University Times

PSC gets $8.5 million NIH renewal

The Pittsburgh Supercomputing Center has received a five-year, $8.5 million grant from the National Institutes of Health’s National Center for Research Resources (NCRR), to renew its program in biomedical supercomputing.

Established in 1987, PSC’s biomedical supercomputing program — renamed National Resource for Biomedical Supercomputing (NRBSC) last year — was the first such program in the country external to NIH. Along with core research in the life sciences, NRBSC develops collaborations with biomedical researchers at many centers around the country and provides computational resources, outreach and training.

Since its inception, NRBSC has provided access to computing resources for more than 1,200 biomedical research projects involving more than 3,500 researchers at 245 research institutions in 46 states and two territories. NRBSC workshops on computational biology have trained more than 3,300 researchers in the use of high-performance computing for biomedical research.

The renewal award supports NRBSC’s research in three core areas: spatially realistic cellular modeling, large-scale volumetric visualization and analysis, and computational structural biology.

Spatially realistic cellular modeling centers on realistic three-dimensional cellular models to simulate the movements and reactions of molecules within and between cells, using software developed at NRBSC.

Volumetric visualization also uses software developed at NRBSC that enables multiple users to share, view and analyze very large-scale three- and four-dimensional datasets, such as time series of mouse cardiac function obtained from high-resolution CAT scan imaging.

Structural biology focuses on the development of computational tools used to determine the structure of proteins from their amino-acid sequence and also the development of quantum-mechanical simulation methods for biomolecules such as enzymes.

“Our long-term vision includes integration of these areas to enable multi-scale modeling of molecules, cells and tissues, with a substantial future impact on human health care,” said PSC senior scientist Joel Stiles.

Stiles, a medical doctor and computational physiologist, has faculty appointments in biology, computational biology and neuroscience at Pitt and Carnegie Mellon University. He also is scientific director of NRBSC.

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PennDOT grant will fund environmental research

The Pennsylvania Department of Transportation has awarded $2.1 million to Pitt to conduct environmental research for Interstate-99 road construction. The project examines construction methods that filter and channel water flow to help preserve native vegetation and wildlife. Rafael G. Quimpo, professor of civil and environmental engineering, is the project’s principal investigator.

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New 2-D model shows the way that pulsating gels pulse

One of the oddities of science is a class of polymers called Belousov-Zhabotinsky (BZ) gels that expand and contract on their own.

“They don’t need any external control — you put them in a bath of solution with some reagents, and they beat spontaneously like a heart,” said Anna Balazs, Distinguished Professor and Robert von der Luft Professor in the Department of Chemical and Petroleum Engineering and a researcher in Pitt’s Gertrude E. and John M. Petersen Institute of NanoScience and Engineering.

The oscillation occurs because the gels contain a metal catalyst linked to the backbone of their polymer chain. The movement results in beautiful patterns that can be seen by the naked eye.

The way those gels change shape had never been examined theoretically, until now.

Balazs, along with postdoctoral researcher Victor Yashin, has formulated the first general model to study large-scale shape changes in responsive gels. Their work has been published in the journal Science.

Previous calculations on the gels’ reactions have been able only to predict changes in their volume — how much the material would swell or shrink.

A new computer model created by Balazs and Yashin captures changes in the shape of the material as well. The researchers’ gel lattice spring model captures two-dimensional deformations and chemical reactions within a swollen network of polymers. The model represents the material as a lattice of springs, like hooked-together Slinky toys: When the material is deformed, it springs back.

When Balazs and Yashin applied their new technique to gels undergoing the BZ reaction, they observed traveling waves of local swelling that formed a rich variety of dynamic patterns and gave rise to distinctive oscillations in the gel’s shape.

“This will open up a whole new field for studying morphological transformations in this soft material,” said Balazs. “It is a nice computational tool for starting to investigate shape changes in gels.”

