AMPHIBIANS AND DEADLY FUNGUS

FROM:  NATIONAL SCIENCE FOUNDATION 

Amphibians can acquire resistance to deadly fungus

Discovery will help conservation efforts

Emerging fungal pathogens pose a greater threat to biodiversity than any other parasitic group, scientists say, causing population declines of amphibians, bats, corals, bees and snakes.

Now research results published this week in the journal Nature reveal that amphibians can acquire behavioral or immunological resistance to a deadly chytrid fungus implicated in global amphibian population declines.

"Acquired resistance is important because it is the basis of vaccination campaigns based on 'herd immunity,' where immunization of a subset of individuals protects all from a pathogen," said Jason Rohr, a biologist at the University of South Florida (USF) who led the research team along with Taegan McMahon of the University of Tampa.

Experiments in the study revealed that after just one exposure to the chytrid fungus, frogs learned to avoid the deadly pathogen.

"The discovery of immunological resistance to this pathogenic fungus is an exciting fundamental breakthrough that offers hope and a critical tool for dealing with the global epidemic affecting wild amphibian populations," said Liz Blood, a program officer in the National Science Foundation's Directorate for Biological Sciences, which funded the research through its MacroSystems Biology Program.

In further experiments in which frogs could not avoid the fungus, frog immune responses improved with each fungal exposure and infection clearance, significantly reducing fungal growth and increasing the likelihood that the frogs would survive subsequent chytrid infections.

"The amphibian chytrid fungus suppresses the immune responses of amphibian hosts, so many researchers doubted that amphibians could acquire effective immunity against this pathogen," Rohr said.

"However, our results suggest that amphibians can acquire immunological resistance that overcomes chytrid-induced immunosuppression and increases survival."

Rohr also noted that "variation in the degree of acquired resistance might partly explain why fungal pathogens cause extinctions of some animal populations but not others."

Conservationists have collected hundreds of amphibian species threatened by the fungus and are maintaining them in captivity with the hope of re-establishing them in the wild.

But reintroduction efforts so far have failed because of the persistence of the fungus at collection sites.

"An exciting result from our research is that amphibian exposure to dead chytrid induced a similar magnitude of acquired resistance as exposure to the live fungus," McMahon said.

"This suggests that exposure of waterbodies or captive-bred amphibians to dead chytrid or chytrid antigens might offer a practical way to protect chytrid-naive amphibian populations and to facilitate the reintroduction of captive-bred amphibians to locations in the wild where the fungus persists."

Immune responses to fungi are similar across vertebrates, and many animals are capable of learning to avoid natural enemies, Rohr said.

"Our findings offer hope that amphibians and other wild animals threatened by fungal pathogens--such as bats, bees and snakes--might be capable of acquiring resistance to fungi and so might be rescued by management approaches based on herd immunity."

Rohr cautioned, however, that "although this approach is promising, more research is needed to determine the success of this strategy."

The study team also included: USF researchers Brittany Sears, Scott Bessler, Jenise Brown, Kaitlin Deutsch, Neal Halstead, Garrett Lentz, Nadia Tenouri, Suzanne Young, David Civitello and Nicole Ortega; Matthew Vensky of Allegheny College; J. Scott Fites, Laura Reinert and Louise Rollins-Smith of Vanderbilt University; and Thomas Raffel of Oakland University.

-NSF-
Media Contacts
Cheryl Dybas, NSF

NSF REPORTS OCEAN MICROBES HAVE DAILY CYCLES OF ACTIVITY

FROM:  NATIONAL SCIENCE FOUNDATION 

Ocean's microbial megacity: Like humans, the sea's most abundant organisms have clear daily cycles

Coordinated timing may have implications for ocean food web

Imagine the open ocean as a microbial megacity, teeming with life too small to be seen.

In every drop of water, hundreds of types of bacteria can be found.

Now scientists have discovered that communities of these ocean microbes have their own daily cycles--not unlike the residents of a bustling city who tend to wake up, commute, work and eat at the same times.

Light-loving photoautotrophs--bacteria that need solar energy to help them photosynthesize food from inorganic substances--have been known to sun themselves on a regular schedule.

But in new research results published in this week's issue of the journal Science, researchers working at Station ALOHA, a deep ocean study site 100 kilometers north of Oahu, Hawaii, observed species of bacteria turning on cycling genes at slightly different times.

The switches suggest a wave of activity that passes through the microbial community.

"I like to say that they are singing in harmony," said Edward DeLong, a biological oceanographer at the University of Hawaii at Manoa and an author of this week's paper.

"For any given species, the gene transcripts for specific metabolic pathways turn on at the same time each day."

The observations were made possible by advanced microbial community RNA sequencing techniques, which allow for whole-genome profiling of multiple species at once.

DeLong and colleagues deployed a free-drifting robotic Environmental Sample Processor (ESP) as part of a National Science Foundation (NSF) Center for Microbial Oceanography: Research and Education (C-MORE) research expedition to Station ALOHA.

Riding the same ocean currents as the microbes it follows, the ESP is equipped to harvest the samples needed for this high-frequency, time-resolved analysis of microbial community dynamics.

What the scientists saw was intriguing: different species of bacteria expressing different types of genes in varying, but consistent, cycles--turning on, for example, restorative genes needed to rebuild solar-collecting powers at night, then ramping up with different gene activity to build new proteins during the day.

"It was almost like a shift of hourly workers punching in and out on a clock," DeLong said.

"This research is a major advance in understanding microbial communities through studies of gene expression in a dynamic environment," said Matt Kane, a program director in NSF's Directorate for Biological Sciences, which co-funds C-MORE with NSF's Directorate for Geosciences.

"It was accomplished by combining new instrumentation for remote sampling with state-of-the-art molecular biological techniques."

The coordinated timing of gene firing across different species of ocean microbes could have important implications for energy transformation in the sea.

"For decades, microbiologists have suspected that marine bacteria were actively responding to day-night cycles," said Mike Sieracki, a program director in NSF's Directorate for Geosciences.

"These researchers have shown that ocean bacteria are indeed very active and likely are synchronized with the sun."

The mechanisms that regulate this periodicity remain to be determined.

Can you set your watch by them?

DeLong said that you can, but it matters whether you're tracking the bacteria in the lab or at sea.

For example, maximum light levels at Station ALOHA are different than light conditions in experimental settings in the laboratory, which may have an effect on microbes' activity and daily cycles.

"That's part of why it's so important to conduct this research in the open ocean environment," said DeLong.

"There are some fundamental laws to be learned about how organisms interact to make the system work better as a whole and to be more efficient."

Co-authors of the paper are Elizabeth Ottesen, Curtis Young, Scott Gifford, John Eppley, Roman Marin III, Stephan Schuster and Christopher Scholin.

The research also was funded by the Gordon and Betty Moore Foundation.

-NSF-


Media Contacts
Cheryl Dybas,

GETTING INTO THE GUTS OF BEES

FROM:  NATIONAL SCIENCE FOUNDATION 

Bees from the inside out

Researchers work to save bees by studying the diversity of microbes that live in their guts and the impacts on these microbes of exposure to antibiotics

It is 1,825 miles from New Haven, Conn., to Austin, Tex., which typically means 30 hours of driving and three nights in motels, not an easy trip for anyone. But for researchers moving from Yale University to a new lab at the University of Texas last August, it proved especially challenging. They made the journey in a minivan with a pet cat and 100,000 bees.

"That was probably the most heroic event in our beekeeping saga to date," says evolutionary biologist Nancy Moran, a professor at the University of Texas at Austin, who studies symbiosis, particularly among multi-cellular hosts and microbes. "We didn't want to be without bees upon arrival in Texas, and it wasn't a good time of year to start new colonies."

The bees--chauffeured by graduate student Waldan Kwong and postdoctoral fellow Gordon Bennett--traveled in boxes nailed shut, with duct tape over the cracks between the boxes, so they couldn't fly around in the minivan, and wire mesh over the front, so they could cool themselves, but not escape. They also received wet sponges at regular intervals to keep them hydrated.

"They [Kwong and Bennett] just turned up the air conditioning all the way, and wore sweaters," Moran says. "Bees are less excitable when it's cooler. At night, they waited to park the minivan until after dark, and then opened the windows so the bees didn't overheat in the closed space. It seemed unlikely that anyone would try to steal something from a van full of bees."

The bees arrived in Austin with no problems, and now live on top of a building on campus, "where their main forage might be drops of soda on discarded cans around campus," says Moran, who for many years studied the maternally transmitted symbionts of aphids and other sap-feeding insects, but has expanded in recent years to bees. Symbionts are organisms that co-exist and depend on each other for survival.

"I've worked for many years on genomic evolution in bacteria, but also love insects and insect biology," she says. "So this is a system that has both."

Understanding the gut microbes in bees

Today, the broad aim of her research is to understand the diversity and function of the gut microbiota in honeybees and bumblebees, emphasizing genomic approaches, not unlike the current research interest in the human microbiome.

"It has a number of parallels with the gut microbiota of humans and other mammals, because it is a long co-evolved and specialized bacterial community, and because it impacts the health of the hosts," she says.

The gut microbiota is another dimension of animal biodiversity, particularly when the animals have distinctive and co-evolved bacterial species in their guts, Moran says.

