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November 25, 2015

Research Notes

Cleft lip & palate genomes studied

A federal initiative to accelerate research into pediatric diseases and conditions will fund an effort led by the School of Dental Medicine and the Graduate School of Public Health to examine the entire genomes of nearly 1,300 people to learn more about the causes of cleft lip and palate and look for treatments.

In its first round of funding under the Gabriella Miller Kids First Research Act, the National Institutes of Health, Office of the NIH Director, selected this proposal to sequence the whole genomes of 430 children with clefts and their parents. According to NIH, this is among the largest whole-genome sequencing effort to examine an oral condition that it has ever initiated.

Said project director and principal investigator Mary L. Marazita, faculty member and vice chair of dental medicine’s Department of Oral Biology and director of the Center for Craniofacial and Dental Genetics: “This sequencing will provide a wealth of data that will be made available to scientists everywhere, providing the basis for years of research into causes, prevention and treatment of cleft lip and palate.”

Cleft lip and palate are among the most common birth defects, affecting about 1 in 700 babies. It occurs when a baby’s lip or mouth does not form properly during pregnancy, leaving a gap that can make it hard for the child to eat or speak. In about 70-80 percent of cases, the cause is believed to be due at least in part to genetics, but other factors, such as smoking during pregnancy, also can contribute to the chance of having a child with cleft lip or palate.

Said principal investigator Eleanor Feingold, faculty member in human genetics and senior associate dean at the public health school: “In addition to looking at variations in genes that might lead us to treatments, we’re also looking for answers for parents who have a child with a cleft and want to know if any future children are at risk. This project will help us improve genetic counseling so we can tell parents if their family is predisposed to cleft lips and palates or if it’s a genetic aberration that is highly unlikely to happen again.”

Marazita has studied cleft lip and palate since the 1980s, building a database of almost 6,000 families with the condition. The research team will mine that database for appropriate “trios” — mother, father and child with cleft lip or palate — who will have their whole genomes sequenced to find the variations that caused the child’s cleft.

This will allow researchers to determine if the child’s cleft was from a variant passed along by one of the parents or if it arose spontaneously.

Pitt will provide DNA samples for 430 trios to the McDonnell Genome Institute at Washington University in St. Louis for sequencing. In about three months, the information will come back to Pitt for analysis and will be shared through a centralized data repository.

Additional co-investigators from Pitt are Elizabeth Leslie, Seth Weinberg, Alexandre Vieira and Manika Govil of dental medicine and John Shaffer of public health.


Lower pregnancy weight reduces risk of infant death

Achieving a healthy weight before becoming pregnant and gaining an appropriate amount of weight during pregnancy significantly reduce the risk of the baby dying in his or her first year of life, according to new research from Pitt’s public health school.

The findings, published in Obesity, highlight the need for a comprehensive approach to obesity reduction among women of reproductive age that includes weight counseling before conception and during pregnancy.

Said lead author Lisa Bodnar, faculty member in the Department of Epidemiology: “One in three women start pregnancy at an unhealthy weight, and more than half of women gain either too much or too little weight during pregnancy. While more research needs to be conducted, we are hopeful that this study can be used to start a dialogue between physicians and women on the importance of not only gaining a healthy amount of weight while pregnant, but also reducing excess weight before they become pregnant as a potential way to improve infant survival.”

Every year, approximately 24,000 infants die in their first year of life in the United States. The U.S. rate of 6.1 deaths per 1,000 live births ranks 26th in the world, despite a 20 percent decline in the U.S. infant mortality rate from 1990 to 2010.

Bodnar and her colleagues examined records from more than 1.2 million births that occurred from 2003 to 2011 in Pennsylvania, including 5,530 infant deaths. Infant deaths were defined as the death of an infant before his or her first birthday.

The mothers were classified as underweight, normal weight, overweight or obese according to three grades, based on their pre-pregnancy body mass index — a measure of weight versus height. In each weight group, the researchers also examined the impact on infant mortality when women gained significantly more or less weight during pregnancy than Institute of Medicine guidelines which, for example, recommend a weight gain of 25-35 pounds for normal-weight women and 11-20 pounds for obese women.

In all the weight classes except the most obese, gaining less than or much more than recommended amounts increased the risk of infant death. However, even when obese women gained the optimal weight during pregnancy, their risk of infant death still was about twice as great as that of women who began pregnancy at a normal weight.

