard, but his in vitro data looks promising.”

This research is supported by Brigham and Women’s Hospital. The authors report no conflicts of interest.


The Harvard-MIT Division of Health Sciences and Technology (HST) brings together the Massachusetts Institute of Technology (MIT), Harvard Medical School (HMS), Harvard University, the Boston area teaching hospitals and an assortment of research centers in a unique collaboration that integrates science, medicine and engineering to solve problems in human health.

World's Rarest Big Cat Gets a Check-Up

The world’s rarest big cat is alive and well. At least one of them, that is, according to researchers from the Wildlife Conservation Society (WCS) who captured and released a female Far Eastern leopard in Russia last week.

The capture was made in Primorsky Krai along the Russian-Chinese border by a team of scientists from WCS and the Russian Academy of Sciences Institute of Biology and Soils (IBS). The team is evaluating the health and potential effects of inbreeding for this tiny population, which experts believe contains no more than 10-15 females. Other collaborators include: Wildlife Vets International, National Cancer Institute, and the Zoological Society of London.

The Far Eastern leopard is perhaps the world’s most endangered big cat, with an estimated 25-40 individuals inhabiting a narrow strip of land in the far southeastern corner of the Russian Federation.

The leopardess, nicknamed “Alyona” by the researchers who captured her, was in good physical condition, weighing a healthy 85 pounds (39 kilograms). A preliminary health analysis revealed that she is he is believed to be between 8-10 years old. The animal has since been released unharmed.

Specialists are continuing to analyze blood samples as well as an electrocardiogram, which will reveal genetic information to assess levels of inbreeding. Three leopards captured previously (2 males and 1 female) in 2006 and 2007 all exhibited significant heart murmurs, which may reflect genetic disorders.

“We are excited by the capture, and are hopeful that ongoing analysis of biomedical information will confirm that this individual is in good health,” said Alexey Kostyria, Ph.D., senior scientist at IBS and manager for the WCS-IBS project. “This research is critical for conservation of the Far Eastern leopard, as it will help us to determine the risks posed by inbreeding and what we can do to mitigate them.”

One of the options scientists are considering is trans-locating leopards from other areas to increase genetic diversity -- similar to what happened with Florida panthers when animals from Texas were brought in to supplement the remaining population. Today, Florida panthers have risen from less than ten individuals to a population of approximately 100.

The leopard capture and release was overseen by representatives of the Russian federal agency “Inspection Tiger,” a special department of the Ministry of Natural Resources.

“This project has been ongoing for just over two years, and scientific work to capture Amur tigers and Far Eastern leopards in this part of Primorsky Krai has always been distinguished by the participation of world-class specialists and use of the best equipment and methodologies,” said Sergei Zubtsov, the head of Inspection Tiger. “I want to note that the leopard captured for medical analysis and released represents another achievement for this highly-qualified team, and that one of the most important things is that she was not harmed at any point in the capture process. I hope that such fruitful collaboration will continue in the future.”

Over the last 100 years, Far Eastern leopard numbers have been reduced by poaching combined with habitat loss. However, both camera-trapping and snow-tracking surveys indicate that the population has been stable for the last 30 years, but with a high rate of turnover of individuals. If inbreeding or disease can be kept in check, WCS and its partners believe there is great potential for increasing survival rates and habitat recovery in both Russia and Northeast China.

The Wildlife Conservation Society’s work to protect Far Eastern leopards receives funding by the following U.S. government agencies: U.S. Fish & Wildlife Service’s Rhinoceros and Tiger Conservation Fund, National Fish and Wildlife Foundation’s Save the Tiger Fund, and U.S. Forest Service International Program.

The Far Eastern leopard is listed under CITES (Convention on International Trade in Endangered Species), which protects it against illegal trade for fur and medicinal purposes.