The gels have potential as materials that can do active work. They could be the artificial muscle for a micro-sized robot, for example, or could deliver pulses of drugs to a patient.

“You could make little autonomous devices for a couple hours and, when they stop running, add more reagent,” said Balazs.

In future studies, Balazs plans to take advantage of the 2-D network construct to examine chemically or physically heterogeneous gels.

The research was funded by the National Science Foundation.

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Certain anesthetics may promote amyloid plaques

Giving elderly patients certain general anesthetics could increase their risk of developing Alzheimer’s disease and other memory and attention problems, said researcher Pravat Mandal.

The finding, based on recent experiments, suggests that anesthetists need to log more carefully the combinations and doses of anesthetics they give their patients in order to properly assess the risks.

Doctors have been aware of a link between surgery and cognitive problems for decades, but it has not been clear whether post-operative cognitive dysfunction was the result of the surgery itself or the anesthetics, said Mandal, an assistant professor of psychiatry in the School of Medicine.

While it has been suggested that heart bypass surgery in particular could make the protective blood-brain barrier leaky, allowing immune tissue or unwanted debris into the brain, animal studies and test tube experiments are beginning to show that certain anesthetics reduce the rate at which brain cells are born and develop, a factor that seems to be important to normal memory function.

They also may affect the rate at which beta amyloid proteins bind together, a cause for concern since the formation of clumps or “plaques” of beta amyloid is characteristic of Alzheimer’s disease and may contribute to brain cell death.

At the annual meeting of the Society for Neuroscience last month, Mandal presented findings that the inhaled anesthetics halothane and isoflurane encourage clumping of beta amyloid protein, as do high concentrations of the commonly used intravenous anesthetic propofol. The work also was published in the Oct. 28 issue of New Scientist.

The findings back up a previous study in which Mandal used NMR spectroscopy to show that halothane interacts directly with a pocket in the beta amyloid protein, changing its shape and encouraging neighboring proteins to bind. As little as six hours of exposure to halothane is sufficient to trigger protein clumping similar to that seen in people with Alzheimer’s, he said.

Although halothane rarely is used in North America or Europe, it is commonly used in Asia and Africa because it is very cheap. “It is a seriously deadly combination when an older person receives halothane,” said Mandal, noting that as people age, the amount of beta amyloid in the brain increases.

The other anesthetics studied are used more widely in the U.S. and Europe, often in combination, although these seem to take longer to exert their potentially deadly effects, he said. Another intravenous anesthetic, thiopental (also known as thiopentone,) appears to have no effect on the proteins, he said.

Mandal said he hopes that the findings will prompt further study of the dangers and benefits of each anesthetic. “The main focus should now be using an anesthetic that does not have any undesirable and deadly effects,” he said.

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Researchers garner NARSAD awards

Pitt researchers were among the recipients of the National Alliance for Research on Schizophrenia and Depression’s top prizes for outstanding achievements for psychiatric research.

David A. Brent was awarded the Ruane Prize for Child and Adolescent Psychiatric Research, Susan Amara received a Distinguished Investigator Award and nine other Pitt/Western Psychiatric Institute and Clinic researchers were awarded 2006 Young Investigator awards.

NARSAD’s annual prizes are awarded to scientists for outstanding achievements in the areas of schizophrenia, mood disorders, childhood and adolescent disorders and cognitive neuroscience research.

The Ruane prize goes to outstanding scientists carrying out research on the causes, pathophysiology, treatment and prevention of severe childhood psychiatric illness. Brent shares this year’s award with David Shaffer of Columbia University.

Brent is academic chief in the Division of Child and Adolescent Psychiatry at WPIC and holds an endowed chair in suicide studies at the School of Medicine. His research has focused on the study of risk factors for adolescent depression and suicidal behavior and the translation of those findings to the prevention and treatment of these conditions.

