IQ Link to Baby's Weight Gain in First Month

New research from the University of Adelaide shows that weight gain and increased head size in the first month of a baby's life is linked to a higher IQ at early school age.

IQ Link to Baby's Weight Gain in First Month
(Credit: © JPC-PROD / Fotolia)

The study was led by University of Adelaide Public Health researchers, who analysed data from more than 13,800 children who were born full-term.

The results, published in the international journal Pediatrics, show that babies who put on 40% of their birthweight in the first four weeks had an IQ 1.5 points higher by the time they were six years of age, compared with babies who only put on 15% of their birthweight.

Those with the biggest growth in head circumference also had the highest IQs.

"Head circumference is an indicator of brain volume, so a greater increase in head circumference in a newborn baby suggests more rapid brain growth," says the lead author of the study, Dr Lisa Smithers from the University of Adelaide's School of Population Health.

"Overall, newborn children who grew faster in the first four weeks had higher IQ scores later in life," she says.

"Those children who gained the most weight scored especially high on verbal IQ at age 6. This may be because the neural structures for verbal IQ develop earlier in life, which means the rapid weight gain during that neonatal period could be having a direct cognitive benefit for the child."

Previous studies have shown the association between early postnatal diet and IQ, but this is the first study of its kind to focus on the IQ benefits of rapid weight gain in the first month of life for healthy newborn babies.

Dr Smithers says the study further highlights the need for successful feeding of newborn babies.

"We know that many mothers have difficulty establishing breastfeeding in the first weeks of their baby's life," Dr Smithers says.

"The findings of our study suggest that if infants are having feeding problems, there needs to be early intervention in the management of that feeding."
 
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A Robot That Runs Like a Cat

Thanks to its legs, whose design faithfully reproduces feline morphology, EPFL's four-legged "cheetah-cub robot" has the same advantages as its model: it is small, light and fast. Still in its experimental stage, the robot will serve as a platform for research in locomotion and biomechanics.

This is cheetah-cub, a compliant quadruped robot.
(Credit: (c) EPFL)

Even though it doesn't have a head, you can still tell what kind of animal it is: the robot is definitely modeled upon a cat. Developed by EPFL's Biorobotics Laboratory (Biorob), the "cheetah-cub robot," a small-size quadruped prototype robot, is described in an article appearing today in the International Journal of Robotics Research. The purpose of the platform is to encourage research in biomechanics; its particularity is the design of its legs, which make it very fast and stable. Robots developed from this concept could eventually be used in search and rescue missions or for exploration.

This robot is the fastest in its category, namely in normalized speed for small quadruped robots under 30Kg. During tests, it demonstrated its ability to run nearly seven times its body length in one second. Although not as agile as a real cat, it still has excellent auto-stabilization characteristics when running at full speed or over a course that included disturbances such as small steps. In addition, the robot is extremely light, compact, and robust and can be easily assembled from materials that are inexpensive and readily available. 

Faithful reproduction

The machine's strengths all reside in the design of its legs. The researchers developed a new model with this robot, one that is based on the meticulous observation and faithful reproduction of the feline leg. The number of segments -- three on each leg -- and their proportions are the same as they are on a cat. Springs are used to reproduce tendons, and actuators -- small motors that convert energy into movement -- are used to replace the muscles.

"This morphology gives the robot the mechanical properties from which cats benefit, that's to say a marked running ability and elasticity in the right spots, to ensure stability," explains Alexander Sprowitz, a Biorob scientist. "The robot is thus naturally more autonomous."

Sized for a search

According to Biorob director Auke Ijspeert, this invention is the logical follow-up of research the lab has done into locomotion that included a salamander robot and a lamprey robot. "It's still in the experimental stages, but the long-term goal of the cheetah-cub robot is to be able to develop fast, agile, ground-hugging machines for use in exploration, for example for search and rescue in natural disaster situations. Studying and using the principles of the animal kingdom to develop new solutions for use in robots is the essence of our research."