"In insects, this doesn't always appear to be true--many seem to have a selected set of bacteria taken up from the environment, and the bacteria can live in a range of habitats outside the gut," she says. "But in honeybees and bumblebees, the gut is dominated by a small number of tightly related groups.

"Why? The primary reason seems to be that sociality--social interactions--gives a route for dependable transmission between individuals. Interactions within the bee colonies are the basis for transfer of the symbionts to newly emerged adult bees. This is where the system parallels that of humans and other mammals, all of which are social at least to the extent of having extended maternal care. Gut symbionts of mammals are specialized and transmitted via these social interactions."

Microbial gut symbionts are essential for the life of most animal species, but their diversity and functions in hosts and their responses to ecological disturbance are poorly understood, she says. Apis mellifera, the honeybee, has a distinctive set of about eight symbiotic bacterial species, some of which occur in other Apis species and in the related genus Bombus--bumblebees.

Bees, of course, are critically important ecologically and economically, particularly in agriculture, where honeybees pollinate an estimated $15 billion worth of agricultural products in the United States, including more than 130 fruits, according to the U.S. Department of Agriculture. In recent years, however, there has been increasing concern over rampant bee colony losses, dubbed "Colony Collapse Disorder," and the overall health of bees in general. [Colony Collapse Disorder ]

While Moran and her colleagues are primarily trying to gain a basic understanding of biodiversity and function in the bee gut microbial community system, "some bumblebees are becoming rare and have shrunken ranges. Are we also losing diversity of their gut microbiota, and will this be a factor in trying to conserve these species?" she asks. "Are problems with gut microbiota part of the problem of honeybee health, or could microbiota be preserved in a way that helps bees thrive?

"A big part of the problem with bee health is undoubtedly the decreasing availability of diverse floral resources, and possibly nesting sites in the case of bumblebees," she adds. "But exposure to toxins and to diseases also play a part, based on numerous studies. Gut microbes very plausibly play a role in host resistance to these things, and also in improving nutrition. So we hope that we find something useful for bees."

The National Science Foundation (NSF) is funding her work with $2,006,416 over five years, awarded in 2010.

Antibiotic resistance

Moran's research has revealed that bacteria in the guts of honeybees are highly resistant to the preventive antibiotic tetracycline--probably the result of decades of exposure to it because of its use by beekeepers to prevent bacterial diseases. Moran's team identified eight different tetracycline resistance genes among U.S. honeybees that were exposed to the antibiotic, but the genes were largely absent in bees from countries where such antibiotic use is banned.

"In the bee system, even though transmission is mostly within colonies, the symbionts are much more likely to undergo horizontal transmission," she says, meaning transmission among members of the same species that are not parent and child. "This has massive consequences for patterns of genome evolution in the symbionts. Because they are undergoing recombination, and have larger genetic population sizes, they retain normal genome sizes, and have far more dynamic genomes.

"The antibiotic resistance study was an early hint about the dynamic nature of these genomes," she adds. "It turns out that in the United States, antibiotics have been used widely in beekeeping since the 1950s, mostly tetracycline. And the gut microbiota of U.S. honeybees is a treasure trove of tetracycline resistance genes that have been horizontally transferred from other bacteria. Now we are finding that strains of the bee gut microbiota show a large set of 'accessory' genes and functions. A given strain can have hundreds of genes that are not present in another strain of the same species, and that affect functions such as sugar metabolism, or ability to break down components of pollen cell walls."

Until recently, none of these bacterial species had been cultured in the lab, "but now all of them can be," she says, crediting the work of Kwong, and Philipp Engel, a postdoctoral fellow now in Switzerland.

"In fact, we have given official names to the bacterial species that are our main focus: Snodgrassella alvi, Gilliamella apical, and Frischella perrara," named after three biologists who made major contributions in honeybee biology, Robert Snodgrass, Martha Gilliam and Karl von Frisch.

"These three live together in one part of the honeybee ileum (part of the digestive tract), and two of them also live in bumblebees," she says. "But we are finding that there are diverse strains within each species, and that different bee species and different colonies within a species seem to have different strains of symbionts."

Another postdoctoral fellow in her lab, Hauke Koch, was the first to find that gut symbionts of bumblebees protect against protozoan parasites, "so we are trying to see if the same is true in honeybees, and also to extend the findings in bumblebees," she says.

She and her collaborators also conducted a survey of gut symbionts in three bumblebee species to determine whether environmental factors--especially agricultural management or geographic location--affected symbiont communities.

"And it turns out that different bumblebee species all have some of the same symbionts, particularlySnodgrassella and Gilliamella, but one bumble bee species seemed to sometimes miss being inoculated," she says. "The 'right' symbionts are simply absent from some individuals. This is very different from honeybees, where every worker bee has the main symbionts, and we think it might relate to their different life cycles and social lives."

This work provides a baseline for understanding how the gut microbiota of honeybees and bumblebees varies among colonies, and how this variation might affect colony health.

"By establishing methods for culturing and type strains that can be studied by different laboratories, we can start to untangle the mechanistic basis for colonizing hosts," she says. "And we can start to understand how the normal microbiota interacts with disease agents that infect bees."

The temperament of bees

When it's time to start new colonies, Moran's lab orders bees from different places around the country, but favors northern California bees because of their "very sweet personalities," meaning they stay calm when the hive is opened, and don't line up in an aggressive manner, preparing to attack, she says. "One can approach the hives without alarming them," she says. "Feisty bees are touchy and prone to attack when someone just gets close to the hive. We had some Texas bees, but they were a bit feisty, perhaps they did not like being plopped down in New England," before she moved to Austin.

Lab technician Kim Hammond cares for the bees and has developed into a master beekeeper, Moran says. "In fact, maybe she's too good –we can't recover the disease organisms that most beekeepers complain about, even when we would like to sample them in our colonies. She keeps the bee colonies very healthy, and we sometimes cannot detect pathogens that are generally common.

"The main ones are Nosema species, which are eukaryotic pathogens related to fungi, and RNA viruses, such as `Deformed Wing Virus,"' she adds. "In some of our experiments we want to infect bees with pathogens, to see if the microbiota protects against pathogens. In those cases we have to go to other beekeepers to try and find the disease organisms."

New to bee research and wanting to learn the basics of beekeeping, Moran actually kept several colonies in her own yard for several years.

"But I have to admit I am afraid of stings," she says. "Yes I did get stung a few times. In working directly with the colonies, it is usual to occasionally be stung. Of course we wear bee suits. In the lab, we mostly work with young worker bees, which do not sting much, plus we have them contained. If a student researcher is worried about stings, we just have them work on aspects that have no risk. But we do keep an epinephrine kit around for possible cases of a sting of someone allergic who might not realize the risk. So far we haven't had anything at all serious."

And, of course, there is at least one sweet fringe benefit of the research. "We get honey, which is very helpful as gifts to make people worry less about being stung," she says.

Editor's Note: This Behind the Scenes article was first provided to LiveScience in partnership with the National Science Foundation.

-- Marlene Cimons
Investigators
Nancy Moran
Related Institutions/Organizations
University of Texas at Austin

FDA APPROVES MEDTRONIC COREVALVE SYSTEM

FROM:  U.S. FOOD AND DRUG ADMINISTRATION 

Medtronic CoreValve System - P130021/S002

This is a brief overview of information related to FDA’s approval to market this product. See the links below to the Summary of Safety and Effectiveness Data (SSED) and product labeling for more complete information on this product, its indications for use, and the basis for FDA’s approval.

Product Name: Medtronic CoreValve System
PMA Applicant: Medtronic CoreValve LLC
Address: Medtronic CoreValve LLC, 3576 Unocal Place, Santa Rosa, CA 95403
Approval Date: June 12, 2014
Approval Letter: http://www.accessdata.fda.gov/ cdrh_docs/pdf13/P130021S002a.pdf

What is it? The Medtronic CoreValve System (often referred to as the CoreValve) consists of a catheter-based artificial aortic heart valve and accessories used to implant the valve without open-heart surgery. The valve is made of pig tissue attached to a flexible, self-expanding, nickel-titanium frame for support.

How does it work? The CoreValve is compressed and placed on the end of a tube-like device called a delivery catheter. It is then inserted through the femoral artery in the leg. If the femoral arteries are not suitable, the valve can also be inserted through other arteries or through the aorta. The catheter is pushed through the blood vessels until it reaches the diseased aortic valve. The valve is then released from the catheter, it expands on its own, and anchors to the diseased valve. The CoreValve functions the same as a normal valve, helping the blood flow properly by opening and closing like a door to force the blood to flow in the correct direction.

When is it used? The CoreValve is used in patients whose own aortic heart valve is diseased due to calcium build up, which causes the valve to narrow (aortic stenosis) and restricts blood flow through the valve. As the heart works harder to pump enough blood through the smaller opening, the heart eventually becomes weak. This can lead to symptoms and life-threatening heart problems such as fainting, chest pain, heart failure, irregular heart rhythms (arrhythmias), or cardiac arrest. Once symptoms of severe aortic stenosis occur, over half of the patients die within two years if the diseased valve is not replaced.

The CoreValve should only be used in patients who cannot undergo, or are at high risk for open heart surgery as determined by their heart team (a cardiologist and surgeon).