Said co-author Katherine Himes, faculty member in the School of Medicine’s Department of Obstetrics, Gynecology and Reproductive Health: “Obesity and infant mortality are among the most critical public health issues today. Our study highlights the importance of discussing weight loss with obese women prior to pregnancy because losing weight during pregnancy may increase the risk of her baby dying. We hope this information empowers providers, including obstetricians, family doctors and primary care physicians, to discuss the benefits of preconception weight loss with all obese, reproductive-age women.”

Additional Pitt authors on this research were Lara Siminerio and Sara Parisi. Also contributing were colleagues from the University of British Columbia, Emory University and the University of California-Berkeley.

The research was funded by NIH and the Thrasher Research Fund.


Hillman Foundation funds additional DC power work

In the late 1880s, Pittsburgh native George Westinghouse (using the work and genius of Nikola Tesla) won the campaign to base the United States’ electric power grid on alternating current (AC). Thomas Edison, a proponent of direct current (DC), tried to paint AC as dangerous, but as things stood at the time, an AC grid was cheaper and more efficient, could carry electricity over longer distances, and was easier to build, so it prevailed.

Over the past year, with the help of a $400,000 grant from the Henry L. Hillman Foundation, Gregory Reed, director of the Center for Energy and the Swanson School of Engineering’s Electric Power Systems Lab and faculty member in electrical and computer engineering, established the DC-AMPS program (Direct Current Architecture for Modern Power Systems) and has been working to bring DC technology to the forefront, as well as bringing local and regional companies, the City of Pittsburgh and community partners into the fold.

Reed has received another Hillman grant, totaling $2.5 million over three years, to build upon the initial success of the DC-AMPS program, to bring a DC power grid even closer to fruition, and to make Pitt and Pittsburgh the epicenter of an emerging DC power industry.

Said Reed: “We want to be the place where everybody comes to benchmark DC developments and to be a leading region of research and demonstration in this emerging technological field. We want to draw more and more companies and end-users to the region to work with us, to be part of these important developments that are related to energy reliability and security, and to support economic development and job growth.”

Reed’s approach specifically addresses DC technology and is focused on finding ways to, in the not-too-distant future, upgrade the longstanding AC power grid to more of a DC grid, which he believes has become a more efficient and logical way of addressing energy-delivery needs, especially in the 21st century and beyond.

“Your laptop runs on a few volts DC; it has to be converted from AC by that box, the converter on the power cord,” he noted. The same is the case for high-definition televisions, most appliances, cell phones and other consumer devices and office and business equipment, including data centers and new forms of lighting.

“Very few items today require three-phase alternating current. The use and development of today’s evolving energy mix, which includes more DC resources such as solar photovoltaics, as well as electric vehicles and battery storage systems, also makes the transition to DC more sensible and viable for future power-delivery needs.”

Reed and members of his lab also are advancing research into high-voltage DC systems, which present the potential of developing a commercially viable high-voltage DC grid.

“We’d like to develop DC microgrids, community microgrids in residential developments, offices, commercial buildings and industrial facilities,” he added. “I’ve been working on this for well over a decade, and we know that DC offers a much better match between energy transmission and utilization in many applications.”

To achieve these ends, Reed and colleagues face several technological challenges. Reed says that his team will work to develop better power electronics conversion and control systems (like the aforementioned box on a laptop’s power cord), better integration technologies for the power generated by DC microgrids, and possibly new electronic devices compatible with DC power.


Network diagnosis, repair improved

A proposed automated system will allow users to provide network administrators with information about faulty connections, greatly speeding network diagnosis and repair. This system, to be called TestRig 2.0, is the goal of a new $300,000 National Science Foundation grant to researchers at the Pittsburgh Supercomputing Center (PSC), a joint effort of Pitt and Carnegie Mellon University.

Said Chris Rapier, PSC senior research programmer and principal investigator for the grant: “When researchers encounter network problems, they naturally reach out to network engineers. However, the engineers have to rely on the user to provide them with enough information to properly diagnose the problem. This means multiple rounds of email, phone calls, tests and oftentimes results in significant delays.”