Amara, the Thomas Detre Professor and chair of the Department of Neurobiology and co-director of Pitt’s Center for Neuroscience, will identify and study genes in zebrafish that affect the actions of the reuptake inhibitor class of antidepressants. Findings from Amara’s study are expected to increase knowledge about the mechanism of action of antidepressant medications.

The Distinguished Investigator Award was created to support significant research by established scientists — full professors or their equivalent — who are on the cusp of a breakthrough. Amara has been awarded a one-year grant of $100,000 to advance her project. She is among 20 scientists who are receiving the award this year in the competitive grant program.

NARSAD Young Investigator Awards went to Pitt researchers:

— Ranita Basu, to study why people with schizophrenia are at increased risk for cardiovascular disease.

— Kodavali Venkata Chowdari, to study the relationship between schizophrenia and the gene GAD67, which codes for a protein involved in the expression in the brain of the neurotransmitter GABA.

— Erika E. Forbes, to use imaging and behavioral tests to monitor how adolescents with major depressive disorder deal with positive emotions.

— Takanori Hashimoto, to examine alterations that appear to underlie working, or short-term, memory deficits in schizophrenia.

— Hank P. Jedema, to conduct studies of neural system interaction in mood and anxiety disorders to learn how a brain structure called the bed nucleus of the stria terminalis mediates stress in healthy and depressed individuals.

— Cecile D. Ladouceur, to use imaging technology to see whether adolescents at risk for bipolar disorder show brain abnormalities before the onset of symptoms.

— Daniel Lodge, to study aberrant signaling of the neurotransmitter dopamine, believed to play a major role in schizophrenia.

— Clinton B. McCracken, to work with a rodent model to determine how deep brain stimulation produces its therapeutic effects in treatment-resistant depressed patients.

— Holly A. Swartz, to investigate whether psychotherapy, which has shown to be effective for people with bipolar disorder I, also works for bipolar disorder II.

NARSAD created the Young Investigator Award to help promising scientists entering research (such as post-doctoral fellows, advanced standing medical residents and assistant professors) generate pilot data necessary to obtain larger grants. Each researchers will receive $60,000 from NARSAD over the next two years for their respective studies.

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Genetic link to Crohn’s disease discovered

A new genetic link to Crohn’s disease has been discovered by a consortium of researchers that includes several from Pitt. The discovery is reported in Science Express, an online publication posted by the journal Science.

While most of the mutations in the gene, which codes for a receptor in a major inflammatory pathway, are strongly associated with Crohn’s, one type of mutation appears to confer significant protection. The finding, say the researchers, points to a crucial target for drugs that might better manage Crohn’s disease and ulcerative colitis (collectively known as inflammatory bowel disease or IBD).

Previous genetic studies found a link between Crohn’s disease and mutations in a gene known as CARD15, but those mutations alone are not considered to account for all of the genetic components of the disease. In the current study, researchers scanned the genes of people with and without Crohn’s disease and found three genes most strongly associated with the disease. Of those, two were in the CARD15 gene, but the third variation was in a different gene on a different chromosome. That variation coded for a protein that is part of the immune cell receptor for interleukin-23 (IL-23), an important mediator of inflammation.

When researchers began looking for all of the variations in the IL-23 receptor gene of affected individuals to determine which ones were the most detrimental, they found that several variations were associated with increased risk but one appeared to confer a very strong protection against IBD.

In an early stage clinical trial led by other investigators, IBD patients given a monoclonal antibody that blocks IL-23 and a related inflammatory mediator saw their conditions improve. And recent studies in mice in which the gene for IL-23 is deleted showed that IL-23 is essential for the development and maintenance of chronic intestinal inflammation. Such evidence, combined with the current discovery, suggests therapies that target the IL-23 pathway may lead to more individualized, better-directed therapies for IBD, the authors said.

“Crohn’s and colitis are chronic conditions that profoundly impact the day-to-day lives of affected individuals,” said first author of the study, Richard H. Duerr, associate professor of medicine and human genetics at Pitt. “Moreover, IBD often runs in families, making the pinpointing of the responsible genes especially important if we are to find ways to better treat or even prevent IBD.”