What will it accomplish? The CoreValve can help correct the blood flow problem associated with aortic stenosis in patients who need open-heart surgery to replace the diseased valve, but the surgical procedure is highly risky, or too risky. In the U.S. clinical trial, the CoreValve was shown to be reasonably safe and effective for those patients without the need for open-heart surgery. However, implanting the CoreValve also carries the risk of serious complications such as death, stroke, acute kidney injury, heart attack, bleeding, complications with the arteries used to insert the valve, and the need for a permanent pacemaker. For some patients with coexisting conditions or diseases, the risks may be especially high. Patients should discuss with their doctors the benefits and risks of this device.

When should it not be used? The CoreValve should not be used in patients who:

have an infection in the heart or elsewhere.
have an artificial (mechanical) aortic valve.
cannot tolerate blood thinning medicines.
have sensitivity to Nitinol (Titanium or Nickel) or to fluid used during the procedure to   see internal structures (contrast media).
Additional information: The Summary of Safety and Effectiveness Data and labeling are available online.

TREATING AIDS WITH SUPERCOMPUTERS

FROM:   NATIONAL SCIENCE FOUNDATION 

Computing a cure for HIV

Nine ways NSF-supported supercomputers help scientists understand and treat the disease

HIV/AIDS has caused an estimated 36 million deaths, according to the World Health Organization, and remains a major menace worldwide. Today, approximately 35 million people are living with the human immunodeficiency virus (HIV), including more than a million individuals in the United States.

The tendency of HIV to mutate and resist drugs has made it particularly difficult to eradicate. Some treatments have shown progress in slowing or even stopping the progress of the virus, but no cure or vaccine has been discovered that can truly stamp out the disease.

In the last decade, scientists have begun using a new weapon in the fight against HIV: supercomputers.

Scientists harness the power of thousands of computer processors simultaneously to better understand how the HIV virus interacts with the cells it infects, to discover or design new drugs that can attack the virus at its weak spots and even to use genetic information about the exact variants of the virus to develop patient-specific treatments.

Among the researchers using supercomputers to study HIV is Klaus Schulten, the keynote speaker at the 2014 International Supercomputing Conference, held earlier this week in Leipzig, Germany. Schulten, a professor of physics at the University of Illinois at Urbana-Champaign, invented the Nanoscale Molecular Dynamics (NAMD) software program, one of the most widely used tools for understanding diseases at a molecular level.

Supported by the National Science Foundation (NSF) and using some of the nation's most powerful supercomputers, teams of researchers are pushing the limits of what we know about HIV, and how we can treat it.

Below are nine examples of how scientists are applying massive computing power and computational know-how to combat the disease.

1) Modeling HIV: from atoms to actions

In order for HIV to infect non-dividing cells, the HIV virus must enter the cell and entice cellular proteins to act as chaperones, ushering the virus towards the cell nucleus and helping it integrate its genes into the cell's genome. This infection process offers opportunities for medical intervention and may suggest new HIV treatments. However the dynamics of the process can only be "observed" through computational modeling and simulation.

The size of the HIV capsid or shell, combined with its irregular shape, had long prevented scientists from simulating the full capsid structure with adequate resolution. But researchers from Klaus Schulten's group at the University of Illinois at Urbana-Champaign, using the NSF-funded Blue Waters supercomputer, observed how the capsid interacts with drugs and host proteins at the atomic level. The model, consisting of about 1,300 proteins and 4 million atoms, is currently the largest entry in the Research Collaboratory for Structural Bioinformatics Protein Data Bank, a repository for the three-dimensional structural data of large biological molecules.

2) Discovery of hidden pocket in HIV protein leads to ideas for new inhibitors

Researchers from the University of California, San Diego; the Salk Institute for Biological Studies and the National Cancer Institute collaborated on an effort to discover new drug candidates to combat HIV.

With the help of the San Diego Supercomputer Center, the scientists ran molecular simulations to capture the movements of a small pocket on the virus's surface that they believed could be targeted by drugs to prevent the replication of the virus. Using the pocket as a target, they virtually screened thousands of compounds and tested 16 for their ability to block HIV infection in human tissue cultures. Ultimately, they discovered two compounds that inhibit HIV replication and block the activity of reverse transcriptase as effectively as a leading FDA-approved drug, nevirapine. The researchers believe these compounds have the potential to develop into future drugs and are exploring them further.

3) Preventing HIV from reaching its mature state

The mature capsid of the HIV virus is comprised of thousands of interlinked proteins that act like a suit of armor around the virus's genetic material. If this armor-like structure does not form, then the virus is unable to infect cells.

Researchers from the University of Chicago used the Kraken supercomputers at the National Institution for Computational Science (NICS) to study how the mature HIV capsid formed. They found that the seemingly complicated behavior of the capsid's self-assembly was relatively simple once they understood the shape and behavior of the proteins that made it up. The work advanced our understanding of the HIV life cycle and is inspiring the development of new drugs to disrupt the virus's growth. Results appeared in the Biophysical Journal in October 2012.

4) Crowdsourcing a cure

After scientists repeatedly failed to piece together the structure of a protein-cutting enzyme that plays an important role in HIV, they called on the players of FoldIt, an online puzzle video game, to find a solution. Using FoldIt, "citizen scientists" were able to determine how the enzyme folded and solved the mystery of its structure. With further help from the game-players, researchers were able to identify target drugs to neutralize the enzyme.

FoldIt is part of an experimental research project supported by NSF and developed by the University of Washington's Center for Game Science in collaboration with the UW Department of Biochemistry. The case of the crowdsourced protein structure serves as a critical example of how games with a purpose can solve real-world problems.

5) Virtual screening of HIV inhibitors

A team of researchers from Pennsylvania used computer modeling and virtual screening, powered by supercomputers, to identify novel inhibitors of HIV and better understand how they react with the HIV virus. They focused on small molecules that block the interaction between the receptors on the surface of human cells and an important protein on the surface of the HIV envelope.

Using the Blacklight system at the Pittsburgh Supercomputing Center, the researchers virtually screened more than 10 million compounds to find small molecules that would be a good molecular fit for the protein that they were targeting. From the 10 million, they identified six, small-molecule, HIV surface protein complexes that display unique modes of binding. Taken together, they constitute what the researchers believe is a potent class of entry inhibitors against HIV.

6) Membrane effects

Some proteins that anchor HIV to cell membranes are thought to promote the development of the virus. Researchers have found that combining experimental methods with computer simulations can reveal much about the cell-binding dynamics.

Hirsh Nanda of the National Institute of Standards and Technology leads a research team that studies the initial stages of the formation of new HIV virus particles in an infected cell. During these first steps, HIV proteins latch onto cell membranes.

Using the Kraken supercomputer at NICS, Nanda's team was able to study the forces that govern protein assemblies on membranes in far greater detail and much faster than if they were using their lab's computers. Kraken also greatly accelerated the analysis of experimental neutron scattering data that they used to compare with simulations.

The simulations revealed that an important HIV surface protein simultaneously binds to the cell membrane and to viral RNA in order to change shape. Also revealed was how another HIV protein transitions between compact and extended structures upon anchoring to the cell membrane. These discoveries are inspiring new treatment approaches that center on membrane interactions.

7) Computing patient-specific treatment methods

Doctors know that there are many different strains of HIV and that drugs for the disease do not have the same effects in all people. Subtle genetic differences between strains and among individuals lead to a range of treatment outcomes. Using the NSF-supported Kraken and Ranger supercomputers, researchers from University College London and Rutgers University determined the shape of a key protein involved in HIV infection in an individual patient, and then ranked the drug molecules most likely to block the activity.

The project demonstrated how researchers might use genetic sequencing techniques and massive computations to design patient-specific treatment protocols in near-real-time. In the future, it is expected that this type of patient-specific drug selection will become routine.

The research was reported at the annual meeting of the American Association for the Advancement of Science and was published in the Journal of Chemical Theory and Computation.

8) Preparing the next generation to continue the fight

At Merrimack College in Massachusetts, students are learning how to conduct virtual screening using the Stampede supercomputer. Virtual screening uses computational methods to identify small molecules that are likely to bind to a known drug target, often a protein. The method has become a valuable tool for many biotechnology and pharmaceutical companies.

The activity exposes students to massive computing resources and shows them a method of conducting science that few previously knew existed. It's one of many ways that educators around the nation are beginning to prepare students for the workforce of the future by incorporating computational techniques into their curriculum.

9) A boy and the BEAST

When Armand Bilge was a 10th-grader at Lexington High School in Massachusetts, he created a map and timeline that identified when HIV arrived in the Americas, and where and when HIV spread across these continents. To do so, Bilge used a combination of molecular sequencing software and NSF-funded high-performance computing resources.

As a member of an after-school computer club, Bilge used a software program called BEAST to create a detailed evolutionary tree, based on similarities and differences in the 3,000 nucleotide subunits of a gene among 400 known HIV strains. The software ran on the CIPRES (CyberInfrastructure for Phylogenetic Research) science gateway, a public resource developed by the San Diego Supercomputer Center and supported by NSF that allows those interested in evolutionary relationships to study virtually every species on Earth.

Bilge's conclusions support previously published results of HIV experts that suggest that "a single introduction of the virus in Haiti in the mid-1900s resulted in its dispersion across the American continent." The project won first place in biology for the 2012 Massachusetts Science and Engineering Fair.