It’s not unusual for this process to take days, if not weeks, before the engineers receive enough information to start their diagnosis and implement a solution. TestRig will get around this back-and-forth cycle, giving the user a dynamically generated Linux disk image that reboots the system into a known good environment and automatically performs a variety of tests. TestRig then will send the test results to the appropriate network engineer without user intervention.

“It’s automated from start to finish,” Rapier added. “So where it once took days to collect the relevant information, it can now be completed in less than 15 minutes.

Importantly, TestRig will be made available to network operations centers (NOCs) and engineers without requiring the installation of any local infrastructure. “The goal is to make this as easy as possible,” Rapier said. “So instead of having the NOCs install servers, distribute the bootable disk images and maintain databases, we’ll do all that for them. All they will need to do is sign up for our service and create a local account that can receive the files.”

TestRig will perform tests using existing perfSONAR network measurement servers. The project builds on PSC’s ongoing Web10G effort to open TCP/IP networking protocols so that network administrators and users can identify and repair networking problems.


Partnership aims at rare diseases

Pitt has a new research collaboration with global biopharmaceutical company Shire designed to advance potential treatments for rare diseases, where sizable unmet need exists.

According to patient advocacy organization Global Genes, rare diseases affect more than 320 million people worldwide — 10 times the number affected by all cancers combined and approximately the same number who suffer from the global epidemic of diabetes.

Scientists have identified thousands of rare diseases, often having origins in genetic mutations that can be passed from one generation to the next.

These rare diseases usually are extremely severe, cause significant suffering and very often result in death early in life. While each individual disease generally affects fewer than several hundred thousand people, collectively these rare diseases account for a massive global burden of underserved patients.

Said Dietrich Stephan, who is leading the collaboration for Pitt and is chair of public health’s Department of Human Genetics: “Our scientific teams have been among the most prolific in determining the fundamental causes of rare diseases over the past decades.

“Based on these new insights into the core pathogenesis of rare diseases, we have, in many cases, developed new preclinical models of disease and lead compounds to fuel new drug development — the essential ingredients for this broad-based partnership in the rare disease area.

“Given the scale of resources and level of expertise within this partnership, I am hopeful many new life-changing therapies will be developed,” Stephan added.


Brain implant technology advanced

With the potential to allow quadriplegics to operate robotic limbs, to reverse damage caused by Parkinson’s disease and to map the pathways of the 100 billion neurons of the brain, microelectrode arrays — or electronic brain implants — are key to the human-computer interface. Two NIH grants totaling $4.7 million, awarded to researchers at the Swanson school, will help to further research in improving how the implants perform in the brain and survive the body’s immune responses.

Implants come in many shapes and sizes and contain anywhere from one to hundreds of electrodes in a single array. Large arrays allow for better connectivity with the brain, but they also have a greater risk of triggering the body’s defense mechanisms. This causes inflammation of the neural tissue, which can significantly reduce the quality of the implant’s signals over time. Even though it won’t cause harm to the patient, the body’s rejection of foreign substances is one of the major obstacles limiting the usage of microelectrode arrays.

Researchers at the Neural Tissue/Electrode Interface and Neural Tissue Engineering (NTE) Laboratory have been developing ways to integrate the implants with the host neural tissue. Last summer, Xinyan “Tracy” Cui, William Kepler Whiteford Professor of bioengineering and director of the NTE lab, received an NIH grant to research a method of disguising microelectrode arrays by coating them with biological molecules the brain won’t recognize as intruders.

The new grants from NIH will expand the NTE lab’s research into other areas of microelectrode array technology. Cui will serve as principal investigator of “Inhibition of Neural Electrode-Mediated Inflammation and Neuronal Cell Death.” The study will receive $3.1 million over five years and will uncover the role of the caspase-1, an enzyme activated at the earliest detectable moment after ischemia, trauma and other neurodegenerative conditions.

Said Chui: “Caspase-1 is a key mediator of both inflammation and programmed cell death, both of which are thought to degrade neural recording and stimulation performance. Once we identify it as a major pathway, we can disrupt it.

“In this new study, we are going to use two-photon live animal imaging in conjunction with molecular and electrophysiological methods to study the cellular response around the electrode implant site in real-time.”

Takashi “TK” Kozai, bioengineering faculty member in the Swanson school, will lead the two-photon imaging, which can capture images at a deep level of tissue in live animals. Although this form of microscopy has become popular in neuroscience and biology, it has not been widely used to examine the interaction between electrode implants and brain tissue.

