A new study provides a mechanistic explanation of how ribonucleotides embedded in genomic DNA are recognized and removed from cells. Two mechanisms, enzymes called ribonucleases (RNases) H and the DNA mismatch repair system, appear to interplay to root out the RNA components.

"We believe this is the first study to show that cells utilize independent repair pathways to remove mispaired ribonucleotides embedded in chromosomal DNA, which can be sources of genetic modification if not removed," said Francesca Storici, an assistant professor in the School of Biology at the Georgia Institute of Technology. "The results also highlight a novel case of genetic redundancy, where the mismatch repair system and RNase H mechanisms compete with each other to remove misincorporated ribonucleotides and restore DNA integrity."

The findings were reported Dec. 4, 2011 in the advance online publication of the journal Nature Structural & Molecular Biology. The research was supported by the Georgia Cancer Coalition, National Science Foundation and Georgia Tech Integrative BioSystems Institute.

Storici and Georgia Tech biology graduate students Ying Shen and Kyung Duk Koh conducted the study in collaboration with Bernard Weiss, a professor emeritus in the Department of Pathology and Laboratory Medicine at Emory University.

"We wanted to understand how cells of the bacterium Escherichia coli and the yeast Saccharomyces cerevisiae tolerate the presence of different ribonucleotides embedded in their genomic DNA. We found that the structure of a ribonucleotide tract embedded in DNA influenced its ability to cause genetic mutations more than the tract's length," said Storici.

With double-stranded DNA, when wrong bases are paired or one or few nucleotides are in excess or missing on one of the strands, a mismatch is generated. If mismatches are not corrected, they can lead to mutations.

The researchers found that single mismatched ribonucleotides in chromosomal DNA were removed by either the mismatch repair system or RNase H type 2. Mismatched ribonucleotides in the middle of at least four other ribonucleotides required RNase H type 1 for removal.

"We were excited to find that a DNA repair mechanism like mismatch repair was activated by RNA/DNA mismatches and could remove ribonucleotides embedded in chromosomal DNA," explained Storici. "In future studies, we plan to test whether other DNA repair mechanisms, such as nucleotide-excision repair and base-excision repair, can also locate and remove ribonucleotides in DNA."

Using gene correction assays driven by short nucleic acid polymers called oligonucleotides, the researchers showed that when ribonucleotides embedded in DNA were not removed, they served as templates for DNA synthesis and produced a mutation in the DNA. If both the mismatch repair system and RNase H repair mechanisms are disabled, ribonucleotide-driven gene modification increased by a factor of 47 in the yeast and 77,000 in the bacterium.

Defects in the mismatch repair system are known to predispose a person to certain types of cancer. Because the mismatch repair system is conserved from unicellular to multicellular organisms, such as humans, this study's findings open up the possibility that defects in the mismatch repair system could have consequences more critical than previously thought given the newly identified function of mismatch repair to target RNA/DNA mispairs.

The results also provide new information on the capacity of RNA to play an active role in DNA editing and remodeling, which could be the basis of an unexplored process of RNA-driven DNA evolution.

This project was supported by the National Science Foundation (NSF) (Award No. MCB-1021763). The content is solely the responsibility of the principal investigators and does not necessarily represent the official views of the NSF.

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Wang is perhaps best known for nanogenerators that harvest mechanical energy from the environment, taking advantage of the piezoelectric properties of zinc oxide nanowires to produce electrical current. Starting with output that could barely be measured in 2006, his research team has steadily improved the devices until today arrays of connected nanogenerators can produce as much as 30 volts.

More recently, he has used the piezoelectric properties of the nanostructures to control charge transport in electronic devices, a technology known as piezotronics, which provides an alternative to traditional CMOS technology. He has also coined the term "piezo-phototronics" to describe techniques for controlling electro-optical processes in devices such as light-emitting diodes.

By leaving a gap in the PowerPoint slide he uses to describe his family of zinc oxide nanostructures, Wang suggests there's more ahead.