-- Aaron Dubrow, NSF
Investigators
John Towns
Dan Stanzione
Ralph Roskies
Philip Andrews
Gregory Peterson
Patricia Kovatch
Nancy Wilkins-Diehr

RESEARCHERS SAY NEW DEVICE WILL SAVE LIVES OF THOSE AFFLICTED WITH HEART FAILURE

FROM:  NATIONAL SCIENCE FOUNDATION 

A new tool for the early detection of heart failure

Researchers believe it will save lives and result in big savings to health care costs
Until recently, a reliable, low-cost, non-invasive method to measure changes that occur in the water content of the lungs did not exist. Yet, having such a device could be an important tool for the early detection of heart failure, which afflicts an estimated 5.1 million Americans and is a leading cause of hospitalization and death.

"There is a significant need," says Magdy Iskander, a professor of electrical engineering at the University of Hawaii at Manoa, and director of the Hawaii Center for Advanced Communications of the university's college of engineering, citing additional conditions that potentially could benefit from the new technology, including edema, emphysema, dehydration, blood infection, acute lung injury and the effects of critical burns.

"The impact could be tremendous, particularly for predicting heart failure," he says.

Heart failure costs the nation an estimated $32 billion annually, which includes the cost of health care services, medications to treat heart failure, and missed days of work, according to the federal Centers for Disease Control and Prevention. Furthermore, heart failure is a frequent reason patients are readmitted to hospitals within 30 days of their initial discharge.

"Annually more than one million patients are hospitalized due to heart failuree, which accounts for a total Medicare expenditure exceeding $17 billion," Iskander says.

The National Science Foundation (NSF)-funded scientist has invented a new type of stethoscope he believes will prompt significant and positive changes for patients suffering from heart failure and other related conditions. It attaches to the body surface much like an EKG sensor--there is no need to implant it--and uses a novel radio frequency (RF) sensor to detect small changes in lung water, and monitor vital signs including heart and respiration rate, and stroke volume. The device uses low level RF signals, two-thirds lower than the average cell phone signal, he says.

Since the lungs normally do contain some water, the idea is to first use the device to obtain a baseline in order to identify future changes, "before there are problems," he says. In hospitals, the stethoscope could be an important component of so-called "bridge clinics" that monitor patients after discharge to prevent readmission.

Under the Affordable Care Act, Medicare can reduce hospital payments for excessive readmissions. "Thus hospitals are motivated because now they are penalized when patients come back with heart failure within 30 days," he says.

He also envisions its use in "telemedicine," where an internet hookup will connect to a patient wearing the device, and will be able to measure important vital signs remotely, and transmit data on a regular basis, without having to go to the doctor or hospital in person, unless it is necessary.

"The most important thing is that we believe it will help save lives," Iskander adds. "But it also will almost certainly result in big savings in health care costs."

The cardio-pulmonary stethoscope evolved from research Iskander conducted years ago for the Air Force, when he was studying the effects of electromagnetic radiation on humans and developing safety standards for microwave exposure.

"We were trying to evaluate safe levels, and the biological effects of working with microwaves, and we were exploring the use of microwaves in medical applications," he says.

In doing so, he discovered that microwave signals reflect changes in lung water, forming the basis for his invention.

"If the lungs have too much water, the magnitude of the microwave signal is reduced because water absorbs microwaves," he says. "The more water, the weaker the signal."

NSF supported Iskander with a $50,000 Innovation Corps (I-Corps) grant, awarded in 2013, which supports a set of activities and programs that prepare scientists and engineers to extend their focus beyond the laboratory into the commercial world.

The goal of the I-Corps program is to help researchers translate their discoveries into technologies with near-term benefits for the economy and society. It is a public-private partnership program that teaches grantees to identify valuable product opportunities that can emerge from academic research, and offers entrepreneurship training to student participants.

Iskander recently formed a company, MiWa Technologies, which ultimately will manufacture and market the stethoscope. He has applied for patents, and is seeking additional funding for continuing research and to conduct clinical trials. A recent National Institutes of Health scientific review panel called the clinical significance of his work "very high," adding that the tool could "significantly impact the assessment and management of subjects with HF (Heart Failure) and respiratory failure."

Years ago, when he designed his first cardio-pulmonary stethoscope, he estimates that the components would have cost about $150,000 to build one instrument. Today, thanks to wireless technology and digital processing, the same components that go into manufacturing cell phones, his costs are but a fraction of that amount. Moreover, "the stethoscope actually is more accurate," he says.

-- Marlene Cimons, National Science Foundation
Investigators
Magdy Iskander
Nuri Celik
Zhengqing Yun
Marcelo Kobayashi

NSF FUNDS RESEARCH ON CRUSTACEAN PATHOGENS

FROM:  NATIONAL SCIENCE FOUNDATION 

Summer brings crab feasts--and concerns for Chesapeake blue crabs

Infectious diseases play a part in crab population declines

It's almost summer. Seafood restaurants from coast-to-coast are serving platter after platter of steaming crabs, ready for hammering and picking. The supply seems endless, but is it?

Not if we're talking about blue crabs from Chesapeake Bay.

The bay's iconic blue crab population has dropped to levels not seen since before restrictions were placed on the fishery more than five years ago. What's to blame?

A long and, by Mid-Atlantic standards, brutal winter has been fingered as one culprit. In one of the worst die-offs in recent history, more than a quarter of the Chesapeake's blue crabs perished in the frigid waters.

More than cold water to blame

But that's not the only factor, says disease ecologist Jeff Shields of the Virginia Institute of Marine Sciences in Gloucester Point, Va.

"Several commercially important crustacean populations, including blue crabs, have had declines linked to diseases," says Shields. "In most cases, though, the underlying causes have been difficult to pinpoint because crustacean pathogens [infectious agents] aren't very well known."

To help determine what's infecting Chesapeake blue crabs and other crustaceans, the National Science Foundation (NSF) awarded Shields a grant through the joint NSF-NIH Ecology and Evolution of Infectious Diseases Program.

"We know very little about how disease affects populations of marine invertebrates and even less about how disease might interact with other stressors, such as overfishing," says Dave Garrison, director of NSF's Biological Oceanography Program, which also funded the research.

"This study is a major step toward discovering new ways of wisely managing our coastal resources."

One Chesapeake Bay blue crab killer may be a single-celled parasitic dinoflagellate named Hematodinium, a scourge that infects blue crabs and is of concern in fisheries not only in the Chesapeake, but around the world.

Outbreak in the crab pot and the shedding house

The parasite was first reported along the U.S. East Coast in the 1970s and found in the Chesapeake's blue crabs in the 1990s.

In a Hematodinium outbreak, some 50 percent of crabs caught in fishing pots may die. That number jumps to 75 percent in "shedding houses" where crabs molt their shells, then are collected for the soft-shell industry.

"Infection is almost always fatal--for the crabs," says Shields, who adds that the disease isn't harmful to humans.

In a breakthrough for blue crabs, Shields and colleagues recently succeeded in their effort to uncover the life history of Hematodinium.

"Describing the entire life cycle of Hematodinium is an important step toward controlling the infection," says Shields. "With all the parasite's stages in culture in the lab, we can learn when Hematodinium is most infectious."

The biologists made their discovery by looking at many parasite generations over a year-long period.

Answers under a microscope

Through the research, scientists now know that Hematodinium takes some 40 to 50 days to develop. "That matches what we see in the field," he says. "We think infection is linked with blue crabs' molting cycles."

Hematodinium usually infects young crabs. Some 50 to 70 percent of juvenile blue crabs along the Virginia coast carry the pathogen, "and it's prevalent in bays and inlets along the entire U.S. East Coast," says Shields.

The high cost--to the crab population and to the humans that depend on it--comes in the deaths of young blue crabs before they can make their way from coastal spawning grounds to brackish tributaries, where they become large enough to legally catch.

"Imagine a harvest with 50 percent more crabs," says Shields. "The toll exacted by Hematodinium is very clear."

The parasite is after more than blue crabs, however.

"You can't fish out the blue crabs somewhere and hope this pathogen will be gone," says Shields. "It's also in many other crustaceans, including spider crabs, rock crabs and other swimming crabs."

Insights from the bay's shape

Outbreaks of Hematodinium are linked with certain geographic features, such as shallow bays, lagoons and fjords. "Such features are ideal for the growth and spread of pathogens, as they serve to focus transmissive stages or retain them within the system," writes Shields in a paper published in the Journal of Invertebrate Pathology.

Four factors may facilitate epidemics of Hematodinium and other pathogens: relatively "closed" host (crab) populations, with little immigration and emigration of juveniles and adults; bays with restricted water exchange with the open ocean, which hold in pathogens; stressful environmental conditions, such as overfishing and seasonal hypoxia, or "dead zones"; and pathogens that can rapidly multiply.

"The Chesapeake has several of these features," Shields says.

Managing for pathogens

Shields and colleagues are working to understand how Hematodinium is transmitted in wild crustacean populations and at shrimp farms and other aquaculture operations. "We hope to develop 'best practices' for managing, in particular, the Chesapeake's wild blue crabs."

Diseases can have serious effects on commercial fisheries, Shields says. "But there's a perception among resource managers and fishers that diseases aren't important to the fishing industry, or that little can be done to manage them."

Too few fishery models use information like disease prevalence and distribution, according to Shields, and fisheries management decisions often don't consider disease.

"Estimates of disease-induced effects such as mortality or 'negative marketability' can be incorporated into existing models to improve stock assessment and management," Shields writes in the Journal of Invertebrate Pathology.

