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October 9, 2014

Research Notes

Spider colonies may prove group selection

The notion of group selection — that members of social species exhibit individual behavioral traits that render a population more or less fit for survival — has been bandied about in evolutionary biology since Darwin. The essence of the argument against the theory is that it’s a fuzzy concept without the precision of gene-based selection.

Jonathan Pruitt, behavioral ecology faculty member in the Department of Biological Sciences in the Dietrich School of Arts and Sciences, has published a paper in Nature that may be proof of group selection’s validity.

Other studies have hinted at the legitimacy of group selection. But, Pruitt said, “Our study shows group selection acting in a natural setting — on a trait known to be heritable — and that has led to colony-level adaptation.”

Pruitt and a colleague from the University of Vermont examined colonies of Anelosimus studiosus spiders composed of a mixture of individuals with docile and aggressive traits. In nature, individual colonies differ in their docile-to-aggressive ratio.

Pruitt constructed experimental colonies of known composition, tweaking the docile-to-aggressive ratio in each. What he found was that docile-to-aggressive ratios are driven by the site at which the colonies are placed. Certain ratios yield high colony survivorship in certain geographical locations but not in others.

Over the span of two generations, the docile-to-aggressive ratios of perturbed native colonies — those that have lost their site-specific optimal docile-to-aggressive ratio — change. Colonies that find themselves at risk of extinction re-establish their group composition to better match the ratio that their native site calls for. The experimental colonies that were moved across sites, however, changed their ratio to one that “would have promoted their survival had they remained at their home site, regardless of their contemporary environment,” Pruitt said.

“These findings provide compelling evidence that the mechanisms that colonies use to regulate their compositions are themselves locally adapted, presumably because of the survival advantages they confer to the colony.”

Social work prof to help pharmacists prevent opioid abuse

School of Social Work faculty member Jerry Cochran has received a $15,000 grant from Pitt’s Central Research Development Fund to develop a drug abuse screening tool for pharmacy settings, and to assess the results, to help minimize opioid medication misuse.

The non-medical use of prescription opioids has reached epidemic proportions in the U.S. Research shows that policies attempting to curtail access to pain medications likely have driven large increases in street heroin use.

The most devastating aspect of the current epidemic in the U.S. is overdose deaths, which from 1999 to 2008 increased fourfold, with nearly 50 individuals dying each day from an opioid analgesic overdose in 2010.

Policy and practice-level efforts have attempted to safeguard access to these medications but benefits from these efforts have not been clear. However, one relatively unexplored but potentially effective method to address opioid pain medication misuse could be screening, brief intervention and referral to treatment (SBIRT).

Currently, these screenings are used in health care settings by a variety of providers to identify and help substance abusers reduce or eliminate use, but pharmacy settings have received limited attention in previous research and implementation efforts.

Despite this lack of attention, pharmacies likely could be highly effective in delivering these services, given the fact that pharmacies are primary locations where individuals obtain opioid medications for diversion and abuse, and that pharmacists are consistently ranked among the most trusted professionals in the nation.

The project will recruit adult, non-cancer treatment patients filling a prescription for opioid pain medication from three western Pennsylvania pharmacy sites. The study aims to demonstrate that patients at-risk and/or abusing medication can be identified in the pharmacy setting, and it will assess whether pharmacists can effectively engage with their patients about opioid medication misuse.

$17 million grant could improve traumatic brain injury studies

University researchers are key players in a national “dream team” that seeks to identify the best biological and imaging markers of traumatic brain injury (TBI). This effort will improve the ability of clinical trials to find effective treatments for the condition, which annually affects 2.5 million people in the U.S., particularly athletes and soldiers.

The $17 million initiative, called the TBI Endpoints Development (TED) Award, is funded by the Department of Defense (DOD) and includes many universities, the Food and Drug Administration (FDA), companies and philanthropies. It is overseen by the University of California-San Francisco.