Around the world, large carnivores are faced with a variety of threats including habitat loss, depletion of prey, conflicts with people, poaching, and disease. The U.S. Congress is currently considering legislation called the Great Cats and Rare Canids Act, which would directly benefit the Far Eastern leopard and over a dozen big cat and rare dog species by creating a fund for research and monitoring, law enforcement training, and other conservation efforts. This bill has received support from several leaders in the U.S. Congress – notably Senators Joe Lieberman (CT-I), Barbara Boxer (CA-D) and Sam Brownback (KS-R) and Representatives Tom Udall (NM-D), John Tanner (TN-D), Hal Rogers (KY-R) and Ed Royce (CA-R). Timely action by the U.S. Senate would ensure passage of this important legislation.

Landmark Study Unlocks Stem Cell, DNA Secrets to Speed Therapies

In a groundbreaking study led by an eminent molecular biologist at Florida State University, researchers have discovered that as embryonic stem cells turn into different cell types, there are dramatic corresponding changes to the order in which DNA is replicated and reorganized.

The findings bridge a critical knowledge gap for stem cell biologists, enabling them to better understand the enormously complex process by which DNA is repackaged during differentiation -- when embryonic stem cells, jacks of all cellular trades, lose their anything-goes attitude and become masters of specialized functions.

As a result, scientists now are one significant step closer to the central goal of stem cell therapy, which is to successfully convert adult tissue back to an embryo-like state so that it can be used to regenerate or replace damaged tissue. Such therapies hold out hope of treatments or cures for cancer, Parkinson’s disease, multiple sclerosis, spinal cord injuries and a host of other devastating disorders.

Using mouse and human embryonic stem cells, FSU researchers employed advanced imaging techniques and state-of-the-art genomics technology to demonstrate, with unprecedented resolution along long stretches of chromosomes, which sequences are replicated first, and which occur later in the process of differentiation.

“Understanding how replication works during embryonic stem cell differentiation gives us a molecular handle on how information is packaged in different types of cells in manners characteristic to each cell type,” said David M. Gilbert, the study’s principal investigator. “That handle will help us reverse the process in order to engineer different types of cells for use in disease therapies.” Internationally renowned for his body of cutting-edge research on chromosomal structure and reproduction that he began as a doctoral student at Stanford University in the 1980’s, Gilbert joined the FSU faculty and was appointed as the first J. Herbert Taylor Distinguished Professor of Molecular Biology in 2006.

Results from the FSU study, which includes contributions from researchers at three other institutions, are described in a paper published in the October 7, 2008, edition of PLoS (Public Library of Science) Biology, a peer-reviewed journal that showcases biological science research of exceptional significance. So prodigious were the findings that the current paper -- “Global Reorganization of Replication Domains During Embryonic Stem Cell Differentiation” -- is focused solely on results observed in the mouse embryonic stems cells; data on the human cells will be detailed in a future report.

“We know that all the information (DNA) required to take on the identity of any tissue type is present in every cell, because we already can, albeit very inefficiently, create whole animals from adult tissue through cloning,” Gilbert said. “We also can make a kind of artificial embryonic stem cells, called induced pluripotent stem cells, out of many adult cell types, but there are two major hurdles remaining. First, the methods currently used rely on the unnatural retroviral insertion of genes into patients’ cells, and these genes are capable of forming tumors. Second, this method is very inefficient as well because only one in 1,000 cells into which the genes are inserted becomes pluripotent. We must learn how cells lose pluripotency in the first place so we can do a better job of reversing the process without risks to patients.

“The challenge is, adult cells are highly specialized and over the course of their family history over many generations they’ve made decisions to be certain cell types rather than others,” he said. “In doing so, they have tucked away the information they no longer need on how to become other cell types. Hence, all cells contain the same genetic information in their DNA, but during differentiation they package it with proteins into ‘chromatin’ in characteristic ways that define each cell type. The rules that determine how cells package DNA are complicated and have been difficult for scientists to decipher.”

But, Gilbert noted, one time that the cell “shows its cards” is during DNA replication.

“During this process, which was the focus of our FSU research, it’s not just the DNA that replicates,” he said. “All the packaging must be replicated as well in each cell division cycle.”

He explained that embryonic stem cells have many more, smaller “domains” of organization than differentiated cells, and it is during differentiation that they consolidate information.

