A team of University of Pittsburgh researchers has uncovered new details about the biology of telomeres, “caps” of DNA that protect the tips of chromosomes and play key roles in a number of health conditions, including cancer, inflammation and aging.
The new findings were published today in the journal Nature Structural and Molecular Biology.
Telomeres, composed of repeated sequences of DNA, are shortened every time a cell divides and therefore become smaller as a person ages. When they become too short, telomeres send a signal to the cell to stop dividing permanently, which impairs the ability of tissues to regenerate and contributes to many aging-related diseases, explained lead study author Patricia Opresko, Ph.D., associate professor of Environmental and Occupational Health at Pitt, and member of the University of Pittsburgh Cancer Institute Molecular and Cellular Cancer Biology program and Carnegie Mellon University Center for Nucleic Acids Science and Technology.
In contrast, in most cancer cells, levels of the enzyme telomerase, which lengthens telomeres, are elevated, allowing them to divide indefinitely.
“The new information will be useful in designing new therapies to preserve telomeres in healthy cells and ultimately help combat the effects of inflammation and aging. On the flip side, we hope to develop mechanisms to selectively deplete telomeres in cancer cells to stop them from dividing,” said Dr. Opresko.
A number of studies have shown that oxidative stress—a condition where damaging molecules known as free radicals build up inside cell—accelerates telomere shortening. Free radicals can damage not only the DNA that make up telomeres, but also the DNA building blocks used to extend them.
Oxidative stress is known to play a role in many health conditions, including inflammation and cancer. Damage from free radicals, which can be generated by inflammation in the body as well as environmental factors, is thought to build up throughout the aging process.
The goal of the new study was to determine what happens to telomeres when they are damaged by oxidative stress. The researchers suspected that oxidative damage would render telomerase unable to do its job.
“Much to our surprise, telomerase could lengthen telomeres with oxidative damage,” Dr. Opresko said. “In fact, the damage seems to promote telomere lengthening.”
Next, the team looked to see what would happen if the building blocks used to make up telomeres were instead subjected to oxidative damage. They found that telomerase was able to add a damaged DNA precursor molecule to the end of the telomere, but was then unable to add additional DNA molecules.
The new results suggest that the mechanism by which oxidative stress accelerates telomere shortening is by damaging the DNA precursor molecules, not the telomere itself. “We also found that oxidation of the DNA building blocks is a new way to inhibit telomerase activity, which is important because it could potentially be used to treat cancer.”
Dr. Opresko and her team are now beginning to further explore the consequences of oxidative stress on telomeres, using a novel photosensitizer, developed by Marcel Bruchez at Carnegie Mellon University that produces oxidative damage selectively in telomeres. “Using this exciting new technology, we’ll be able to learn a lot about what happens to telomeres when they are damaged, and how that damage is processed,” she said.
The university began as the Carnegie Technical Schools founded by Andrew Carnegie in 1900. In 1913, the school became the Carnegie Institute of Technology and began granting four-year degrees. In 1967, the Carnegie Institute of Technology merged with the Mellon Institute of Industrial Research to form Carnegie Mellon University.
The university’s 140-acre (0.57 km2) main campus is 3 miles (4.8 km) from Downtown Pittsburgh and abuts the Carnegie Museums of Pittsburgh, the main branch of the Carnegie Library of Pittsburgh, Schenley Park, Phipps Conservatory and Botanical Gardens, and the campus of the University of Pittsburgh in the city’s Oakland and Squirrel Hill neighborhoods, partially extending into Shadyside.
Carnegie Mellon has seven colleges and independent schools: the Carnegie Institute of Technology (engineering), College of Fine Arts, Dietrich College of Humanities and Social Sciences, Mellon College of Science, Tepper School of Business, H. John Heinz III College and the School of Computer Science.
Carnegie Mellon University research articles from Innovation Toronto
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Technology rises to efficiency challenge
A Washington State University research team has designed a tiny, wireless data center that someday could be as small as a hand-held device and dramatically reduce the energy needed to run such centers.
Their idea is a paradigm shift in the management of big data, said Partha Pratim Pande, a computer engineering professor in the School of Electrical Engineering and Computer Science.