Said TED investigator Stephen Wisniewski, senior associate dean and co-director of the Epidemiology Data Center at the Graduate School of Public Health: “This project is going to redefine how we measure the outcomes for traumatic brain injury studies. We need a more robust, detailed way to determine what challenges a person faces when he suffers a traumatic brain injury, and that is what we’re setting out to accomplish.”

Under Wisniewski, public health will run the data analysis for the project. The school will compile data from previous studies and analyze it to see what existing methods for measuring traumatic brain injuries prove most promising. That information will be used as a launch point for clinical evaluation in real-life situations.

David Okonkwo, neurological surgery faculty member and clinical director of the Brain Trauma Research Center at the School of Medicine, is co-leading the second branch of the project to test those findings through the previously announced $18.8 million National Institutes of Health (NIH) project called Transforming Research and Clinical Knowledge in TBI, or TRACK-TBI.

Said Okonkwo: “In the clinical component of the TED project, we will take the insights Dr. Wisniewski and his team gather from their systematic review of previous research and apply that to real-world TBI cases. If we can more accurately identify and quantify these injuries, we will be better able to select appropriate patients for clinical trials and to evaluate the success or failure of our therapies.”

TED will examine data from thousands of patients to identify effective measures of brain injury and recovery, using biomarkers from blood, new imaging equipment and software and other tools. The research collaborators will be collecting a broad range of long-term data from existing studies and databases, and integrating these into a dataset that can be interrogated for TBI associations and causes in a way that has never before been possible.

The project is designed specifically to overcome the difficulty in demonstrating the effectiveness of TBI drugs and medical devices by actively involving the FDA in clinical-trial design from the outset. It also fosters collaboration between DOD, NIH, foundation-funded research networks, industry co-sponsors such as General Electric and patient advocacy groups to develop procedures, outcomes measures and standards for interpreting clinical data.

Each year, more than 2.5 million people in the U.S. seek medical care for traumatic brain injuries that arise when blows to the body or nearby explosions cause the brain to collide with the inside of the skull. According to the U.S. Centers for Disease Control and Prevention, an estimated 2 percent of the U.S. population now lives with TBI-caused disabilities at an annual cost of about $77 billion. No TBI treatment has proved to be effective.

Dental med gets $11.8 million for cleft lip, palate study

Researchers at the School of Dental Medicine have been awarded a $11.8 million, five-year grant from the National Institute of Dental and Craniofacial Research, part of NIH, to continue their exploration of the genetic roots of cleft lip and cleft palate and to expand the effort to include populations in Colombia, Nigeria, the Philippines and Pennsylvania.

Orofacial clefts (OFCs), which are small gaps in the lip or palate that can form when a baby’s mouth doesn’t develop properly during pregnancy, occurs in 1 out of 700 live births worldwide, noted Mary L. Marazita, faculty member and vice chair of the Department of Oral Biology and director of the Center for Craniofacial and Dental Genetics (CCDG).

Said Marazita: “Orofacial clefts present a significant public health challenge as these patients typically require surgical, nutritional, dental, speech and behavioral treatments for years. We hope to build on the progress we’ve made in our previous studies by identifying genetic susceptibility not only for the overt defects, but also for more subtle features such as changes in facial structure that we have found in relatives of participants with OFCs.”

Marazita and Seth M. Weinberg, oral biology faculty member and director of the CCDG Imaging and Morphometrics Lab, lead the coordinating center for the project, which includes researchers from the University of Iowa, the Newborn Screening Foundation in the Philippines, the Lancaster Cleft Palate Clinic, Nigeria’s University of Lagos, Colombia’s Foundation Clinica Noel and KU Leuven University in Belgium.

For the work’s next phase, the team will recruit for genetic studies about 6,100 individuals from more than 1,500 families with a history of cleft lip with or without cleft palate, or cleft palate alone, from a low-risk population in Nigeria; high-risk populations in the Philippines and Colombia; and mid-risk populations in Pittsburgh and Lancaster, as well as 2,000 unrelated individuals with no history of OFC.