“In fact, ‘domain consolidation’ is what we call the novel concept we discovered,” he said.

Gilbert likened the concept of domain consolidation to the undeclared or “undifferentiated” college student who then consolidates her literature resources during the course of declaring a major and specialization. “From a student with books on all subjects on all of her bookshelves comes a student who has placed all texts pertaining to her major on the eye-level shelf and moved the distantly-related, potentially distracting texts to the hard-to-reach bottom or top shelves,” he said.

“Now, our challenge as scientists,” said Gilbert, “is to build on what we’ve learned about domain consolidation so that we can efficiently and safely create patient-specific induced pluripotent stem cells or even coax the body’s cells to change their specialization in response to medications.”

Invasive Papaya Pest Discovered in AsiaThanks to efforts by scientists in a Virginia Tech-led program, the papaya mealybug — an emerging threat from India to Indonesia — is being identified and contained.

Attacks by the papaya mealybug are a serious threat. In Indonesia, India, countries in the Caribbean and South America, the Hawaiian Islands, and Florida, papaya means millions of dollars for farmers, middlemen, and processors. In West Java, the scourge has wiped out most of the papaya plantations.

In May, 2008, a team from the Integrated Pest Management Collaborative Research Support Program (IPM CRSP), managed by Virginia Tech’s Office of International Research, Education, and Development, identified papaya mealybug on papaya trees at the Bogor Botanical Gardens in West Java, Indonesia.

It was the first reported occurrence of papaya mealybug in Indonesia and Southeast Asia.

A specialist in mealybug taxonomy at the California Department of Agriculture confirmed the identification as papaya mealybug — an unarmored scale insect found in moist, warm climates.

Two months later, on a trip to Tamil Nadu Agricultural University in Coimbatore, India, Muni Muniappan, director of the IPM CRSP at Virginia Tech, recognized the telltale sticky residue on papayas he saw there as papaya mealybug.

In each case, IPM scientists alerted government authorities and advised them on appropriate actions to take. These discoveries are crucial; the sooner authorities can arrest the spread of the papaya mealybug, the better their chances of saving this lucrative tropical crop.

While papaya is an exotic fruit in the northern hemisphere, papain, a product of papaya, is used in a variety of ways every day, including the production of chewing gum, shampoo, and toothpaste and tooth whiteners; as a meat tenderizer; and in the brewing and textile industries. In many tropical countries, papaya is an important commercial crop and a key component of the daily diet.

The papaya mealybug originated in Mexico, where it developed alongside natural enemies and was first identified in 1992. It wasn’t until it jumped countries and started proliferating in places where it had no natural enemies that it began to pose problems. In 1995, it was discovered on the Caribbean island of St. Martin. By the year 2000, it had spread to 13 countries in the Caribbean, to Florida in the United States, and to three countries each in Central and South America.

The papaya mealybug is a particularly devastating pest because it is polyphagous—it feeds on many things. The insect’s host range includes more than 60 species of plants: cassava, papaya, beans, eggplant, melons, hisbiscus, plumeria, pepper, sweet potato, tomato, citrus, mango, and sour sop.

On papaya plants, the mealybug infests all parts of the young leaves and fruits, mostly along the veins and midrib of the older leaves. Young leaves become crinkly and older leaves turn yellow and dry up. Terminal shoots become bunchy and distorted. Affected trees drop flowers and fruits. To add insult to injury, the mealybug secretes a honeydew-like substance that turns into a thick sooty mold growth, making the fruit inedible and unusable for the production of papain.

The good news is that the U.S. Department of Agriculture’s Animal and Plant Health Inspection Service (APHIS) has developed a biological control program to tackle the pest. Biological control is an integrated pest management tactic that pits natural enemies against pests. APHIS has identified three parasitoids including parasitic wasps that are highly effective at containing the mealybug. These natural enemies are being cultured in a laboratory in Puerto Rico and are offered free to countries that request them.