Pande, who is collaborating with WSU professor Deuk Heo and a team from Carnegie Mellon University, presented the preliminary design for a data-center-on-a-chip this week at the Embedded Systems Week conference in Pittsburgh. The researchers recently received a $1.2 million National Science Foundation grant to further develop their transformative idea.
Data centers and high performance computing clusters are energy hogs, requiring enormous amounts of power and space. Often requiring air conditioners to cool their many processors, data centers consumed about 91 billion kilowatt-hours of electricity in the U.S. in 2013, which is equivalent to the output of 34 large, coal-fired power plants, according to the National Resources Defense Council.
Large data farms run by companies like Facebook have made significant energy efficiency improvements, but many data servers at small businesses around the country still consume significant resources. Sustainable computing has become of increasing interest to researchers, industry leaders and the public.
“We have reached our power limit already,” said Pande. “To address our energy efficiency challenges, this architecture and technology need to be adopted by the community.”
3D chip three times more efficient
Unlike portable devices that have gone wireless, data farms that provide instant availability to text messages, video downloads and more still use conventional metal wires on computer chips, which are wasteful for relatively long-range data exchange.
Most data centers are made up of several processing cores. One of their major performance limitations stems from the multi-hop nature of data exchange. That is, data has to move around several cores through wires, slowing down the processor and wasting energy.
Pande’s group in recent years designed a wireless network on a computer chip. Similar to the way a cell phone works, the system includes a tiny, low-power transceiver, on-chip antennas and communication protocols that enable wireless shortcuts.
The new work expands these capabilities for a wireless data-center-on-a-chip. In particular, the researchers are moving from two-dimensional chips to a highly integrated, three-dimensional, wireless chip at the nano- and microscales that can move data more quickly and efficiently.
For instance, the researchers will be able to run big data applications on their wireless system three times more efficiently than the best data center servers.
Personal cloud computing possibilities
As part of their grant, the researchers will evaluate the wireless data center to increase energy efficiency while also maintaining fast, on-chip communications. The tiny chips, consisting of thousands of cores, could run data-intensive applications orders of magnitude more efficiently compared to existing platforms. Their design has the potential to achieve a comparable level of performance as a conventional data center using much less space and power.
It could someday enable personal cloud computing possibilities, said Pande, adding that the effort would require massive integration and significant innovation at multiple levels.
“This is a new direction in networked system design,” he said. “This project is redefining the foundation of on-chip communication.”
More than a decade ago, Ralph Hollis invented the ballbot, an elegantly simple robot whose tall, thin body glides atop a sphere slightly smaller than a bowling ball. The latest version, called SIMbot, has an equally elegant motor with just one moving part: the ball.
The only other active moving part of the robot is the body itself.
The spherical induction motor (SIM) invented by Hollis, a research professor in Carnegie Mellon University’s Robotics Institute, and Masaaki Kumagai, a professor of engineering at Tohoku Gakuin University in Tagajo, Japan, eliminates the mechanical drive systems that each used on previous ballbots. Because of this extreme mechanical simplicity, SIMbot requires less routine maintenance and is less likely to suffer mechanical failures.
The new motor can move the ball in any direction using only electronic controls. These movements keep SIMbot’s body balanced atop the ball.
Early comparisons between SIMbot and a mechanically driven ballbot suggest the new robot is capable of similar speed — about 1.9 meters per second, or the equivalent of a very fast walk — but is not yet as efficient, said Greg Seyfarth, a former member of Hollis’ lab who recently completed his master’s degree in robotics.
Induction motors are nothing new; they use magnetic fields to induce electric current in the motor’s rotor, rather than through an electrical connection. What is new here is that the rotor is spherical and, thanks to some fancy math and advanced software, can move in any combination of three axes, giving it omnidirectional capability. In contrast to other attempts to build a SIM, the design by Hollis and Kumagai enables the ball to turn all the way around, not just move back and forth a few degrees.
Though Hollis said it is too soon to compare the cost of the experimental motor with conventional motors, he said long-range trends favor the technologies at its heart.
“This motor relies on a lot of electronics and software,” he explained. “Electronics and software are getting cheaper. Mechanical systems are not getting cheaper, or at least not as fast as electronics and software are.”