Said Weinberg: “Recent studies indicate different genes seem to be involved in different ethnic groups, so we must broaden our perspective to understand the factors that lead to clefts. We have limited information about the development of cleft palate alone, for example. This research effort will greatly add to our knowledge.”

The team also will assess participants for subclinical manifestations of genetic predisposition for OFCs with high-resolution ultrasound scanning of mouth muscles, lip print patterns, 3-D imaging of facial surfaces and more. Their previously published studies have shown that relatives of OFC patients are more likely to have subtle defects in the orbicularis oris muscle around the mouth, and facial differences such as mid-face retrusion, such as a jaw or tooth set behind its normal position, and wider faces. OFC patients also report a family history of cancer more often than unaffected individuals, said Marazita.

“Minor dental abnormalities, facial shape differences, altered speech patterns and other less obvious changes in the mouth could all be part of a spectrum of defects that have the same genetic causes as cleft lip and palate,” she said. “If we can unravel those relationships and identify the biological pathways that cause them, we will gain insights that may lead to better treatments and better long-term outcomes for affected individuals.”

Discovery could create spin-based computing

Electricity and magnetism rule the digital world. Semiconductors process electrical information, while magnetic materials enable long-term data storage. A physics research team has discovered a way to fuse these two distinct properties in a single material, paving the way for new ultrahigh density storage and computing architectures.

While phones and laptops rely on electricity to process and temporarily store information, long-term data storage still is achieved largely via magnetism. Discs coated with magnetic material are locally oriented (e.g. North or South to represent 1 and 0), and each independent magnet can be used to store a single bit of information. However, this information is not directly coupled to the semiconductors used to process information. Having a magnetic material that can store and process information would enable new forms of hybrid storage and processing capabilities.

Such a material has been created by the Pitt research team led by Jeremy Levy, Distinguished Professor of Condensed Matter Physics in the Dietrich school and director of the Pittsburgh Quantum Institute.

Levy, other researchers at Pitt and colleagues at the University of Wisconsin-Madison published their work in Nature Communications, elucidating their discovery of a form of magnetism that can be stabilized with electric fields rather than magnetic fields.

Working with a material formed from a thick layer of one oxide — strontium titanate — and a thin layer of a second material — lanthanum aluminate — these researchers have found that the interface between these materials can exhibit magnetic behavior that is stable at room temperature. The interface is normally conducting, but by chasing away the electrons with an applied voltage (equivalent to that of two AA batteries), the material becomes insulating and magnetic. The magnetic properties are detected using magnetic force microscopy, an imaging technique that scans a tiny magnet over the material to gauge the relative attraction or repulsion from the magnetic layer.

The newly discovered magnetic properties come on the heels of a previous invention by Levy, so-called “Etch-a-Sketch Nanoelectronics” involving the same material. The discovery of magnetic properties now can be combined with ultra-small transistors, terahertz detectors and single-electron devices previously demonstrated.

Said Levy: “Magnetic materials tend to respond to magnetic fields and are not so sensitive to electrical influences. What we have discovered is that a new family of oxide-based materials can completely change its behavior based on electrical input.”

This discovery was supported by grants from NSF, the Air Force Office of Scientific Research and the Army Research Office.

Rheumatology joins NIH study of lupus, rheumatoid arthritis

The Division of Rheumatology and Clinical Immunology of the School of Medicine, led by chief Larry W. Moreland, has been chosen as one of 11 research sites in an NIH private-public partnership designed to better identify and develop new diagnostics and drugs for rheumatoid arthritis (RA) and lupus.

Said Moreland: “This is a tremendous collaborative effort involving physicians and researchers across disciplines, including basic scientists, clinical researchers, orthopaedic surgeons, radiologists and numerous clinical rheumatologists.”

The lab of Mandy McGeachy, faculty member in medicine, will direct the basic science effort.