The IPM CRSP, funded by the U.S. Agency for International Development, is a consortium of integrated pest management scientists working to raise the standard of living in developing countries. The IPM CRSP team that traveled to Indonesia included Robert Hedlund, Cognizant Technical Officer for the USAID-funded program; Muniappan; Clemson University entomology Professors Merle Shepard and Gerry Carner; Clemson economics Professor Mike Hammig; Yulu Xia, assistant director of the NSF Center for IPM at North Carolina State; and Aunu Rauf, professor of entomology at Bogor Agricultural University in Indonesia.

While the challenge of reclaiming the papaya plantations from the papaya mealybug seems daunting, Muniappan is optimistic. “The use of parasitoids has been very effective in Caribbean and Latin American countries, and in Florida, Guam, and Palau,” he said. “But we need to be vigilant.”

Complement enhances tumour evasion


A seemingly illogical link between activation of immune sensors and the ability of tumours to escape the immune system. The unexpected result reveals a new drug target for cancer treatment.

The complement system comprises a cascade of proteins that act as a fire alarm to alert the immune system to the presence of infection. In a bizarre twist, Lambris and colleagues show that tumour activation of one of the complement proteins – C5 – in fact leads to suppression of the anti-tumour immune response.

The surprising outcome is explained by the observation that the activated protein recruits ‘suppressor’ cells to the site. These act to disarm other immune cells and stop them from killing the tumour. Importantly, the authors show that blocking the activity of C5 slows tumour growth in mice and this treatment is as effective as taxol, a commonly used anti-cancer drug.

Author contact:
John Lambris (University of Pennsylvania, Philadelphia, PA, USA)
Tel: +1 215 746 5765; E-mail: lambris@mail.med.upenn.edu

Glacier acceleration through subsurface ocean warming

The sudden acceleration in 1997 of Jakobshavn Isbræ, one of Greenland’s largest outlet glaciers, was caused by subsurface ocean warming, according to research. The study suggests that ocean temperatures may be more important for glacier flow than previously thought. The prediction of future rapid dynamic responses of other outlet glaciers to climate change may therefore require detailed knowledge of regional ocean dynamics.

David Holland and colleagues present hydrographic data that show a sudden increase in subsurface ocean temperature in 1997 along the entire west coast of Greenland. The arrival of relatively warm water that originated from the Irminger Sea near Iceland could therefore have triggered the increase in the glacier speed. The authors trace these oceanic changes back to changes in the atmospheric circulation in the North Atlantic region.

Author contact:
David Holland (New York University, NY, USA)
Tel: +1 212 998 3245; E-mail: holland@cims.nyu.edu

Thwarting tumour invasion


A mechanism used by metastasising tumour cells to invade lung tissue and establish secondary tumours. The research identifies a promising drug target to prevent the spread of cancer.

Primary tumours prepare the lung for invasion by inducing chemokines – chemical factors normally used to recruit immune cells during infection – which guide migration of tumour cells to the secondary site. Hiratsuka and colleagues show that primary tumours also induce lung cells to produce an additional factor, serum amyloid A3 (SAA3). SAA3 accelerates the recruitment of primary tumour cells by switching on genes involved in inflammation and boosting the production of chemokines. Importantly, the team show that blocking SAA3 or its receptor strikingly reduces lung metastasis in mice.

Metastasis is difficult to predict and even harder to treat. The new findings offer researchers vital clues for understanding how cancer cells can establish new tumours at sites quite distant from the original tumour.

Author contact:
Yoshiro Maru (Tokyo Women's Medical University School of Medicine, Japan)
Tel: +81 3 5269 7417; E-mail: ymaru@research.twmu.ac.jp

Risk factor for narcolepsy


A genetic variant that predisposes to narcolepsy has been identified, according to a study. Narcolepsy is characterized by excessive daytime sleepiness, impaired vision, and muscle weakness that may lead to collapse. It occurs in approximately 1 in 2,500 individuals in the United States and Europe, but is at least 4 times more frequent in Japanese.

Katsushi Tokunaga and colleagues carried out a genome-wide association of Japanese individuals, and found one variant to be significantly associated with risk of narcolepsy. They also found support for the association in Koreans, but not in individuals of European or African descent, probably because the frequency of the risk variant is much lower in the latter two populations.