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New Layer of the Human Cornea Discovered

Scientists at The University of Nottingham have discovered a previously undetected layer in the cornea, the clear window at the front of the human eye.

Scientists have discovered a previously undetected layer in the cornea, the clear window at the front of the human eye. (Credit: © Kesu / Fotolia)

The breakthrough, announced in a study published in the academic journal Ophthalmology, could help surgeons to dramatically improve outcomes for patients undergoing corneal grafts and transplants.

The new layer has been dubbed the Dua's Layer after the academic Professor Harminder Dua who discovered it.

Professor Dua, Professor of Ophthalmology and Visual Sciences, said: "This is a major discovery that will mean that ophthalmology textbooks will literally need to be re-written. Having identified this new and distinct layer deep in the tissue of the cornea, we can now exploit its presence to make operations much safer and simpler for patients.

"From a clinical perspective, there are many diseases that affect the back of the cornea which clinicians across the world are already beginning to relate to the presence, absence or tear in this layer."

The human cornea is the clear protective lens on the front of the eye through which light enters the eye. Scientists previously believed the cornea to be composed of five layers, from front to back, the corneal epithelium, Bowman's layer, the corneal stroma, Descemet's membrane and the corneal endothelium.

The new layer that has been discovered is located at the back of the cornea between the corneal stroma and Descemet's membrane. Although it is just 15 microns thick -- the entire cornea is around 550 microns thick or 0.5mm -- it is incredibly tough and is strong enough to be able to withstand one and a half to two bars of pressure.

The scientists proved the existence of the layer by simulating human corneal transplants and grafts on eyes donated for research purposes to eye banks located in Bristol and Manchester.

During this surgery, tiny bubbles of air were injected into the cornea to gently separate the different layers. The scientists then subjected the separated layers to electron microscopy, allowing them to study them at many thousand times their actual size.

Understanding the properties and location of the new Dua's layer could help surgeons to better identify where in the cornea these bubbles are occurring and take appropriate measures during the operation. If they are able to inject a bubble next to the Dua's layer, its strength means that it is less prone to tearing, meaning a better outcome for the patient.

The discovery will have an impact on advancing understanding of a number of diseases of the cornea, including acute hydrops, Descematocele and pre-Descemet's dystrophies.

The scientists now believe that corneal hydrops, a bulging of the cornea caused by fluid build up that occurs in patients with keratoconus (conical deformity of the cornea), is caused by a tear in the Dua layer, through which water from inside the eye rushes in and causes waterlogging. 

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Brain-Computer Interfaces: Just Wave a Hand

Small electrodes placed on or inside the brain allow patients to interact with computers or control robotic limbs simply by thinking about how to execute those actions. This technology could improve communication and daily life for a person who is paralyzed or has lost the ability to speak from a stroke or neurodegenerative disease.

This image shows the changes that took place in the brain for all patients participating in the study using a brain-computer interface. Changes in activity were distributed widely throughout the brain. (Credit: Jeremiah Wander, UW)

Now, University of Washington researchers have demonstrated that when humans use this technology -- called a brain-computer interface -- the brain behaves much like it does when completing simple motor skills such as kicking a ball, typing or waving a hand. Learning to control a robotic arm or a prosthetic limb could become second nature for people who are paralyzed.

"What we're seeing is that practice makes perfect with these tasks," said Rajesh Rao, a UW professor of computer science and engineering and a senior researcher involved in the study. "There's a lot of engagement of the brain's cognitive resources at the very beginning, but as you get better at the task, those resources aren't needed anymore and the brain is freed up."

Rao and UW collaborators Jeffrey Ojemann, a professor of neurological surgery, and Jeremiah Wander, a doctoral student in bioengineering, published their results online June 10 in the Proceedings of the National Academy of Sciences.

In this study, seven people with severe epilepsy were hospitalized for a monitoring procedure that tries to identify where in the brain seizures originate. Physicians cut through the scalp, drilled into the skull and placed a thin sheet of electrodes directly on top of the brain. While they were watching for seizure signals, the researchers also conducted this study.