Wang received a 2011 Materials Research Society Medal Nov. 30th at the organization's fall meeting in Boston. The medal's commendation notes his "seminal contributions in the discovery, controlled synthesis, and fundamental understanding of zinc oxide nanowires and nanobelts, and the design and fabrication of novel, nanowire-based nanosensors, piezotronic devices and nanogenerators for energy harvesting."

Wang joined Georgia Tech in 1995, after earning his Ph.D. at Arizona State University and working for Oak Ridge National Laboratory and the National Institute of Standards and Technology (NIST). His first interest was electron microscopy, where he helped other Georgia Tech researchers see the world of the very small.

He got his first major international attention from research on carbon nanotubes -- tiny structures of interlocked carbon atoms that helped create a new research area in the mid-1990s. Collaboration with Georgia Tech physicist Walt de Heer -- now known for his work with epitaxial graphene -- produced a 1996 paper on nanotube properties that included a microscope image of a carbon particle on the end of a nanotube. Analyzing the nanotube's vibration allowed the researchers to determine the approximate mass of the particle, and their device become known worldwide as a "nanobalance."

But Wang soon realized that the popularity of carbon nanotubes made that research field a crowded one. In search of a research area with more opportunity, he returned to his undergraduate roots in oxide materials -- zinc oxide in particular.

"Zinc oxide has a lot of advantages because of its semiconducting, piezoelectric, optical and other properties for sensors, transducers, energy applications and other uses," he noted. "I wanted to have a material that I could develop, to study the material in great detail, and to own the key intellectual property."

He began work on the material in 1999 and quickly produced significant results, including the development of "nanobelts" reported in the journal Science in 2001. Details of the structures and their synthesis attracted other researchers, and the paper has now been cited more than 3,500 times.

The nanobelt paper was followed by years of work investigating the properties and synthesis of zinc oxide structures. Perhaps the most significant advance was the ability to grow aligned arrays of zinc oxide nanowires, knowledge that led directly to the development of nanogenerators. Reported in April 2006 in the journal Science, nanogenerators drew international attention to Georgia Tech and rapidly led to a series of improvements that opened up new ways of powering nanometer-scale devices for building self-powered nanotechnology. The generators now produce enough power to operate conventional electronic components such as LED displays.

In the last few years, Wang has branched out into new forms of electronic devices, including piezotronic logic gates and memory, as well as light-emitting diodes enhanced with the piezo-phototronic effect. Multiple devices have been combined into self-powered sensing systems that not only detect harmful materials, but also alert authorities wirelessly. He has also built systems that combine different kinds of power harvesting, such as nanogenerators and photovoltaic cells -- and developed a hybrid cell for the first time.

"When nobody else is paying attention to a technology area, that is when you can be a pioneer," he said. "By the time most people have begun to pay attention to it, you have already made significant progress."

In his 16-year career at Georgia Tech, Wang has produced 28 patent applications, along with another dozen invention disclosures. He has formed a startup company to commercialize the technology, and published more than 20 articles in Science and high-profile Nature journals. Overall, he estimates his research team has produced more than 700 publications that have been cited 45,000 times with an h index of 103.

"When we began this work, we could see only dots -- no picture," he added. "Today we are able to see the big picture of what can be done with these nanostructures."

Though the MRS Medal recognizes Wang's research accomplishments, he's also proud of his role as teacher and mentor to students -- hundreds of them since 1995. Wang leads a large research group composed of post-doctoral fellows, graduate students and undergraduate students. From his laboratory have come seven graduates who now hold assistant professor positions at prestigious U.S. institutions -- and more than 50 working at universities in China or Taiwan.

"As a professor, I view my job as having two parts: being an outstanding scientist and an outstanding educator," he said. "Our most important products are the students. If they can go on to be faculty members at the most prestigious universities in the world, we have done our job."

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"We offered Georgia Aquarium leaders accurate predictions on how the new AT&T Dolphin Tales exhibit would impact guest flow within the aquarium and how to optimize the operations logistics, efficiency and show schedules for the new exhibit," said Eva K. Lee, a professor in the H. Milton Stewart School of Industrial and Systems Engineering at Georgia Tech.