Disease may be the sleeper in the decline of the Chesapeake Bay blue crab.

Hard-hit by freezing temperatures, low-oxygen waters and overfishing, unless disease is taken into account, believes Shields, the next blue crabs caught may be headed not to your dinner table, but to the crustacean equivalent of the ICU.

-- Cheryl Dybas, NSF
Investigators
Harry Wang
Kimberly Reece
Jeffrey Shields
Related Institutions/Organizations

THE FOX WHO GOT READY FOR AN ICE AGE

FROM:  NATIONAL SCIENCE FOUNDATION 

"Out of Tibet" hypothesis: Cradle of evolution for cold-adapted mammals is in Tibet

Extinct Tibetan fox, ancestor of today's arctic fox, used Tibet as training ground for Ice Age climate

June 11, 2014

For the last 2.5 million years, Earth has experienced millennial-long cold and warm cycles. During cold periods, continental-scale ice sheets have blanketed large tracts of the Northern Hemisphere.

As climate warmed, glaciers receded, leaving Yosemite-like valleys and similar geologic features behind.

The advance and retreat of the ice sheets also had a profound influence on the evolution and geographic distribution of many animals, including those that live in far northern regions.

New results from research conducted in the Himalayan Mountains and published this week in the journal Proceedings of the Royal Society B: Biological Sciences identify a recently discovered three to five million-year-old Tibetan fox, Vulpes qiuzhudingi, as the likely ancestor of the living arctic fox, Vulpes lagopus.

The finding lends support to the idea that the evolution of present-day animals in the Arctic traces back to ancestors that adapted to life in cold regions in the high-altitude Tibetan Plateau.

The paper's lead author is Xiaoming Wang of the Natural History Museum of Los Angeles County. Co-authors are Zhijie Jack Tseng from the University of Southern California, Qiang Li from the Chinese Academy of Sciences, Gary Takeuchi from the Page Museum at the La Brea Tar Pits and Guangpu Xie from the Gansu Provincial Museum.

The scientists, part of a team of geologists and paleontologists led by Wang, uncovered fossil specimens of the Tibetan fox in the Zanda Basin in southern Tibet.

In addition to the fox, the team also discovered extinct species of a wooly rhino (Coelodonta thibetana), three-toed horse (Hipparion), Tibetan bharal (Pseudois, known as blue sheep), chiru (Pantholops, known as Tibetan antelope), snow leopard (Uncia), badger (Meles), and 23 other mammals.

The new fossil assemblage lends credence to a scenario the scientists call the "Out of Tibet" hypothesis.

It argues that some Ice Age megafauna--which in North America include the woolly mammoth, saber-toothed cat and giant sloth--used ancient Tibet as a training ground for developing adaptations that allowed them to cope with a harsh climate.

"The concept 'Out of Tibet' is an exciting insight for the origin of cold-adapted mammals of the Pleistocene," says Rich Lane, program director in the National Science Foundation's (NSF) Division of Earth Sciences, which funded the research.

"It parallels the 'Out of Africa' theory for the evolution of hominids. Together they may be a model for wider application in biological history and geography."

Tibet, Wang says, is a rich but grueling location for paleontological fieldwork.

Fifteen summer field seasons and a great deal of luck have led to his and his colleagues' successes.

Their expeditions involve a one-week journey to Lhasa, then a four-day drive into the remote "layer cake" sediments of the Zanda Basin--a drive made in old-model Land Cruisers known for becoming mired in streambeds.

At the more than 14,000-foot elevation, it's difficult to breathe, water freezes overnight in camps, and the scientists often must walk alone in search of fossils.

They've trained their eyes to search for ancient lake margins, where megafauna are reliably found.

Despite the challenges, Wang says that it's his favorite place to look for fossils.

"It's a pristine environment, the Tibetan people are kind, and in paleontological terms," he says, "it's relatively unexplored."

-- Cheryl Dybas, NSF (703) 292-7734 cdybas@nsf.gov
-- Kristin Friedrich, L.A. County Museum of Natural History (213) 763-3532 kfriedri@nhm.org
Investigators
Xiaoming Wang

THE WORLD OF MICRO-LOCOMOTION

FROM:  NATIONAL SCIENCE FOUNDATION 

Microorganisms: Studying the mechanics of their locomotion

Research has potential for improvements in treating diseases and reproductive health and creating new drug delivery systems

Bacteria often must swim through intricate environments in the human body to get where they need to go. How they do it is what fascinates Henry Fu.

"A microbiologist might look at the biology, or biochemical pathways," says Fu, an assistant professor of mechanical engineering at the University of Nevada, Reno. "I am focused on the mechanics, rather than the biology."

Fu's goal is to understand the locomotion of bacteria and other microorganisms, such as sperm and protists, when they swim through such complex substances as mucus or bodily tissues. While both do contain fluid, they are more complicated than water, and bacteria almost certainly need different forces to navigate through them.

"People have tried to understand how they swim through regular water for a very long time, probably 50 or 60 years, but I want to know how this swimming is modified when they are swimming through things more complicated than water, like mucus," says the National Science Foundation (NSF)-funded scientist. "Mucus is more viscous and has elastic properties. People think of mucous as smooth and continuous, but it has a network of fibers. I'm looking at how those fibers interact with the microorganisms."

His work potentially has broad implications in the treatment of diseases, for example, in figuring out ways to block infection by halting a bacterium's movement, even after it has entered the body, such as in Lyme disease, where "bacteria have to burrow through your tissues to get to your bloodstream," Fu says. "Understanding how they do that could be potentially important in order to stop them."

The research also could prove valuable in reproductive health, where "the properties of mucus can affect the likelihood of fertilization," Fu says. "This could be important in treating infertility or contraception, when you could make it easier--or harder--for the sperm to move."

Researchers also could apply mechanical engineering lessons learned toward creating new drug delivery systems, such as nano-robots that could carry chemotherapy through the body to target a growing tumor.

Microorganisms swim by moving parts of their bodies. For example, many swimming bacteria have a tail-like flagellum, which rotates like a propeller, pushing them forward, while some algae have two flagella that "they can use like breast stroke," Fu says. "Part of what I am looking at is how they translate this motion into propelling themselves in the direction of where they want to go."

His research mostly is theoretical--in the computer and with pen and paper--designing models of these swimmers to see how they behave in different environments, and with variations to their swimming motions.

"What we do as modeling is based on well-known fundamental physics laws," he explains. "We could tell the computer the shape of a bacterium and its swimming motion, or how it is rotating, and the properties of the material or fluid it is moving in. We then ask it how it will move, and how much force and energy it will take. We might also ask what might happen if the flagellum or cell had a different shape."

Fu is conducting his research under an NSF Faculty Early Career Development (CAREER) award, which he received in June 2013. The award supports junior faculty who exemplify the role of teacher-scholars through outstanding research, excellent education, and the integration of education and research within the context of the mission of their organization. He is receiving $400,003 over five years.

As part of the grant's educational component, he plans to create "Move Like a Microbe," a simulation of microscale microbial locomotion that "will bring the research to life for the public, and K-12 students, by providing a hands-on demonstration of how microorganisms are able to swim, and explain the consequences of microbial locomotion in everyday life," he says.

"Because microorganism are so small and because what they experience in a fluid environment is different from what we expect, this demonstration helps put them in the shoes of a microorganism," he adds. "They can control it, and make it swim, and feel the forces that the microorganism feels--and they will be learning about what it's like to try to swim when you're a tiny thing."

-- Marlene Cimons, National Science Foundation
Investigators
Henry Fu

GENERIC CELEBREX APPROVED BY FDA FOR ARTHRITIS, OSTEOARTHRITIS

FROM:  U.S. FOOD AND DRUG ADMINISTRATION 

FDA approves first generic versions of celecoxib

May 30, 2014

Release

The U.S. Food and Drug Administration today approved the first generic versions of Celebrex (celecoxib) capsules, a treatment for rheumatoid arthritis, osteoarthritis, short-term (acute) pain, and other conditions.

Teva Pharmaceutical Industries received approval to market celecoxib capsules in 50 milligram, 100 mg, 200 mg, and 400 mg strengths, and has 180-day exclusivity on the 100 mg, 200 mg, and 400 mg strength products. Mylan Pharmaceuticals, Inc. received approval to market 50 mg celecoxib capsules.

“It is important for patients to have access to affordable treatment options for chronic conditions,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “Health care professionals and patients can be assured that these FDA-approved generic drugs have met our rigorous approval standards.”

Celecoxib is a Non-Steroidal Anti-Inflammatory Drug (NSAID). All NSAIDs have a Boxed Warning in their prescribing information (label) to alert health care professionals and patients about the risk of heart attack or stroke that can lead to death. This chance increases for people with heart disease or risk factors for it, such as high blood pressure, or taking NSAIDs for long periods of time. The Boxed Warning also highlights the risk of serious, potential life-threatening gastrointestinal (GI) bleeding that has been associated with use of NSAIDs.

In the clinical trials for Celebrex, the most commonly reported adverse reactions in patients taking the drug for arthritis were abdominal pain, diarrhea, indigestion (dyspepsia), flatulence, swelling of the feet or legs (peripheral edema), accidental injury, dizziness, inflammation of the throat (pharyngitis), runny nose (rhinitis), swollen nasal passages, (sinusitis), upper respiratory tract infection, and rash.

