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June 25, 2015

Research Notes

Neighborhood quality linked to cellular aging

Regardless of chronological age, people who live in neighborhoods with high crime, noise and vandalism are biologically more than a decade older than those who do not, according to a study led by researchers from the School of Nursing and the UPMC Aging Institute. The findings were published online in PLOS ONE.

Said lead author Mijung Park, nursing faculty member: “Strong research evidence supports that living in disadvantaged neighborhoods has an unfavorable impact on mental and physical health. Our team examined whether these environments also have a direct impact on cellular health. We found that, indeed, biological aging processes could be influenced by socioeconomic conditions.”

The research team focused on telomeres, which are stretches of DNA at the ends of chromosomes that often are compared to caps on shoelaces because they protect the DNA strands from damage. Telomeres get trimmed each time the cell divides because they are not fully copied by enzyme mechanisms, and it is thought that aging occurs when the telomeres become too short for DNA replication and cell division to proceed normally. Telomere shortening can be accelerated with exposure to biological or psychological stresses such as cancer, anxiety and depression, Park said.

Working with researchers from Amsterdam, the team examined telomere length in white blood cells of 2,902 Dutch individuals participating in the Netherlands Study of Depression and Anxiety and determined the quality of the neighborhoods in which they resided using measures of perceived neighborhood disorder, fear of crime and noise. They found that the telomeres of people reporting poor neighborhood quality were significantly shorter than telomeres of those who did not.

“The differences in telomere length between the two groups were comparable to 12 years in chronological age,” Park said. “It’s possible that their cells are chronically activated in response to psychological and physiological stresses created by disadvantaged socioeconomic, political and emotional circumstances.”

Other members of the study team included Charles F. Reynolds III, UPMC Endowed Professor of Geriatric Psychiatry and Professor of Neurology, Behavioral and Community Health Sciences, and Clinical and Translational Science, and researchers from Amsterdam.

The study was supported by the National Institutes of Health (NIH) and the Geestkracht program of the Netherlands Organization for Health Research and Development.


Gene therapy prevents Parkinson’s in animal study

Gene therapy to reduce production of a brain protein successfully prevented development of Parkinson’s disease in an animal study, according to researchers at the School of Medicine. The findings, published online in the Journal of Clinical Investigation, could lead to new understanding of how genetic and environmental factors converge to cause the disease and the development of effective treatments to prevent progression of the disease.

Scientists have observed dysfunction of mitochondria, which make energy for cells, in Parkinson’s disease, as well as Lewy bodies, which are characteristic clumps of the cellular protein a-synuclein within neurons, noted principal investigator Edward A. Burton, neurology faculty member in medicine.

Said Burton: “Until now, these have been pursued largely as separate lines of research in Parkinson’s disease. Our data show that mitochondria and a-synuclein can interact in a damaging way in vulnerable cells, and that targeting a-synuclein might be an effective strategy for treatment.”

The team wanted to see what would happen if they knocked out the production of a-synuclein in the brain’s substantia nigra, home to the dopamine-producing cells that are lost as Parkinson’s disease progresses. To do so, they used a harmless virus called AAV2 engineered to transport into the neuron a small piece of genetic code that blocks production of a-synuclein. They delivered the gene therapy to the brains of rats and then exposed the animals to the pesticide rotenone, which inhibits mitochondrial function.

Said co-investigator J. Timothy Greenamyre, Love Family Professor of Neurology and director of the Pittsburgh Institute for Neurodegenerative Diseases: “Our previous work established that rotenone exposure in rats reproduces many features of Parkinson’s disease that we see in humans, including movement problems, Lewy bodies, loss of dopamine neurons and mitochondrial dysfunction. We found that our gene therapy prevented those symptoms from appearing, which is very exciting.”

Each side of the brain controls the opposite side of the body. The left sides of rats that received gene therapy to the right side of the brain did not become stiff and slow, while their right sides did. The researchers determined that dopamine neurons on the treated side of the brain were protected from rotenone, accounting for the substantial improvement in movement symptoms. In contrast, untreated animals and animals that received a control virus that does not reduce a-synuclein production developed progressive Parkinsonism and loss of dopamine neurons.