The new 84,000-square-foot AT&T Dolphin Tales attraction, which opened in April 2011, includes a theater with performances of Atlantic Bottlenose dolphins in a Broadway-style production with live actors and trainers, all set to an orchestral soundtrack. The exhibit also features a lobby area where visitors can be face-to-face with the dolphins through a 25-foot viewing window.

"We knew that managing the flow of guests through the new AT&T Dolphin Tales exhibit was going to be more difficult than the other aquarium galleries because guests would be entering and exiting the exhibit through the same space," said Brian Davis, director of education and guest programs at the Georgia Aquarium. "The logistical predictions and recommendations Georgia Tech provided us were extremely accurate and enabled us to ensure an amazing guest experience while remaining fiscally responsible."

To provide recommendations to the Georgia Aquarium on how to optimize visitor flow through the new exhibit, Lee and Georgia Tech graduate student Chien-Hung Chen created RealOpt-ABM, a large-scale modeling and decision support software suite that could model guest movement through the entire aquarium.

With this software, the researchers predicted guest flow through the new exhibit and the impact of the new exhibit to surrounding areas and overall visitor flow. They were also able to determine the best strategies for show scheduling, resource allocation, space usage, and theater loading and unloading. RealOpt-ABM produced recommendations that were implemented for operations design of the new exhibit, according to Joe Handy, vice president of guest experience at the Georgia Aquarium.

According to Lee, the software's success lies in its integrated simulation and optimization approach and its inclusion of human cognitive and behavioral elements. The software's computational speed also allowed for rapid solution strategies and on-the-fly reconfigurations. Facility layout, physical design and activities at specific points of interest were captured in sub-models, which were aggregated and coupled to form the overall model.

"RealOpt-ABM incorporated advances in agent-based simulation that capture the stochastic nature of the events within the aquarium, optimization of resource allocation and show schedules, and modeling of human cognitive decisions that affect show preference and guest behavior," explained Lee.

To validate the model, Lee, research engineer Niquelle Brown and 10 Georgia Tech students analyzed guest flow and behavior patterns in the entire aquarium before the new exhibit opened. Through time-motion studies in 2010, they collected guest flow data and captured the decisions guests made, such as turning left or right when they arrived at an intersection and how long guests spent in each exhibit area. The data showed that guest movement changed based on the time of day and what time guests arrived at the museum.

Using RealOpt-ABM, the researchers accurately predicted the amount of time required to load and unload the AT&T Dolphin Tales theater, depending on the number of guests, which led to a recommendation that performances be separated by at least 90 minutes to minimize congestion. The researchers also recommended that on days with fewer than 6,000 aquarium attendees, only two shows should be offered. This recommendation was based on the need to maintain the comfort and health of the dolphins while minimizing unnecessary operations costs.

RealOpt-ABM also detailed the optimal number and location of ticket scanners and traffic controllers and the best time to open the theatre doors so that the waiting time and queue length were acceptable. The study also predicted that unless other provisions were made, a large percentage of the new exhibit's lobby area would be occupied by baby strollers that were not allowed in the theater. Lee's team recommended the creation of valet stroller parking in the main lobby of the aquarium to avoid logistics bottlenecks and congestion in the exhibit lobby area.

This logistics research project is one of six finalists for the 2011 Daniel H. Wagner Prize for Excellence in Operations Research Practice, which is given by the Institute for Operations Research and the Management Sciences (INFORMS). The winner will be selected on Nov. 14 at the INFORMS Annual Meeting, following presentations by the finalists.

"Effective strategies for managing guest flow are imperative for the successful operation of the aquarium and we trust Georgia Tech's logistics advice 100 percent," said Davis. "As the Georgia Aquarium continues to grow and expand, we will always look to Georgia Tech's expertise to maximize the experience for our guests."

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Chemical doping is routinely used in conventional three-dimensional semiconductors to control the density of electron carriers that are essential to the operation of devices such as transistors. But graphene, a semi-metal available in sheets just one atom thick, has properties very different from traditional materials such as silicon -- though researchers say doping will still be needed for producing electronic devices.