The risk variant is located between the genes CPT1B and CHKB, each of which is a reasonable candidate to have a role in the disorder. The gene CPT1B encodes an enzyme involved in fatty acid oxidation, which has been implicated in sleep regulation. CHKB encodes an enzyme that catalyzes the production of one of the major components of cellular membranes, which is a precursor to a molecule that has been linked to the sleep-wake cycle.

Author contact:
Katsushi Tokunaga (University of Tokyo, Japan)
Tel: +81 3 5841 3692; E-mail: tokunaga@m.u-tokyo.ac.jp

Researchers Develop New Model for Cystic Fibrosis



In a first, researchers at the University of Iowa and the University of Missouri (MU) have developed a pig model for cystic fibrosis (CF) that appears to closely mimic the disease in human infants. The striking similarities between disease manifestations in the CF piglets and human newborns with CF suggest that this new model will help improve understanding of the disease and may also speed discovery of new treatments. The study is published in the Sept. 26 issue of Science.

CF is a common hereditary disease that affects multiple organ systems, including the intestines, pancreas, and lung. Mice with CF-causing mutations have helped researchers learn more about this disease, however, differences in physiology and biology mean that mice with CF mutations do not develop many of the typical symptoms that affect humans with CF.

"Lack of a better model has hampered our ability to answer long-standing questions in CF," explained Christopher Rogers, Ph.D., a former postdoctoral fellow in internal medicine at the UI Roy J. and Lucille A. Carver College of Medicine, and one of the study's lead authors. "The CF pig provides a unique opportunity to study one of the most common genetic diseases, and we hope to translate this new knowledge into better therapies and preventions."

In addition to Rogers, co-lead authors of the study were David Stoltz, M.D., Ph.D., UI assistant professor of internal medicine, and David Meyerholz, D.V.M., Ph.D., UI assistant professor of pathology.

The senior study author was Michael Welsh, M.D., UI professor of internal medicine and molecular physiology and biophysics, who holds the Roy J. Carver Chair of Internal Medicine and Physiology and Biophysics. Welsh also is a Howard Hughes Medical Institute investigator.

CF occurs when a person inherits two mutated copies of the CFTR gene leading to loss of ion channel function that adversely affects many organs. To create the CF pigs, the researchers used gene targeting to disrupt one copy of the normal gene in pig cells. They then cloned these altered cells to produce pigs with only one good copy of the gene. Like human CF-carriers, these animals did not show disease symptoms. The pigs were then bred naturally, and about one in four of the piglets were born with two disrupted copies of the gene.

The researchers established that piglets lacking CFTR have the abnormal ion channel activity that is a hallmark of CF disease. They also showed that the CF piglets develop the same disease characteristics that are commonly seen in newborn humans with CF, including a bowel obstruction known as meconium ileus, which often is the first sign of CF in humans. The pigs also have an abnormal pancreas, liver, and gall bladder, similar to CF patients.

"Thus far, the clinical, physiological and age-related appearance of disease in the pigs, as well as the organs involved, mimic CF seen in people," Stoltz said.

A primary cause of death and disability in patients with CF is lung disease. However, many questions remain about how infection and inflammation leads to lung damage. In the study, the lungs of the newborn CF pigs appeared similar to the lungs of their normal littermates and had no sign of infection or inflammation, possibly shedding some initial insight on the process. As the CF pigs mature and are exposed to airborne bacteria and viruses, the researchers hope to learn more about how and why lung disease develops in patients with CF.

"Researchers can now begin to study the disease progression as it is happening, something not possible in humans," Meyerholz said.

The research team included UI scientists from internal medicine, pediatrics, surgery and periodontics. In addition, Randall Prather, Ph.D., the distinguished professor of reproductive biology at MU College of Agriculture, Food and Natural Resources, and his colleagues were part of the research team.

The study was funded in part by grants from the National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Disease of the National Institutes of Health, Food for the 21st Century and the Cystic Fibrosis Foundation.