In next steps, the researchers plan to unravel the molecular pathways that enable a-synuclein levels to influence mitochondrial function and develop drugs that can target the underlying mechanisms.

“The viral vector AAV2 has been used safely in Parkinson’s disease patients in clinical trials, so the gene therapy approach might be feasible,” Burton said. “We think targeting a-synuclein has great potential to protect the brain from neurodegeneration in Parkinson’s disease.”

Added Greenamyre: “We hope to be able to translate this general approach of reducing a-synuclein into human clinical trials soon.”

The team included Pitt researchers Alevtina Zharikov, Jason R. Cannon, Victor Tapias, Qing Bai, Max Horowitz, Vipul Shah, Amina El Ayadi and Teresa G. Hastings.

The project was funded by the U. S. Department of Veterans Affairs, NIH, the Blechman Foundation, the Parkinson’s Chapter of Greater Pittsburgh, the JPB Foundation, the American Parkinson Disease Association, the Parkinson’s Unity Walk and Mr. and Mrs. Henry Fisher.


Hot flashes linked with brain changes

Women who experience more hot flashes, particularly while sleeping, during the menopause transition are more likely to have brain changes reflecting a higher risk for cerebrovascular disease, such as stroke and other brain blood flow problems, according to a pilot study led by researchers at the School of Medicine published online in Menopause.

More than 70 percent of women have hot flashes — a sudden feeling of intense warmth and sweatiness — while transitioning into menopause, noted principal investigator Rebecca Thurston, psychiatry faculty member in medicine. While recent research has shown that hot flashes can be linked to signs of subclinical heart disease, such as changes in the blood vessels, as well as high blood pressure and elevated cholesterol levels, Thurston and colleagues examined the possible connection between hot flashes and brain health.

The research team recruited 20 women in midlife who were not taking hormone therapy and, using a device that measures skin conductance, biologically monitored their hot flashes for 24 hours. They also conducted MRI brain imaging on participants to detect white matter hyperintensities, which are bright spots on the scan that are thought to develop due to disease of the brain’s small blood vessels. Participants also kept electronic hot flash diaries.

The women reported an average of three hot flashes per day, but the monitoring showed greater frequency, at an average of eight per day. Some likely were not self-reported because they occurred during sleep, Thurston said. Women who had more monitor-detected hot flashes, particularly during sleep, also had a greater number of white matter hyperintensities on their brain scans.

Said Thurston: “Other factors like age and cardiovascular risk factors did not explain this effect, so these findings suggest there is a relationship between menopausal hot flashes and blood vessel changes in the brain. Further work is needed to understand whether one causes the other, or if hot flashes are a signal of some other vascular process that impacts brain health.”

Thurston added that it might be particularly important for women who are experiencing numerous hot flashes to consider modifying cardiovascular risk factors by quitting smoking and treating high blood pressure.

Pitt research colleagues included Howard J. Aizenstein and Ervin Sejdic. Scientists from the Albert Einstein College of Medicine and the University of Illinois also contributed.

The project was funded by the NIH National Heart, Lung and Blood Institute and the Department of Psychiatry.


Grant explores urban bamboo construction

A Pitt-led consortium is one of 14 new multilateral university partnerships created by the Global Innovation Initiative, a program funded by the U.S. and U.K. governments to foster multilateral research collaboration with higher education institutions in Brazil, China, India and Indonesia. The consortium’s winning proposal, “Bamboo in the Urban Environment,” brings together experts in bamboo and sustainable design to engage in extensive analysis and testing of bamboo as a safe construction resource in urban areas.

With partners at Coventry University (U.K.), the Pitt-led team includes collaborators at Bogor Agricultural University (Indonesia); the Indian Institute of Technology Delhi (India); an intergovernmental partner, the International Network for Bamboo and Rattan (China), and industry partners in the U.S. and the U.K. The two-year, $200,000 award will support multiple international student and faculty exchanges and three international workshop/symposia including a flagship symposium to be held at Pitt in May 2016.