The research team will collect data from a large group of patients already participating in NIH-funded research. The project aims to unravel biological pathways involved in RA by examining surgical tissue samples, performing ultrasound-guided biopsies of inflamed joints and using specialized tissue processing for immune-cell analytics, as well as conducting other tests. The team also has proposed a clinical study in which patients who haven’t responded to first-line therapy with methotrexate will be randomized to receive a biologic therapy.

The incentivized research plan consists of a seed grant from NIH, which then may award larger sums moving forward depending on the progress of the research and further studies to follow.

NIH $5.8M grant will build 3-D liver model

With a $5.8 million, three-year award from NIH, School of Medicine researchers will further develop a state-of-the-art, microfluidic 3-D model system that mimics the structure and function of the liver to better predict organ physiology, assess drug toxicity and build disease models.

The funding supports the next phase of NIH’s tissue chip for drug screening program, which aims to improve ways of predicting drug safety and effectiveness. Researchers will refine existing 3-D human tissue chips and combine them into an integrated system that can mimic the complex functions of the human body.

Said principal investigator D. Lansing Taylor, Allegheny Foundation Professor of Computational and Systems Biology in the medical school and director of Pitt’s Drug Discovery Institute: “We are very enthusiastic about the potential of these microphysiology systems to serve as powerful platforms for studying human diseases and identifying human toxic liabilities.”

The research team, along with additional collaborators, is creating models of the functional unit of the liver, called the acinus, using human liver cells and eventually liver cells derived from precursor cells known as induced pluripotent stem cells, as well as three additional cell types. The liver platform includes microfluidic devices, human cells, engineered matrix materials, fluorescence-based biosensors for real-time physiological readouts and biochemical and mass spectrometry measurements to determine acute and chronic toxicity effects. They also will build a microphysiology database to manage, analyze and model the data collected from the liver constructs.

With such a platform, biomedical scientists will be able to test treatment efficacy in conditions such as non-alcoholic fatty liver disease, liver cancer and breast cancer that has spread to the liver, as well as liver damage including immune-mediated toxicology and fibrosis.  Also, a team of institutions and investigators has been assembled to integrate the liver, kidney and gut models to recapitulate the organ system that is central to drug absorption and metabolism.

The integrated platform will involve the creation of a universal medium, the development of the proper scaling of the interacting organ constructs, physiologically relevant flow, incorporation of a microformulator to add factors from missing organs and micro-analyzers for monitoring parameters such as pH and oxygen.

Fifteen NIH institutes and centers are involved in the coordination of the tissue chip program.

Funding is being provided by the National Center for Advancing Translational Sciences, the National Institute for Biomedical Imaging and Bioengineering, the National Cancer Institute, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Environmental Health Sciences, NIH’s Common Fund and Office of Research on Women’s Health.

Other collaborators hail from Massachusetts General Hospital, Vanderbilt, the University of Washington, Johns Hopkins and Baylor.

Prof wins $450,000 to improve additive manufacturing

Additive manufacturing (AM), or 3-D printing, has rapidly advanced to allow for the production of complex-shaped metal components strong enough for structural applications. However, developing complex geometries with fewer errors and distortions, as well as quality standards to test the manufactured items, have not kept pace with the technology.

Researchers at Swanson School of Engineering are proposing to develop enhanced modeling and simulation technology and new qualification standards that will further the adoption of additive manufacturing by industry.

Aimed at developing standard qualification methods for AM, a three-year, $300,000 grant is being provided by NSF’s Division of Civil, Mechanical and Manufacturing Innovation. To address the modeling and simulation challenge, an additional $150,000 Research for Additive Manufacturing in Pennsylvania (RAMP) grant  is being provided by the Pennsylvania Department of Community and Economic Development and America Makes, otherwise known as the National Additive Manufacturing Innovation Institute.

Principal investigator for both grants is Albert To, mechanical engineering and materials science faculty member. Co-PIs are Minking K. Chyu, the Leighton and Mary Orr Chair professor of materials science and mechanical engineering, associate dean for international initiatives and dean of the Sichuan University-Pittsburgh Institute, and Markus Chmielus, faculty member in mechanical engineering and materials science.