The bad news is that electronic designers working with graphene won't be able to simply apply what they've been doing with three-dimensional semiconductors -- which would translate to vastly degraded material quality for graphene. The good news, according to the study, is that graphene doping can be combined with other processes -- and need be applied only to the edges of nanoscale structures being fabricated.

"We are learning how to manipulate these two-dimensional sheets of carbon atoms to get some very unusual results that aren't available with any other material," said James Meindl, director of Georgia Tech's Nanotechnology Research Center, where the research was conducted. "Doping graphene to try to influence its properties is important to being able to use it effectively."

Details of the research were published online in the journal Carbon on October 29th. The research was supported by the Semiconductor Research Corporation (SRC), the Defense Advanced Research Projects Agency (DARPA) through the Interconnect Focus Center, and the National Science Foundation (NSF).

Because graphene sheets contain so few atoms by area, the substitution of elements such as oxygen or nitrogen for carbon atoms in the lattice -- as in conventional doping -- detracts from the high electron mobility and other properties that make the material interesting. So the researchers are rethinking the doping process to take advantage of graphene's unique properties.

"When we work with a three-dimensional semiconductor, we embed the dopant species in the bulk material and then fabricate it into a device," said Kevin Brenner, a graduate research assistant in the Georgia Tech School of Electrical and Computer Engineering. "With graphene, we will dope the material as we process it and fabricate it into devices or interconnects. Doping may be done as part of other fabrication steps such as plasma etching, and that will require us to reinvent the whole process."

Using sheets of exfoliated graphene, Brenner and collaborators Raghu Murali and Yinxiao Yang evaluated the effectiveness of two different techniques: edge passivation by coupling electron-beam lithography with a common resist material, and adsorption from coating the surface of the material. They found that the edge treatment, which chemically reacts with defects created when the material is cut, was a thousand times more efficient at producing carriers in the graphene sheets than the surface treatment.

"We will only be working with the edges of the material," Brenner explained. "That will allow us to leave the center pristine and free of defects. Using this approach, we can maintain very high mobilities and the special properties of graphene while creating very high carrier densities."

Because of the two-dimensional nature of the graphene, controlling the edge chemistry can provide control over the bulk properties of the sheet. "At nanoscale dimensions, the edge atoms tend to dominate over surface adsorption techniques," he added. "With a seven nanometer by seven nanometer graphene device, passivating just one edge C-atom provides the doping equivalent of covering the entire surface."

For doping the edge of a graphene structure, the team applied a thin film of hydrogen silsesquioxane (HSQ), a chemical normally used as a resist for etching, then used electron beam lithography to cross-link the material, which added oxygen atoms to the edges to create p-type doping. The resist and electron beam system combined to provide nanometer-scale control over where the chemical changes took place.

Doping treatment could also be applied using plasma etching, Brenner said. Controlling the specific atoms used in the plasma, or conducting the etching process in an environment containing specific atoms, could drive those atoms into the edges where they would serve as dopants.

"Anytime you create an edge, you have created a location where you can passivate using a dopant," he added. "Instead of needing to embed it in the surface, you can just take the edge that is already there and passivate it with oxygen, nitrogen, hydrogen or other dopant. It could be almost an effortless process because the doping can be done as part of another step."

Beyond fabricating electronic devices, Nanotechnology Research Center scientists are interested in using graphene for interconnects, potentially as a replacement for copper. As interconnect structures become smaller and smaller, the resistivity of copper increases. Edge-doped graphene sheets exhibit a trend of increasing doping with reduced dimensions, possibly becoming more conductive as their size shrinks below 50 nanometers, making them attractive for nanoscale interconnects.

Armed with basic information about graphene doping, the researchers hope to now begin producing devices to study how graphene actually performs.

"Now that we have made a start at understanding how to dope the material, the next step is to begin putting this into nanoscale devices," Brenner said. "We want to see what kind of performance we can get. That may tell us where graphene's niche could be as an electronic material."

Meindl, who has worked with silicon since the dawn of integrated circuits, says it's too early to predict where graphene will ultimately find commercial applications. But he says the material's properties are too interesting not to explore.

"The chances are that something very interesting and unique will develop from the use of graphene," he said. "But we don't yet have the ability to predict what we will be able to do with this new material."

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