The study’s authors represent the IBD Genetics Consortium, which is funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

In addition to Pitt, the consortium’s member institutions include Yale, Cedars-Sinai Medical Center in Los Angeles, the University of Chicago, Johns Hopkins University, Université de Montréal, Mount Sinai Hospital in Toronto and the University of Toronto.

Other Pitt authors are Miguel Regueiro, associate professor of medicine at the School of Medicine and co-director of UPMC’s Inflammatory Bowel Disease Center, and M. Michael Barmada, associate professor of human genetics, Graduate School of Public Health.

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Stem cells from fat may aid breast reconstruction

Breast cancer survivors might one day avoid the prospect of invasive breast reconstruction surgery, opting instead for an approach that would involve using stem cells derived from their own fat, suggest Pitt researchers who are studying the potential these cells may have for regenerating new breast tissue.

In animal models, the researchers hope to prove that an injection of fat-derived stem cells that are seeded onto microscopic scaffold structures will enable the production of a durable, replacement soft tissue. The team, led by J. Peter Rubin, assistant professor of plastic and reconstructive surgery at the School of Medicine, recently received a three-year grant from the National Cancer Institute to study the issue.

“The surgical options for breast reconstruction involve either the use of implants or a procedure whereby fat tissue taken from another part of the body is shaped into the form of a breast. Neither is ideal nor without risk. The use of adipose or fat-derived stem cells may represent a better solution for soft tissue reconstruction in breast cancer patients,” said Rubin, who also is co-director of the Aesthetic Surgery Center at UPMC.

The use of stem cells to treat disease or regenerate tissue is believed to hold promise because of their potential to develop into different specialized cell types. In other studies, fat-derived stem cells have been shown to differentiate into cells characteristic of those from tissues such as fat, bone, cartilage, nerve, muscle and blood vessels.

Rubin and his colleagues are focusing their efforts on an approach that involves combining fat-derived stem cells taken from breast cancer patients with microscopic beads composed of a type of extracellular matrix that has regenerative properties. Preliminary results indicate that the stem cells easily can attach themselves to these beads and are able to differentiate into mature fat cells. When injected under the skin in a rat model, the cellular combination eventually formed a “mound” of tissue.

“We need to demonstrate that fat-derived stem cells taken from a breast cancer patient behave no differently than those from other women. Moreover, our studies will seek to understand what effect, if any, these stem cells may have on cancer cells. A major question is whether they will in some way promote the growth of cancer cells. We certainly hope this proves not to be the case,” Rubin said.

A 2001 study by researchers from Pitt and UCLA first reported that adult stem cells could be isolated from fat. Since then, laboratory studies have suggested fat-derived stem cells have potential for treating heart attack, stroke or bone injury, although there have been no clinical trials in the United States to date.

Working with Rubin on the NIH-funded grant are co-investigators Kacey G. Marra, Division of Plastic Surgery, School of Medicine, and the Department of Bioengineering in the School of Engineering; Albert D. Donnenberg from the Division of Hematology/Oncology and the University of Pittsburgh Cancer Institute (UPCI), and Vera S. Donnenberg of the Department of Surgery and UPCI.

Stephen Badylak of the Department of Surgery and the McGowan Institute for Regenerative Medicine and Howard D. Edington of the Division of Surgical Oncology and the McGowan Institute were consultants.

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Researchers find what ancient horses left behind

Soil from a Copper Age site in northern Kazakhstan has yielded new evidence for domesticated horses up to 5,600 years ago. Researchers from Pitt and the Carnegie Museum of Natural History have discovered phosphorus-enriched soils inside what appear to be the remains of horse corrals beside pit houses. The soil matches what would be expected from earth once enriched by horse manure.