SIMbot’s mechanical simplicity is a significant advance for ballbots, a type of robot that Hollis maintains is ideally suited for working with people in human environments. Because the robot’s body dynamically balances atop the motor’s ball, a ballbot can be as tall as a person, but remain thin enough to move through doorways and in between furniture. This type of robot is inherently compliant, so people can simply push it out of the way when necessary. Ballbots also can perform tasks such as helping a person out of a chair, helping to carry parcels and physically guiding a person.
Greg Seyfarth and SIMbot
Until now, moving the ball to maintain the robot’s balance has relied on mechanical means. Hollis’ ballbots, for instance, have used an “inverse mouse ball” method, in which four motors actuate rollers that press against the ball so that it can move in any direction across a floor, while a fifth motor controls the yaw motion of the robot itself.
“But the belts that drive the rollers wear out and need to be replaced,” said Michael Shomin, a Ph.D. student in robotics. “And when the belts are replaced, the system needs to be recalibrated.” He said the new motor’s solid-state system would eliminate that time-consuming process.
The rotor of the spherical induction motor is a precisely machined hollow iron ball with a copper shell. Current is induced in the ball with six laminated steel stators, each with three-phase wire windings. The stators are positioned just next to the ball and are oriented slightly off vertical.
The six stators generate travelling magnetic waves in the ball, causing the ball to move in the direction of the wave. The direction of the magnetic waves can be steered by altering the currents in the stators.
Hollis and Kumagai jointly designed the motor. Ankit Bhatia, a Ph.D. student in robotics, and Olaf Sassnick, a visiting scientist from Salzburg University of Applied Sciences, adapted it for use in ballbots.
Getting rid of the mechanical drive eliminates a lot of the friction of previous ballbot models, but virtually all friction could be eliminated by eventually installing an air bearing, Hollis said. The robot body would then be separated from the motor ball with a cushion of air, rather than passive rollers.
“Even without optimizing the motor’s performance, SIMbot has demonstrated impressive performance,” Hollis said. “We expect SIMbot technology will make ballbots more accessible and more practical for wide adoption.”
Carnegie Mellon University and Columbia University collaborators discover the cause of vastly different thermal conductivities in superatomic structural analogues
Researchers found that the thermal conductivity of superatom crystals is directly related to the rotational disorder within those structures. The findings were published in an article in Nature Materials this week.
Carnegie Mellon University’s Associate Professor of Mechanical Engineering Jonathan A. Malen was a corresponding author of the paper titled “Orientational Order Controls Crystalline and Amorphous Thermal Transport in Superatomic Crystals.”
Superatom crystals are periodic–or regular–arrangements of C60 fullerenes and similarly sized inorganic molecular clusters. The nanometer sized C60s look like soccer balls with C atoms at the vertices of each hexagon and pentagon.
“There are two nearly identical formations, one that has rotating (i.e. orientationally disordered) C60s and one that has fixed C60s,” said Malen. “We discovered that the formation that contained rotating C60s has low thermal conductivity while the formation with fixed C60shas high thermal conductivity.”
Although rotational disorder is known in bulk C60, this is the first time that the process has been leveraged to create very different thermal conductivities in structurally identical materials.
Imagine a line of people passing sandbags from one end to the other. Now imagine a second line where each person is spinning around–some clockwise, some counter clockwise, some fast, and some slow. It would be very difficult to move a sandbag down that line.
“This is similar to what is happening with thermal conductivity in the superatoms,” explained Malen. “It is easier to transfer heat energy along a fixed pattern than a disordered one.”
Columbia University’s Assistant Professor of Chemistry Xavier Roy, the other corresponding author of the study, created the superatom crystals in his laboratory by synthesizing and assembling the building blocks into the hierarchical superstructures.
“Superatom crystals represent a new class of materials with potential for applications in sustainable energy generation, energy storage, and nanoelectronics,” said Roy. “Because we have a vast library of superatoms that can self-assemble, these materials offer a modular approach to create complex yet tunable atomically precise structures.”
The researchers believe that these findings will lead to further investigation into the unique electronic and magnetic properties of superstructured materials. One future application might include a new material that could change from being a thermal conductor to a thermal insulator, opening up the potential for new kinds of thermal switches and transistors.