Said Kent Harries, civil and environmental engineering faculty member at the Swanson School of Engineering and the consortium’s principal investigator: “This collaborative research has both significant technical and social relevance through the potential to reduce the cost and environmental impact of safe housing for a significant proportion of the world’s population. With continued population growth, especially in developing and lagging countries, the need for a sustainable yet safe and strong construction material is an incredibly pressing need. This work addresses the global grand challenges of urbanization and resilience in the face of natural hazards and climate change through the use of bamboo, one of nature’s most renewable ‘green’ materials.”

The program also allows for undergraduate and graduate students at each institution to participate in the research.

According to Harries, there is an increasing socio-technical-economic gap developing between those termed scientifically advanced countries (e.g., the U.S. and U.K.) and those that are “proficient” (e.g., Brazil, Russia, India, China and South Africa), developing (e.g., Indonesia) and “lagging” (e.g., Nepal). For those proficient, developing or lagging countries, a lack of stable infrastructure is cited as a primary barrier to the adoption of technology, while the increased emphasis by advanced countries on sustainable practices is viewed as largely unattainable. “Compounding this, migration of the rural poor into urban centers places even greater pressure on informal urban settlements around the world,” he said. “It’s estimated that more than one-third of the world’s urban population lives in inadequate housing. Exposure to natural hazards and the effects of global climate change further compound the global grand challenge of providing adequate and safe urban housing. Bamboo, one of the world’s oldest construction resources, is now being rediscovered as a viable, sustainable and engineered alternative to present construction practices in many areas of the world.”

Harries describes bamboo as “the most rapidly renewable structural material in the world.” Bamboo can grow up to 30 meters in six months and be mature for structural purposes within three years, achieving mechanical properties that surpass those of oak. When used in its untransformed pole-form, bamboo has a smaller environmental impact than other conventional structural materials, including timber. Bamboo’s light weight and relative flexibility make it a particularly attractive alternative for residential construction in seismic regions.

Nonetheless, he said, the majority of knowledge of bamboo construction is based on cultural tradition, with approximately one billion people worldwide living in non-engineered or vernacular bamboo structures. To enable the better use and acceptance of this strong, economical and sustainable material, Harries said that the award will help to empower engineers, architects and builders with modern and comprehensive design and construction standards.

“While the use of bamboo in structures dates back thousands of years, the science is in its infancy,” he said. “Only in the last decade have bamboo construction standards emerged in India and Colombia, as well as being promulgated by the International Standards Organization. By establishing a pathway to standardization we aim to enable greater acceptance of bamboo as a construction material.”

The Global Innovation Initiative is funded by the U.K. Department for Business, Innovation and Skills, which also serves as the implementing partner in the U.K., and the U.S. Department of State. In the United States, the Institute of International Education is implementing the grant program in partnership with the U.S. Department of State’s Bureau of Educational and Cultural Affairs.


Gas wells, lower birth weight associated

Pregnant women living close to a high density of natural gas wells drilled with hydraulic fracturing were more likely to have babies with lower birth weights than women living farther from such wells, according to a Graduate School of Public Health analysis of southwestern Pennsylvania birth records.

The finding does not prove that the proximity to the wells caused the lower birth weights, but it is an association that warrants further investigation, the researchers concluded. The study was funded by The Heinz Endowments and published in PLOS ONE.

Said co-author Bruce Pitt, chair of Pitt’s Department of Environmental and Occupational Health: “Our work is a first for our region and supports previous research linking unconventional gas development and adverse health outcomes. These findings cannot be ignored. There is a clear need for studies in larger populations with better estimates of exposure and more in-depth medical records.”

Unconventional gas development includes horizontal drilling and high-volume hydraulic fracturing known as “fracking.” It allows access to large amounts of natural gas trapped in shale deposits. Prior to 2007, only 44 wells were known to be drilled in Pennsylvania’s Marcellus Shale with such technology. From 2007 to 2010, that expanded to 2,864 wells.

The public health research team cross-referenced birth outcomes for 15,451 babies born in Washington, Westmoreland and Butler counties 2007-10 with the proximity of the mother’s home to wells drilled using unconventional gas development. They divided the data into four groups, depending on the number and proximity of wells within a 10-mile radius of the mothers’ homes.