The Krasnyi Yar site was inhabited by people of the Botai culture of the Eurasian Steppe, who relied heavily on horses for food, tools and transport. The latest evidence was on display recently at the annual meeting of the Geological Society of America.

“There’s very little direct evidence of horse domestication,” said Sandra Olsen, a Carnegie museum archaeologist and horse domestication researcher. That’s because 5,600 years ago there were no saddles or metal bits to leave behind. Equipment like bridles, leads and hobbles would have been made from thongs of horsehide and would have rotted away long ago.

Likewise, horses themselves have not changed much physically as a result of domestication, unlike dogs or cattle. So ancient horse bones don’t easily reveal the secrets of domestication.

With research funding from the National Science Foundation, Olsen’s team took a different tack. They looked for circumstantial evidence that people were keeping horses. One approach was to survey the Krasnyi Yar site with instruments to map out subtle electrical and magnetic irregularities in the soils. With this they were able to identify the locations of 54 pit houses and dozens of post molds where vertical posts once stood. Some of the post molds were arranged circularly, as would be most practical for a corral.

Michael Rosenmeier, an assistant professor of geology and planetary science, collected soil samples from inside the fenced area and outside the settlement. His colleague, associate professor Rosemary Capo, and her students analyzed the samples for nitrogen, phosphorus, potassium and sodium. They found that soil from what were thought to be corrals had concentrations of phosphorus up to 10 times greater than the surrounding soil.

Lots of phosphorus also can indicate a hearth, said Capo, but that phosphorus usually is accompanied by a lot of potassium, which was not the case in the corral at Krasnyi Yar, leading the team to conclude the phosphorus was the remnants of ancient horse manure.

The corral soils also had low nitrogen concentrations, said Capo, reducing the likelihood that the phosphorus came from more recent manure. “That’s good, actually,” she said of the recently completed nitrogen analyses. “It suggests we’ve got old stuff.”

“Even more compelling will be if we find long-lived molecules of fat, or lipids, directly attributed to horse manure in the soils,” said Olsen.

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Pitt, CMU scientists contribute to rare subatomic particle discovery

Researchers at the U.S. Department of Energy’s Fermi National Accelerator Laboratory Collider Detector at Fermilab (CDF), a collaboration that includes researchers from Pitt and Carnegie Mellon University, have discovered two rare types of particles — exotic relatives of the more common proton and neutron.

“Ordinary matter consists of only two of the lightest quarks plus the lightest lepton, known as the electron,” said Joseph Boudreau, associate professor of physics and astronomy at Pitt, who was involved in the research with Pitt professor of physics and astronomy Paul Shepard. “The heavier forms of matter exist only for short periods of time, but they’re just as crucial to our understanding as the stable forms. You can’t explain the proton, the neutron or the electron without explaining the heavier members of the family,” Boudreau said.

The particles, named Sigma-b, are exotic composites, new ways of putting together the heavy and light quarks. “We infer their existence from observing their decay products, and we’re only seeing them now because even the decay products are pretty rare,” Boudreau said.

“The proton and neutron family tree has several different branches,” said CMU physics professor James Russ. “These new particles are very similar to other relatives of the proton studied at Fermilab and elsewhere in a variety of experiments.”

Russ and fellow CMU physics faculty member Manfred Paulini study particles containing heavy quarks as part of the CDF collaboration.

“These particles are like rare jewels that we mined out of our data,” said CDF spokesman Jacobo Konigsberg of the University of Florida. “Piece by piece, we are developing a better picture of how matter is built out of quarks. We learn more about the subatomic forces that hold quarks together and tear them apart. Our discovery helps complete the ‘periodic table of baryons.’”

Baryons, derived from the Greek word barys, meaning “heavy,” are particles that contain three quarks, the most fundamental building blocks of matter.

The CDF collaboration discovered two types of Sigma-b particles, each one about six times heavier than a proton.