Generic prescription drugs approved by the FDA have the same high quality and strength as brand-name drugs. Generic drug manufacturing and packaging sites must pass the same quality standards as those of brand-name drugs.

Information about the availability of generic celecoxib can be obtained from the companies.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation's food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

STUDY LOOKS AT POSITIVE AFFECTS OF INVASIVE SPECIES ON THE ENDANGERED

FROM:  NATIONAL SCIENCE FOUNDATION 

Eradicating invasive species sometimes threatens endangered ones

Study of California Clapper Rail and salt marsh cordgrass Spartina offers new insights

What should resource managers do when the eradication of an invasive species threatens an endangered one?

In results of a study published this week in the journal Science, researchers at the University of California, Davis, examine one such conundrum now taking place in San Francisco Bay.

The study was led by UC Davis researcher Adam Lampert.

"This work advances a framework for cost-effective management solutions to the conflict between removing invasive species and conserving biodiversity," said Alan Tessier, acting deputy division director in the National Science Foundation's (NSF) Directorate for Biological Sciences, which supported the research through NSF's Dynamics of Coupled Natural and Human Systems (CNH) Program.

CNH is also co-funded by NSF's Directorates for Geosciences and Social, Behavioral & Economic Sciences.

"The project exemplifies the goals of the CNH program," says Tessier, "which are to advance the understanding of complex systems involving humans and nature."

The California Clapper Rail--a bird found only in San Francisco Bay--depends on an invasive salt marsh cordgrass, hybrid Spartina, as nesting habitat.

Its native habitat has slowly vanished over recent decades, largely due to urban development and invasion by Spartina.

Study results show that, rather than moving as fast as possible with eradication and restoration plans, the best approach is to slow down the eradication of the invasive species until restoration or natural recovery of the system provides appropriate habitat for the endangered species.

"Just thinking from a single-species standpoint doesn't work," said paper co-author and UC-Davis environmental scientist Alan Hastings.

"The whole management system needs to take longer, and you need to have much more flexibility in the timing of budget expenditures over a longer time-frame."

The scientists combined biological and economic data on Spartina and on the Clapper Rail to develop a modeling framework to balance conflicting management goals, including endangered species recovery and invasive species restoration, given fiscal limitations.

While more threatened and endangered species are becoming dependent on invasive species for habitat and food, examples of the study's specific conflict are relatively rare--for now.

Another case where the eradication of an invasive species threatened to compromise the recovery of an endangered plant or animal is in the southwestern United States, where an effort to eradicate Tamarisk was cancelled because the invasive tree provides nesting habitat for the endangered Southwestern Willow Flycatcher.

"As eradication programs increase in number, we expect this will be a more common conflict in the future," said paper co-author and UC Davis scientist Ted Grosholz.

Other co-authors include scientists James Sanchirico of UC Davis and Sunny Jardine of the University of Delaware.

-NSF-

Media Contacts
Cheryl Dybas, NSF

RESEARCHERS LOOK AT THE BRAIN

FROM:  NATIONAL SCIENCE FOUNDATION 

Engineers ask the brain to say, "Cheese!"

How do we take an accurate picture of the world’s most complex biological structure?

Creating new brain imaging techniques is one of today's greatest engineering challenges.

The incentive for a good picture is big: looking at the brain helps us to understand how we move, how we think and how we learn. Recent advances in imaging enable us to see what the brain is doing more precisely across space and time and in more realistic conditions.

The newest advance in optical imaging brings researchers even closer to illuminating the whole brain and nervous system.

Researchers at the Massachusetts Institute of Technology and the University of Vienna achieved simultaneous functional imaging of all the neurons of the transparent roundworm C. elegans. This technique is the first that can generate 3-D movies of entire brains at the millisecond timescale.

The significance of this achievement becomes clear in light of the many engineering complexities associated with brain imaging techniques.

An imaging wish list

When 33 brain researchers put their minds together at a workshop funded by the National Science Foundation in August 2013, they identified three of the biggest challenges in mapping the human brain for better understanding, diagnosis and treatment.

Challenge one: High spatiotemporal resolution neuroimaging. Existing brain imaging technologies offer different advantages and disadvantages with respect to resolution. A method such as functional MRI that offers excellent spatial resolution (to several millimeters) can provide snapshots of brain activity in the order of seconds. Other methods, such as electroencephalography (EEG), provide precise information about brain activity over time (to the millisecond) but yield fuzzy information about the location.

The ability to conduct functional imaging of the brain, with high resolution in both space and time, would enable researchers to tease out some of the brain's most intricate workings. For example, each half of the thalamus--the brain's go-to structure for relaying sensory and motor information and a potential target for deep brain stimulation--has 13 functional areas in a package the size of a walnut.

With better spatial resolution, researchers would have an easier time determining which areas of the brain are involved in specific activities. This could ultimately help them identify more precise targets for stimulation, maximizing therapeutic benefits while minimizing unnecessary side effects.

In addition, researchers wish to combine data from different imaging techniques to study and model the brain at different levels, from molecules to cellular networks to the whole brain.

Challenge two: Perturbation-based neuroimaging. Much that we know about the brain relies on studies of dysfunction, when a problem such as a tumor or stroke affects a specific part of the brain and a correlating change in brain function can be observed.

But researchers also rely on techniques that temporarily ramp up, or turn off, brain activity in certain regions. What if the effects of such modifications on brain function could then be captured with neuroimaging techniques?

Being able to observe what happens when certain parts of the brain are activated could help researchers determine brain areas' functions and provide critical guidance for brain therapies.

Challenge three: Neuroimaging in naturalistic environments. Researchers aim to create new noninvasive methods for imaging the brain while a person interacts with his or her surroundings. This ability will become more valuable as new technologies that interface with the brain are developed.

For example, a patient undergoing brain therapy at home may choose to send information to his or her physician remotely rather than go to an office for frequent check-ups. The engineering challenges of this scenario include the creation of low-cost, wearable technologies to monitor the brain as well as the technical capability to differentiate between signs of trouble and normal fluctuations in brain activity during daily routines.

Other challenges the brain researchers identified are neuroimaging in patients with implanted brain devices; integrating imaging data from multiple techniques; and developing models, theories and infrastructures for better understanding and analyzing brain data. In addition, the research community must ensure that students are prepared to use and create new imaging techniques and data.

The workshop chair, Bin He of the University of Minnesota-Twin Cities, said, "Noninvasive human brain mapping has been a holy grail in science. Accomplishing the three grand challenges would change the future of brain science and our ability to treat numerous brain disorders that cost the nation over $500 billion each year."

The full workshop report was published in IEEE Transactions on Biomedical Engineering.

An imaging breakthrough

Engineers, in collaboration with neuroscientists, computer scientists and other researchers, are already at work devising creative ways to address these challenges.

The workshop findings place the new technique developed by the MIT and University of Vienna researchers into greater context. Their work had to overcome several of the challenges outlined.

The team captured neural activity in three dimensions at single-cell resolution by using a novel strategy not before applied to neurons--light-field microscopy, using a novel algorithm to reverse distortion, a process known as deconvolution.

The technique of light-field microscopy involves the shining of light at a 3-D sample, and capturing the locations of fluorophores in a still image, using a special set of lenses. The fluorophores in this case are modified proteins that attach to neuron and fluoresce when the neurons activate. However, this microscopy method requires a trade-off between the sample size and the spatial resolution possible, and thus it has not been before used for live biological imaging.

The advantage presented by light-field microscopy, here used in an optimized form, is that the technique may quickly capture the neuronal activity of whole animals, not simply still images, while providing high enough spatial resolution to make functional biological imaging possible.

"This elegant technique should have a large impact on the use of functional biological imaging for understanding brain cognitive function," said Leon Esterowitz, program director in NSF's Engineering Directorate, which provided partial funding for the research.

The researchers, led by Edward Boyden of MIT and Alipasha Vaziri of the University of Vienna, reported their results in this week's issue of the journal Nature Methods.

"Looking at the activity of just one neuron in the brain doesn't tell you how that information is being computed; for that, you need to know what upstream neurons are doing. And to understand what the activity of a given neuron means, you have to be able to see what downstream neurons are doing," said Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT and one of the leaders of the research team.

"In short, if you want to understand how information is being integrated from sensation all the way to action, you have to see the entire brain."

-- Cecile J. Gonzalez,
Investigators
Edward Boyden
Bin He
Related Institutions/Organizations
Massachusetts Institute of Technology
University of Minnesota-Twin Cities

NSF EXAMINES HIV BUDDING FROM CELLS

FROM:  NATIONAL SCIENCE FOUNDATION 

Catching HIV budding from cells: it all comes down to ALIX

Study shows last-minute role of specific protein named ALIX

The secrets of the AIDS virus may all come down to a protein named ALIX.

Researchers have devised a way to watch newly forming AIDS particles emerging or "budding" from infected human cells without interfering with the process.

The method shows that a protein named ALIX (which stands for "alg-2 interacting protein x") gets involved during the final stages of virus replication, not early on, as was believed. ALIX assists in separating new virus buds from a cell. These buds repeat the replication process and further infect their host.

"We watch one cell at a time" and use a digital camera and special microscope to make movies and photos of the budding process, says virologist Saveez Saffarian, a scientist at the University of Utah, and co-author of a paper on HIV budding published this week in the journal PLOS ONE.