“If we could actively control rotational disorder, we would create a new paradigm for thermal transport,” said Malen.
Non-toxic, edible batteries could one day power ingestible devices for diagnosing and treating disease. One team reports new progress toward that goal with their batteries made with melanin pigments, naturally found in the skin, hair and eyes.
The researchers will present their work today at the 252nd National Meeting & Exposition of the American Chemical Society (ACS). ACS, the world’s largest scientific society, is holding the meeting here through Thursday. It features more than 9,000 presentations on a wide range of science topics.
“For decades, people have been envisioning that one day, we would have edible electronic devices to diagnose or treat disease,” says Christopher Bettinger, Ph.D. “But if you want to take a device every day, you have to think about toxicity issues. That’s when we have to think about biologically derived materials that could replace some of these things you might find in a RadioShack.”
About 20 years ago, scientists did develop a battery-operated ingestible camera as a complementary tool to endoscopies. It can image places in the digestive system that are inaccessible to the traditional endoscope. But it is designed to pass through the body and be excreted. For a single use, the risk that the camera with a conventional battery will get stuck in the gastrointestinal tract is small. But the chances of something going wrong would increase unacceptably if doctors wanted to use it more frequently on a single patient.
The camera and some implantable devices such as pacemakers run on batteries containing toxic components that are sequestered away from contact with the body. But for low-power, repeat applications such as drug-delivery devices that are meant to be swallowed, non-toxic and degradable batteries would be ideal.
“The beauty is that by definition an ingestible, degradable device is in the body for no longer than 20 hours or so,” Bettinger says. “Even if you have marginal performance, which we do, that’s all you need.”
While he doesn’t have to worry about longevity, toxicity is an issue. To minimize the potential harm of future ingestible devices, Bettinger’s team at Carnegie Mellon University (CMU) decided to turn to melanins and other naturally occurring compounds. In our skin, hair and eyes, melanins absorb ultraviolet light to quench free radicals and protect us from damage. They also happen to bind and unbind metallic ions. “We thought, this is basically a battery,” Bettinger says.
Building on this idea, the researchers experimented with battery designs that use melanin pigments at either the positive or negative terminals; various electrode materials such as manganese oxide and sodium titanium phosphate; and cations such as copper and iron that the body uses for normal functioning.
“We found basically that they work,” says Hang-Ah Park, Ph.D., a post-doctoral researcher at CMU. “The exact numbers depend on the configuration, but as an example, we can power a 5 milliWatt device for up to 18 hours using 600 milligrams of active melanin material as a cathode.”
Although the capacity of a melanin battery is low relative to lithium-ion, it would be high enough to power an ingestible drug-delivery or sensing device. For example, Bettinger envisions using his group’s battery for sensing gut microbiome changes and responding with a release of medicine, or for delivering bursts of a vaccine over several hours before degrading.
In parallel with the melanin batteries, the team is also making edible batteries with other biomaterials such as pectin, a natural compound from plants used as a gelling agent in jams and jellies. Next, they plan on developing packaging materials that will safely deliver the battery to the stomach.
When these batteries will be incorporated into biomedical devices is uncertain, but Bettinger has already found another application for them. His lab uses the batteries to probe the structure and chemistry of the melanin pigments themselves to better understand how they work.
Figuring Out Why the Computer Rejected Your Loan Application
Machine-learning algorithms increasingly make decisions about credit, medical diagnoses, personalized recommendations, advertising and job opportunities, among other things, but exactly how usually remains a mystery. Now, new measurement methods developed by Carnegie Mellon University researchers could provide important insights to this process.
Was it a person’s age, gender or education level that had the most influence on a decision? Was it a particular combination of factors? CMU’s Quantitative Input Influence (QII) measures can provide the relative weight of each factor in the final decision, said Anupam Datta, associate professor of computer science and electrical and computer engineering.
“Demands for algorithmic transparency are increasing as the use of algorithmic decision-making systems grows and as people realize the potential of these systems to introduce or perpetuate racial or sex discrimination or other social harms,” Datta said.