The CDF experiment identified 103 positively charged Sigma-b particles and 134 negatively charged Sigma-b particles by culling through more than 100 trillion high-energy proton-antiproton collisions produced by Fermilab’s Tevatron collider particle accelerator over the last five years.

Other Pitt researchers involved in the work were postdoctoral research fellows Azizur Rahaman and Karen Gibson and graduate students Chunlei Liu and Mark Hartz.

CDF is an international experiment of 700 physicists from 61 institutions and 13 countries. It is supported by the Department of Energy, the National Science Foundation and a number of international funding agencies. Fermilab is a national laboratory funded by the Office of Science of the U.S. Department of Energy, operated under contract by Universities Research Association, Inc.

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Proteins that affect memory studied

An hour from now, will you remember reading this? It all depends on proteins in your brain called NMDA receptors, which allow your neurons to communicate with each other.

Jon W. Johnson, a Pitt associate professor of neuroscience, and former Pitt graduate student Anqi Qian, now of Carnegie Mellon University in Qatar, have discovered how different types of NMDA (N-methyl-d-aspartate) receptors perform varied functions. Their findings are published in the current issue of the Journal of Neuroscience.

Communication between cells in the brain depends on specialized molecular receptors that conduct charged particles, or ions, between the outside and inside of cells. Ions also modify how receptors work.

Johnson and Qian studied the effects of ions on receptors and found them to vary between different types of receptor molecules. They used computer modeling to show that variation in how ions interact with receptors combined with variation in the structure of receptors is responsible for specialization of receptor function.

“This research helps explain how evolution accomplished a critical goal: producing receptor proteins with finely tuned properties that help optimize brain function,” said Johnson.

A better understanding of how NMDA receptors work could lead to better treatments for schizophrenia, Alzheimer’s disease and stroke, said Johnson.

This research was funded by the National Institutes of Mental Health.

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Rx + computer games better for Alzheimer’s patients

Computer-based tasks aimed at increasing mental activity and enhancing mental function can improve cognition in patients with Alzheimer’s disease, serving as an effective addition to medications commonly used to treat the disease. Researchers found that online computer activities were even more successful than classic mental stimulation exercises commonly used with dementia patients.

The findings, from a joint study between the Pitt School of Medicine and researchers in Barcelona, Spain, were published in the October issue of the Journal of Neurology, Neurosurgery and Psychiatry.

“This study shows that tasks aimed at increasing or maintaining mental function have a place in treating Alzheimer’s alongside pharmacotherapy,” said Oscar Lopez, professor of neurology at the School of Medicine and study co-author.

“While further study is needed, it is encouraging to find that an Internet-based program can work for cognitive stimulation, making it easily available.”

The study, conducted at an adult daycare center and clinic for dementia patients in Barcelona, divided 46 Alzheimer’s disease patients, all of whom were taking cholinesterase inhibitors, into three groups. Some stayed at home and did not participate in activities at the center. The second group participated in a daily program that included 2.5-3.5 hours of cognitive stimulation tasks, musical therapy, arts and crafts, physical activity and programs that reinforced activities of daily living. The third group participated in the same activities plus used an interactive multimedia Internet-based system (IMIS) of cognitive stimulation tasks, 20 minutes a day, three times a week for 24 weeks.

After 12 and 24 weeks of treatment, participants were assessed using standard measures of cognitive function and performance.

After 12 weeks, the group that participated in both the daily program and IMIS showed improved cognitive function and performance on standard assessments that remained at 24 weeks. The group that received only the daily program showed improvement over the control group at 12 weeks, but the effects diminished by 24 weeks.

“While Alzheimer’s disease is a progressive degenerative condition, studies have shown that in the early stages, the brain is still able to learn and change. This indicates that increasing brain activity, especially in regards to memory and cognition, may help stave off cognitive loss in people with Alzheimer’s,” said James T. Becker, professor of psychiatry, neurology and psychology at Pitt and a co-author on the study.