"We saw ALIX recruited into HIV budding for the first time," he says. "Everybody knew that ALIX was involved in HIV budding, but nobody could visualize the recruitment of ALIX into the process."

The finding has no immediate clinical significance for AIDS patients because ALIX is involved in too many critical functions like cell division to be a likely target for new medications, Saffarian says.

"We know a lot about the proteins that help HIV get out of the cell, but we don't know how they come together to help the virus emerge," he says. "In the next 10 to 20 years, we will know a lot more about this mechanism."

Saffarian conducted the research with the paper's first author Pei-I Ku, as well as researchers Mourad Bendjennat, Jeff Ballew and Michael Landesman. All are with the University of Utah.

The research was funded by the National Science Foundation (NSF).

"This project has led to the development of an important technique in basic research in cell biology and virology," says Parag Chitnis, director of NSF's Division of Molecular and Cellular Biosciences.

"It's uncovering a new understanding of the viruses involved in human diseases," says Chitnis. "This is an excellent example of how purely basic research can lead to the fundamental understanding of topics of societal need."

Watch, don't touch, as HIV buds

Biochemical methods used for years involve collecting millions of viruses in lab glassware and conducting analyses to reveal the proteins that make up the virus--for example, by using antibodies that bind to certain proteins and using other proteins to make the first proteins fluoresce so they can be seen.

"You're not doing it one virus at a time," Saffarian says. "The problem is that you don't see the differences among similar viruses. And you don't see the timing of how various proteins come and go to help the virus get out of the cell."

Other methods freeze or otherwise fix cells as new HIV particles emerge, and use an electron microscope to photograph freeze-frame views of viral replication.

Saffarian employs technology known as "total internal reflection fluorescence microscopy" that looks at the dynamic processes in cells.

The method has been used to make images of the budding of HIV and a similar horse virus, EIAV.

But Saffarian says that the EIAV study didn't show ALIX becoming involved in HIV budding, and that it wrongly indicated that ALIX got involved early in the EIAV budding process, suggesting it did the same in HIV budding.

Ku, Saffarian and colleagues combined their microscopy method with an improved way of genetically linking a green fluorescent "label" to ALIX proteins in cloned cells so they could see the proteins without harming their normal function.

The researchers tried numerous so-called "linkers" and found the one that let them see the ALIX proteins as they became involved in HIV budding.

Neither the microscope technology nor labeling proteins with green fluorescence are new, but "what we did that is new is to connect these fluorescence proteins to ALIX using many different kinds of linkers," says Saffarian, to find one that let the ALIX protein function properly.

The problem with research that indicated ALIX was involved early in the budding process was that only one linker was used, and it impaired ALIX's normal function, the scientists say.

Looking at proteins forming HIV

When HIV replicates inside a human cell, a protein named Gag makes up most of the new particles--there are 4,000 copies of the Gag protein in one HIV particle--although other proteins get involved in the process, including ALIX.

Experiments like those by Saffarian use "virus-like particles," which are HIV particles stripped of their genetic blueprint or genome so they don't pose an infection risk in the lab.

"Virus-like particles maintain the same geometry and same budding process as infectious HIV," Saffarian says.

During budding, Gag proteins assemble on the inside of a cell membrane--along with ALIX in the late stages--and form a new HIV particle that pushes its way out of the cell--the process by which AIDS in an infected person spreads from cell to cell.

To look at the budding process, Ku and Saffarian placed human cells containing the particles in a small amount of liquid growth medium in a petri dish and placed it under the microscope, which is in a glass chamber kept at body temperature so the cells can remain alive for more than 48 hours.

A solid-state blue laser was aimed at the sample to make the green-labeled ALIX and red-labeled Gag proteins glow or fluoresce so they could be seen as they assembled into a virus particle.

With red-labeled Gag proteins and green-labeled ALIX proteins, "we could see ALIX come in at the end of the assembly of the virus particle," says Saffarian. Some 100 ALIX proteins converged with the roughly 4,000 Gag molecules and assembled into a new HIV particle.

Enter ALIX

ALIX then brought in two other proteins, which cut off the budding virus particle from the cell when it emerged. ALIX's position during the pinching off of new particles hadn't been recognized before.

The researchers watched the virus particles bud one cell at a time: about 100 particles emerged during a two-hour period. Most of the ALIX proteins left when HIV assembly was complete and returned to the liquid inside a cell.

Saffarian says the discovery that ALIX doesn't get involved until the late stages of HIV budding suggests the existence of a previously unrecognized mechanism that regulates the timing of ALIX and other proteins in assembling new HIV particles.

"We discovered that the cellular components that help with the release of the virus arrive in a much more complex timing scheme than predicted based on the biochemical data," he says.

"The outcome of this study is promising because it uncovers a new regulatory mechanism for recruitment of cellular components to HIV budding sites, and opens the door to exciting future studies on the mechanism of HIV budding."

U.S.-EU HAVE SUCCESS FIGHTING ANTIMICROBIAL RESISTANCE

FROM:  U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

US and EU progress in fight against antimicrobial resistance

International collaboration critical for combating global health crisis

The U.S. Department of Health and Human Services (HHS) and the European Commission released today the first progress report of the Transatlantic Taskforce on Antimicrobial Resistance (TATFAR).  The report renews the commitment of U.S. and European Union (EU) health authorities to pursue specific goals in their joint battle against antimicrobial resistance, a complex, dynamic and multi-faceted concern not bound by borders.  The report also summarizes the advancements made during the first TATFAR implementation period of 2011-2013.

TATFAR was created following the 2009 U.S.-EU presidential summit with the goal of improving cooperation between the U.S. and the EU in three key areas: (1) appropriate therapeutic use of antimicrobial drugs in medical and veterinary communities, (2) prevention of health care- and community-associated drug-resistant infections, and (3) strategies for improving the pipeline of new antimicrobial drugs.

“The partnership offers a unique perspective to tackle antimicrobial resistance worldwide,” said Jimmy Kolker, HHS Assistant Secretary for Global Affairs.  “We hope that the positive outcomes of this partnership will serve as a global model as we continue to work on this critical issue.”

TATFAR identified and adopted 17 recommendations for collaborations between the U.S. and the EU. Implementation of the recommendations has been carried out through increased communication, regular meetings, joint workshops, and the exchange of information, approaches, and best practices.  Moving forward, one new and 15 existing recommendations will serve as the basis for partner agencies in the U.S. and the EU to focus on areas where common actions can deliver the best results in prevention and control of antimicrobial resistance. In 2013 it was decided to renew TATFAR for another two-year term.

“Antimicrobial resistance is a priority of the European Commission, and international cooperation is key in addressing this serious cross border and global health threat.  I am positive that our renewed commitment to TATFAR can make a tangible contribution in the area of global health security,” said John F. Ryan, Acting Director for Public Health in the European Commission.

Notable outcomes of TATFAR activities during 2011-2013 include:

Adoption of procedures for timely international communication of critical events that might indicate new resistance trends with global public health implications;
Publication of a report on the 2011 workshop, “Challenges and solutions in the development of new diagnostic tests to combat antimicrobial resistance” to the TATFAR website; and Joint presentations to the scientific community to increase awareness about the available funding opportunities on both sides of the Atlantic.
Studies estimate that drug-resistant infections result in at least 25,000 deaths in 29 countries in Europe and 23,000 deaths in the U.S. every year.  In addition to the toll on human life, antimicrobial-resistant infections add considerable and avoidable costs to health care systems.  Antimicrobial resistance costs the EU and the U.S. billions every year in avoidable health care costs and productivity losses.

In the U.S. and in the EU, significant progress in reducing specific types of infections has been made.  However, the global problem of antimicrobial resistance continues to escalate. Therefore, the original mandate of the taskforce that ran through 2013 has been extended for at least two additional years.

Forthcoming publications from the taskforce during 2014 that will provide a foundation for specific joint collaborative actions include:

A report summarizing the strategies hospitals in the U.S. and EU should include as part of their programs to improve antimicrobial prescribing practices;
A joint publication summarizing the existing methods for measuring antimicrobial use in hospital settings;
A joint publication describing the need for new vaccines for healthcare-associated infections (HAIs); and
A joint publication comparing the results of the U.S. and EU point prevalence surveys, which are used to estimate the burden of HAIs in each population.

LEARNING TO ADAPT WHEN YOU'RE AN ARTIFICIAL BRAIN

FROM:  NATIONAL SCIENCE FOUNDATION 

Artificial brains learn to adapt

Neural networks imitate intelligence of biological brains

For every thought or behavior, the brain erupts in a riot of activity, as thousands of cells communicate via electrical and chemical signals. Each nerve cell influences others within an intricate, interconnected neural network. And connections between brain cells change over time in response to our environment.

Despite supercomputer advances, the human brain remains the most flexible, efficient information processing device in the world. Its exceptional performance inspires researchers to study and imitate it as an ideal of computing power.

Artificial neural networks

Computer models built to replicate how the brain processes, memorizes and/or retrieves information are called artificial neural networks. For decades, engineers and computer scientists have used artificial neural networks as an effective tool in many real-world problems involving tasks such as classification, estimation and control.

However, artificial neural networks do not take into consideration some of the basic characteristics of the human brain such as signal transmission delays between neurons, membrane potentials and synaptic currents.