“Some companies are already beginning to provide transparency reports, but work on the computational foundations for these reports has been limited,” he continued. “Our goal was to develop measures of the degree of influence of each factor considered by a system, which could be used to generate transparency reports.”
Carnegie Mellon Algorithm Balances “Pick And Place” With “Push And Shove”
Clutter is a special challenge for robots, but new Carnegie Mellon University software is helping robots cope, whether they’re beating a path across the moon or grabbing a milk jug from the back of the refrigerator.
The software not only helped a robot deal efficiently with clutter, but it also surprisingly revealed the robot’s creativity in solving problems.
“It was exploiting sort of superhuman capabilities,” Siddhartha Srinivasa, associate professor of robotics, said of his lab’s two-armed mobile robot, the Home Exploring Robot Butler, or HERB. “The robot’s wrist has a 270-degree range, which led to behaviors we didn’t expect. Sometimes, we’re blinded by our own anthropomorphism.”
In one case, the robot used the crook of its arm to cradle an object to be moved.
“We never taught it that,” Srinivasa added.
Algae may hold the key to feeding the world’s burgeoning population. Don’t worry; no one is going to make you eat them. But because they are more efficient than most plants at taking in carbon dioxide from the air, algae could transform agriculture.
If their efficiency could be transferred to crops, we could grow more food in less time using less water and less nitrogen fertilizer.
New work from a team led by Carnegie’s Martin Jonikas published in Proceedings of the National Academy of Sciences reveals a protein that is necessary for green algae to achieve such remarkable efficiency. The discovery of this protein is an important first step in harnessing the power of green algae for agriculture.
It all starts with the world’s most abundant enzyme, Rubisco.
Researchers from Carnegie Mellon University (CMU) have created the first robotically driven experimentation system to determine the effects of a large number of drugs on many proteins, reducing the number of necessary experiments by 70%.
The model, presented in the journal eLife, uses an approach that could lead to accurate predictions of the interactions between novel drugs and their targets, helping reduce the cost of drug discovery.
“Biomedical scientists have invested a lot of effort in making it easier to perform numerous experiments quickly and cheaply,” says lead author Armaghan Naik, a Lane Fellow in CMU’s Computational Biology Department.
“However, we simply cannot perform an experiment for every possible combination of biological conditions, such as genetic mutation and cell type. Researchers have therefore had to choose a few conditions or targets to test exhaustively, or pick experiments themselves. The question is which experiments do you pick?”
Naik says that careful balance between performing experiments that can be predicted confidently and those that cannot is a challenge for humans, as it requires reasoning about an enormous amount of hypothetical outcomes at the same time.
To address this problem, the research team has previously described the application of a machine learning approach called “active learning”. This involves a computer repeatedly choosing which experiments to do, in order to learn efficiently from the patterns it observes in the data. The team is led by senior author Robert F. Murphy, Professor at the Ray and Stephanie Lane Center for Computational Biology, and Head of CMU’s Computational Biology Department.
Lower-leg Amputees Will Test Carnegie Mellon’s Balance Recovery Technology
Trips and stumbles too often lead to falls for amputees using leg prosthetics, but a robotic leg prosthesis being developed at Carnegie Mellon University promises to help users recover their balance by using techniques based on the way human legs are controlled.
Hartmut Geyer, assistant professor of robotics, said a control strategy devised by studying human reflexes and other neuromuscular control systems has shown promise in simulation and in laboratory testing, producing stable walking gaits over uneven terrain and better recovery from trips and shoves.
Over the next three years, as part of a $900,000 National Robotics Initiative study funded through the National Science Foundation, this technology will be further developed and tested using volunteers with above-the-knee amputations.
Joining Geyer on the research team are Steve Collins, associate professor of mechanical engineering and robotics, and Santiago Munoz, a certified prosthetist orthotist and instructor in the Department of Rehabilitation Science and Technology at the University of Pittsburgh.
“Powered prostheses can help compensate for missing leg muscles, but if amputees are afraid of falling down, they won’t use them,” Geyer said. “Today’s prosthetics try to mimic natural leg motion, yet they can’t respond like a healthy human leg would to trips, stumbles and pushes. Our work is motivated by the idea that if we understand how humans control their limbs, we can use those principles to control robotic limbs.”