Kozai established the Bio-Integrating Optoelectric Neural Interface & Cybernetics Lab and will serve as the principal investigator of the other NIH grant study awarded this year. “Mechanisms Behind Electrode Induced BBB Damage’s Impact on Neural Recording” will receive about $1.6 million for five years. Kozai will examine the damage to the brain caused by blood-brain barrier (BBB) injury from probe implantation.

BBB injury has been found around implanted electrodes, but the extent and the cause-and-effect mechanism underlying BBB damage and neural recording failure has not been established.

After mapping the brain vasculature with two-photon microscopy, Kozai will implant one group of electrodes that pass through large arterioles and another group that avoids major blood vessels.

By comparing the performance of electrodes in the two situations and tracking dynamic changes with two-photon microscopy, Kozai will be able to determine the impact of BBB damage on signal degradation recorded from the implants.

The Pitt co-investigators on these two grants are Alberto Vazquez, Robert Friedlander, Diane Carlisle and Simon Watkins.


Chronic arsenic exposure impairs muscle healing

Chronic exposure to arsenic can lead to stem cell dysfunction that impairs muscle healing and regeneration, according to an animal study conducted by researchers in medicine and public health.

In a report published in the journal Stem Cells, the researchers noted that inhibiting a certain protein in an inflammatory pathway can reverse the harmful effects and that environmental exposures might explain why some people don’t recover easily after injury or surgery.

More than 140 million people worldwide and 4 million Americans chronically ingest arsenic in their drinking water. The 21st most abundant metal in the Earth’s crust, arsenic is naturally present in soil and bedrock-walled wells and has no odor, color or taste.

Said senior investigator Fabrisia Ambrosio, faculty member in physical medicine and rehabilitation: “Whereas previous research has examined the impact of arsenic and other environmental contaminants on stem cell function critical for fetal and child development, there is very little information about how such exposures may affect stem cells and their function in adulthood. We wanted to see if environmentally relevant levels of arsenic impair the ability of skeletal muscle to properly repair after injury, and we found out that it does.”

In the study, mice drank water for five weeks, or about two human years, with the equivalent of 10 times the arsenic level considered safe for humans by federal standards. Similar levels are seen in about 8-10 percent of wells. Then the researchers injured muscle in the exposed mice and compared the outcome to those of mice that weren’t exposed to arsenic.

They found a significant decrease in the ability of the muscle in arsenic-exposed mice to regenerate after the injury, and a consequent impairment of muscle function.

They examined muscle tissue after taking away all the cells, leaving only what’s called the extracellular matrix, and found it had remodeled abnormally, producing structural deficits.

The researchers seeded the arsenic-exposed extracellular matrix with human muscle stem cells to see if healthy muscle would reform.

Said co-investigator Aaron Barchowsky, faculty member in environmental and occupational health: “We found that this pathogenic matrix impaired the ability of our stem cells to form new muscle fibers. This may contribute to an impaired healing response after injury.”

The researchers learned that arsenic caused heightened biochemical signals from a protein complex called NF kappa B, which is involved in matrix remodeling and tissue repair.

“A striking finding is that if we blocked the activation of the NF kappa B program, we saw the arsenic-exposed muscle recovered just fine,” Barchowsky said. “We’d like to go deeper into this in our next steps to explore whether we can reverse arsenic’s impact on a person who has been chronically exposed to it.”

Ambrosio, a physical therapist, noted that some patients have a harder time recovering from surgery or injury.

“From a rehabilitation perspective, it could be important to pay more attention to these environmental factors that may be influencing the ability of tissue to regenerate,” she said. “It would be wonderful if we could identify people who may be predisposed to a diminished healing capacity and then intervene accordingly so they are able to better recover from injuries.”

Pitt co-authors included Changqing Zhang, Ricardo Ferrari, Kevin Beezhold, Kristen Stearns-Reider, Antonio D’Amore, Martin Haschak and Donna Stolz. A researcher from the Scripps Research Institute also contributed.

The project was funded by NIH’s National Institute on Aging and National Institute of Environmental Health Sciences, the Pennsylvania Department of Health and the Pittsburgh Claude D. Pepper Older Americans Independence Center.

—Compiled by Marty Levine




The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

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