A new generation of neural network models -- called spiking neural networks -- are designed to better model the dynamics of the brain, where neurons initiate signals to other neurons in their networks with a rapid spike in cell voltage. In modeling biological neurons, spiking neural networks may have the potential to mimick brain activities in simulations, enabling researchers to investigate neural networks in a biological context.

With funding from the National Science Foundation, Silvia Ferrari of the Laboratory for Intelligent Systems and Controls at Duke University uses a new variation of spiking neural networks to better replicate the behavioral learning processes of mammalian brains.

Behavioral learning involves the use of sensory feedback, such as vision, touch and sound, to improve motor performance and enable people to respond and quickly adapt to their changing environment.

"Although existing engineering systems are very effective at controlling dynamics, they are not yet capable of handling unpredicted damages and failures handled by biological brains," Ferrari said.

How to teach an artificial brain

Ferrari's team is applying the spiking neural network model of learning on the fly to complex, critical engineering systems, such as aircraft and power plants, with the goal of making them safer, more cost-efficient and easier to operate.

The team has constructed an algorithm that teaches spiking neural networks which information is relevant and how important each factor is to the overall goal. Using computer simulations, they've demonstrated the algorithm on aircraft flight control and robot navigation.

They started, however, with an insect.

"Our method has been tested by training a virtual insect to navigate in an unknown terrain and find foods," said Xu Zhang, a Ph.D. candidate who works on training the spiking neural network. "The nervous system was modeled by a large spiking neural network with unknown and random synaptic connections among those neurons."

Having tested their algorithm in computer simulations, they now are in the process of testing it biologically.

To do so, they will use lab-grown brain cells genetically altered to respond to certain types of light. This technique, called optogenetics, allows researchers to control how nerve cells communicate. When the light pattern changes, the neural activity changes.

The researchers hope to observe that the living neural network adapts over time to the light patterns and therefore have the ability to store and retrieve sensory information, just as human neuronal networks do.

Large-scale applications of small-scale findings

Uncovering the fundamental mechanisms responsible for the brain's learning processes can potentially yield insights into how humans learn--and make an everyday difference in people's lives.

Such insights may advance the development of certain artificial devices that can substitute for certain motor, sensory or cognitive abilities, particularly prosthetics that respond to feedback from the user and the environment. People with Parkinson's disease and epilepsy have already benefited from these types of devices.

"One of the most significant challenges in reverse-engineering the brain is to close the knowledge gap that exists between our understanding of biophysical models of neuron-level activity and the synaptic plasticity mechanisms that drive meaningful learning," said Greg Foderaro, a postdoctoral fellow involved the the research.

"We believe that by considering the networks at several levels--from computation to cell cultures to brains--we can greatly expand our understanding of the system of sensory and motor functions, as well as making a large step towards understanding the brain as a whole."

-- Sarah Bates,
-- Silvia Ferrari, Duke University
-- Greg Foderaro, Duke University
-- Xu Zhang, Duke University
Investigators
Silvia Ferrari
Pankaj Agarwal
John Albertson
Craig Henriquez
Gabriel Katul
Ronald Parr
Antonius VanDongen
Related Institutions/Organizations
Duke University

TO ONLY FALL ASLEEP, NSF EXAMINES RESEARCH

FROM:  NATIONAL SCIENCE FOUNDATION 

Finding a formula for zzzzzzzs

Math and a good night's sleep

We boast when our infant finally sleeps through the night. We bemoan the teenager who requires a cannon shot to arise from his bed before noon. And in our "golden" years, we wonder why sleep is so fleeting, yet napping seems to come as easily as breathing. Such are the mysteries of sleep.

And when we think of a way to understand sleep and wakefulness better, it's natural to think of biologists, behavioral scientists, neuroscientists and even mattress makers who for years have studied all kinds of animals and approaches to help us get a better night's sleep. The Centers for Disease Control (CDC) reports that 70 million Americans suffer from chronic sleep problems that range from insomnia and sleep apnea to narcolepsy, restless legs syndrome, and circadian rhythm disorders.

CDC's Sleep and Sleep Disorders Team, which evaluates the prevalence and impacts of sleep insufficiency and sleep disorders has said, "sleep deprivation is associated with injuries, chronic diseases, mental illnesses, poor quality of life..., increased health care costs and lost work productivity."

These days, researchers have found that in taking a collaborative approach to addressing sleep-related issues, mathematics needs to be part of the equation.

Janet Best, a National Science Foundation (NSF)-funded mathematician at The Ohio State University who is affiliated with the NSF-funded Mathematical Biosciences Institute there, has spent the past 10 years studying sleep-wake cycles using mathematical models.

"To understand sleep, we try to reformulate biological questions in terms of mathematics, typically systems of differential equations," she explained. "Sleep is both regular and random. It's regular in that we go to sleep generally at the same time of day. The randomness occurs in infants who seem to have no pattern to their sleep cycles and in the variability of when we might wake up during the night. I've been investigating how neural structures in the brain affect the random and regular transitions between sleep and wake."

By describing through equations the properties of neurons involved in sleep-wake brain circuitry, Best develops mathematical models for the way in which the neurons interact and influence each other. She checks model predictions against data that biologists have accumulated in studies involving both humans and rats. Surprisingly, baby rats' sleep patterns go through similar changes as those of human infants, but it is not clear how similar adult rat sleep is to human sleep.

"The idea is to see how people sleep normally, so we can understand when things go wrong," Best said. "Throughout the night we experience bouts of sleep and wakefulness. There's variability that we're aware of, but actually even more variability is occurring--we only recall longer wake episodes. However, both short and long episodes occur, and that's something I'm trying to understand. Experimentalists collect data on these wake-sleep bouts. Since the length of sleep and wake bouts and the transitions between them show some regular and some random behavior, the differential equations must have both of these facets."

Best became interested in sleep research as a doctoral student in mathematics after she had a bike accident. She suffered a serious head injury and began to experience simultaneous sleep and wakeful moments. In other words--not to be confused with daydreaming--she would experience dreams while being awake, and memories and dreams were being stored in a way that differentiating between the two was difficult. The medical literature of the time, however, said her experience was impossible.

"In 10 years, there have been a lot of changes in this field," she said. "Ten years ago, the emphasis was on regular patterns. Now the random aspects of sleep are getting more attention. Models are now based on the real underlying physiology."

That means that Best now spends a lot of time working with non-mathematicians. Beyond reading research papers by biologists and neuroscientists and using data from their experiments in her model, Best also works directly with sleep researchers who do experiments on rodents or who see patients clinically.

"You need a lot of interaction with biologists and medical scientists, and you have to have conversations with the people who generate the data," Best said. "If I relied just on reading the papers, I would not be able to understand all of the underlying hypotheses and the ways in which the data was collected, and that could significantly affect how I formulate the mathematical models."

Best's research benefits from the Mathematical Biosciences Institute at Ohio State, which hosts 12 workshops a year, drawing world-renowned bioscience experts and providing an important crossroads for biology and mathematics. Best, herself, collaborates with researchers both at Ohio State and at other institutions. In fact, she's currently on sabbatical at Duke University so she can work more closely with some of her collaborators there.

"The understanding of sleep-wake cycles can have enormous impact on developing a better knowledge of the dynamics of the brain and, in turn, how systems within an entire physiological organism interact and function," said Mary Ann Horn, an NSF Division of Mathematical Sciences program director. "Research that involves collaboration between mathematical and biological scientists gives rise to results for which not only does the biology inform the modeling and analysis, but also spurs new mathematical developments as novel techniques are developed to address these challenging questions."

"NSF support has been extremely important to my career," Best said. "It has allowed me to maintain a research group, support graduate students and devote myself 100 percent to my research during the times of year when my academic salary stops."

She believes the BRAIN Initiative, announced by the Obama Administration a little over a year ago, will also help advance this field of study, too.

"It's enormously difficult to figure out how the brain works," she said. "We're talking about 100 billion neurons, all this chemistry, hormones--so many variables. We have to infer how brains accomplish their tasks. And there are always multiple ways that a particular task can happen, so the challenge comes in teasing apart information, and in my case, building a good model that helps fill in the missing pieces."

Best and her collaborators are gradually doing just that when it comes to understanding sleep-wake cycles. Their findings indicate that the longer a "wake bout" during the night, the less likely it is that sleep will come along to interrupt it. And while one might think the same would be true for a "sleep bout," it doesn't appear to be. Sleep bouts seem to be equally prone to interruption at any moment. The mathematical models show how the structure of the neuronal network affects the timing of the sleep-wake bouts.

These findings may not sound particularly groundbreaking, but understanding interesting and unusual phenomena can give clues to the underlying sleep-wake mechanisms. Researchers investigate the mechanisms by transforming them into mathematical models and testing the models against data. If the models work well and provide a good understanding, then the researchers could potentially develop insomnia treatments, effective remedies for medical condition-induced sleep disorders, or strategies to reduce jet lag more quickly.

"There are a lot of data from sleep studies," Best said, "but data by itself does not give understanding. One must understand the underlying neural mechanisms. The sleep-wake field is growing very rapidly now, and this is providing new data for us to interpret and understand. The mathematical analysis and the comparison with new data should enable us to formulate a new understanding of how sleep-wake functions."

-- Ivy F. Kupec,
Investigators
Janet Best
Related Institutions/Organizations
Ohio State University
Mathematical Biosciences Institute