Mothers whose homes fell in the top group for proximity to a high density of such wells were 34 percent more likely to have babies who were small for their gestational age than mothers whose homes fell in the bottom 25 percent, according to the researchers. Small for gestational age refers to babies whose birth weight ranks them below the smallest 10 percent when compared to their peers.

The researchers took into account many factors that could influence a newborn’s weight, including whether the mother smoked, her prenatal care, race, education, age and whether she’d had previous babies, as well as the gender of the baby — and the finding still held.

“Developing fetuses are particularly sensitive to the effects of environmental pollutants,” said Pitt. “We know that fine-particulate air pollution, exposure to heavy metals and benzene and maternal stress all are associated with lower birth weight.”

In southwestern Pennsylvania, the waste fluids produced through hydrofracturing, called “flowback,” can contain benzene. Unconventional gas development also creates an opportunity for air pollution through flaring of methane gas at the wellheads and controlled burning of natural gas that releases volatile organic compounds, including benzene, toluene, ethylbenzene and xylene. Increased truck traffic and diesel-operated compressors also can contribute to air and noise pollution.

“It is important to stress that our study does not say that these pollutants caused the lower birth weights,” said Pitt. “Unconventional gas development is dynamic and varies from site to site, changing the potential for human exposure. To draw firm conclusions, we need studies that thoroughly assess the exposure of a very large number of pregnant women to not just the gas wells but other potential pollutants.”

Shaina L. Stacy, a recent public health graduate, was lead author on this research and Evelyn Talbott, epidemiology faculty member, was senior author. Also contributing were LuAnn L. Brink and Bernard D. Goldstein, both of public health, and Jacob C. Larkin and Yoel Sadovsky of Magee-Womens Research Institute and the School of Medicine.


Important cancer biomarker link discovered

Researchers at the School of Medicine have identified two new classes of RNAs that are closely associated with a protein known to be a prognostic biomarker for breast cancer and could play a role in progression of prostate cancer. Their findings were published in RNA.

Levels of human Y-box binding protein 1 (YB-1), which is involved in many cellular functions, have been shown to correlate with drug resistance and poor patient outcomes in a variety of cancers.

According to senior investigator Bino John, adjunct faculty member in the school, the observation that this cancer biomarker is tightly linked to a large and diverse class of RNAs, and the known associations of some of these RNAs to cancer, opens an opportunity to discover a potentially very important pathway in human biology and cancer.

One of the abundant RNAs that the team discovered was found to originate from the widely known DNA region of the Dicer1 gene and was determined to control multiple genes involved in cancer progression.

“Many small RNAs known as microRNAs already have been shown to correlate with different grades of prostate cancer and could potentially serve as biomarkers for diagnosis and treatment,” John said. “We did this study after computer models led us to hypothesize that there was a connection between YB-1 and microRNAs. What started out as a curiosity-driven experiment ended up being an exhilarating treasure hunt over four years, culminating in the discovery of two big molecular finds from human cells.”

The scientists discovered that YB-1 associated with many microRNAs, and were surprised by the realization that YB-1 associated with thousands of RNAs that were never before known. The team grouped the RNAs into what they called YB-1 associated short non-coding RNAs, or shyRNAs, and their smaller, processed counterparts, dubbed YB-1 associated small RNAs (smyRNAs).

Said co-senior author Donald B. DeFranco, pharmacology and chemical biology faculty member in the school: “We conducted functional assays on one of these RNAs, and found that it had the ability to suppress cancer cell growth when it interacted with YB-1. More work must be done to determine how these shyRNAs interact to influence cancer progression and perhaps influence other diseases.”

The team included Teresa T. Liu, Gustavo Arango-Argoty, Zhihua Li, Yuefeng Lin, Sang Woo Kim and A. Paula Monaghan, all of Pitt at the time of the study, as well as researchers from the University of Regensburg and Helicos Biosciences.

The research was supported by the Mathers Foundation, NIH, the American Cancer Society, Deutsche Forschungsgemeinschaft, the European Research Council and the Bavarian Genome Research Network.


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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