RTI International Metals of Pittsburgh will partner with Pitt on the RAMP grant.

According to To, AM is at a critical juncture in its evolution where both computer modeling and qualification methods need to be enhanced in order to reduce manufacturing time and costs while improving quality and product integrity.

Said To: “Additive manufacturing continues to demonstrate its ability to manufacture very complex lattice structures and geometries, enabling us to build complex structures that would be difficult to replicate using traditional or ‘subtractive’ manufacturing. However, these increasingly complex parts are very time-consuming to model and therefore more prone to errors. The RAMP grant will enable us to develop computer codes that first will automate the finite element simulation of certain AM process and material.

“By improving the modeling of these complex, sometimes microscopic structures, we can design the process path and/or part geometry to reduce residual stress that causes failure to the part during manufacturing.”

Improving the modeling and simulation processes in additive manufacturing goes hand-in-hand with developing new qualification methods that ensure the quality of a manufactured part or component. To notes that additive manufacturing has advanced so rapidly that typical manufacturing standards have yet to catch up.

“Traditional qualification standards are not adequate for additive manufacturing because AM parts are ‘built’ by adding layer upon layer of powdered ceramics, metals and polymers, which therefore exhibit residual stresses and higher numbers of defects,” To said. “For example, in aerospace manufacturing, a machined part is inspected for surface cracks, dimensional accuracy and material composition. To develop qualification methods for AM components, we need a better understanding of the microstructure and its mechanical behavior.”

Accomplishing this, To explained, begins with the use of X-ray micro computerized tomography, or a CT scan. In conjunction with mechanical testing and computer simulation, this will enable the researchers to investigate at the microscopic level the mechanical effects of flaws and residual stress, and later develop a computer-based, non-destructive method that is rapid, reliable and affordable, thereby greatly improving AM techniques and quality.

“Additive manufacturing is poised to revolutionize the production of complex and distinctive parts and machines, but like its predecessor it requires the qualification methods necessary to ensure viability, safety and integrity,” To said. “We are quite literally building the foundation for a 21st-century manufacturing revolution.”

Mechanics, biology combine for discovery about cell communication

When the body forms new tissues during the healing process, cells must be able to communicate with each other. For years, scientists believed this communication happened primarily through chemical signaling.

Now researchers at Pitt and Carnegie Mellon University have found that another dimension — mechanical communication — is equally if not more crucial. The findings, published in the Proceedings of the National Academy of Sciences, could lead to advancements in treatments for birth defects and therapies for cancer patients.

Said Lance Davidson, bioengineering faculty in the Swanson school and co-leader of the study: “It’s like 19th-century scientists discovering that electricity and magnetism were the same force. The key here is using mechanical engineering tools and frameworks to reverse-engineer how these biological systems work, thereby giving us a better chance to develop methods that affect this cellular communication process and potentially treat various diseases related to tissue growth.”

The researchers developed a microfluidic control system that delivers chemicals at extremely low flow rates over very small, specific areas, such as integrated collections of individual cells. They hypothesized that in addition to using chemical signals to communicate with each other, embryonic or regenerative cells also used mechanical processes — pushing and pulling on each other — to stimulate and respond.

“In order to identify these mechanical processes, we really had to control small parts of a multi-cellular tissue, which today’s technology can finally allow us to do,” Davidson explained.

For example, a tissue sample two millimeters across may contain up to 8,000 cells. The microfluidic device enables researchers to “touch” as few as three or four and view the mechanical processes using a high resolution laser scanning microscope to see proteins moving in cells.

When the researchers disabled the mechanical connections between the cells using microfluidics, the ability of cells to communicate with each other dropped substantially.

Although the cells communicated through chemical signaling as well, the cells’ mechanical connections —their ability to push and pull on each other — were dominant in transmitting the signals.

Other researchers included Timothy R. Jackson and Deepthi Vijayraghavan from Pitt, as well as individuals from the Georgia Institute of Technology, Air Liquide and Tufts University.

—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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