The patients were asked to move a mouse cursor on a computer screen by using only their thoughts to control the cursor's movement. Electrodes on their brains picked up the signals directing the cursor to move, sending them to an amplifier and then a laptop to be analyzed. Within 40 milliseconds, the computer calculated the intentions transmitted through the signal and updated the movement of the cursor on the screen.

Researchers found that when patients started the task, a lot of brain activity was centered in the prefrontal cortex, an area associated with learning a new skill. But after often as little as 10 minutes, frontal brain activity lessened, and the brain signals transitioned to patterns similar to those seen during more automatic actions.

"Now we have a brain marker that shows a patient has actually learned a task," Ojemann said. "Once the signal has turned off, you can assume the person has learned it."

While researchers have demonstrated success in using brain-computer interfaces in monkeys and humans, this is the first study that clearly maps the neurological signals throughout the brain. The researchers were surprised at how many parts of the brain were involved.

"We now have a larger-scale view of what's happening in the brain of a subject as he or she is learning a task," Rao said. "The surprising result is that even though only a very localized population of cells is used in the brain-computer interface, the brain recruits many other areas that aren't directly involved to get the job done."

Several types of brain-computer interfaces are being developed and tested. The least invasive is a device placed on a person's head that can detect weak electrical signatures of brain activity. Basic commercial gaming products are on the market, but this technology isn't very reliable yet because signals from eye blinking and other muscle movements interfere too much.

A more invasive alternative is to surgically place electrodes inside the brain tissue itself to record the activity of individual neurons. Researchers at Brown University and the University of Pittsburgh have demonstrated this in humans as patients, unable to move their arms or legs, have learned to control robotic arms using the signal directly from their brain.

The UW team tested electrodes on the surface of the brain, underneath the skull. This allows researchers to record brain signals at higher frequencies and with less interference than measurements from the scalp. A future wireless device could be built to remain inside a person's head for a longer time to be able to control computer cursors or robotic limbs at home.

"This is one push as to how we can improve the devices and make them more useful to people," Wander said. "If we have an understanding of how someone learns to use these devices, we can build them to respond accordingly."

The research team, along with the National Science Foundation's Engineering Research Center for Sensorimotor Neural Engineering headquartered at the UW, will continue developing these technologies.

This research was funded by the National Institutes of Health, the NSF, the Army Research Office and the Keck Foundation. 

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Gene Variants Linked to Educational Attainment

A multi-national team of researchers has identified genetic markers that predict educational attainment by pooling data from more than 125,000 individuals in the United States, Australia, and 13 western European countries.

A multi-national team of researchers has identified genetic markers that predict educational attainment by pooling data from more than 125,000 individuals in the United States, Australia, and 13 western European countries. (Credit: © Tom Wang / Fotolia)

The study, which appears in the journal Science, was conducted by the Social Science Genetic Association Consortium (SSGAC), which includes researchers at NYU, Erasmus University, Cornell University, Harvard University, the University of Bristol, and the University of Queensland, among other institutions.

The SSGAC conducted what is called a genome-wide association study (GWAS) to explore the link between genetic variation and educational attainment -- the number of years of schooling completed by an individual and whether he or she graduated college. In a GWAS, researchers test hundreds of thousands of genetic markers for association with some characteristics such as a disease, trait or life outcome.

Because the sample included people from different countries -- where markers for schooling vary significantly -- the research team adopted the International Standard Classification of Education (ISCED) scale, which is a commonly used method for establishing a uniform measure of educational attainment across cohorts.

Anticipating that very large samples would be required to credibly detect genetic associations, the SSGAC researchers assembled a total sample size more than 10 times larger than any previous genetic study of any social-scientific outcome. The team examined associations between educational attainment and genetic variants called single-nucleotide polymorphisms, or SNPs, which are tiny changes at a single location in a person's genetic code.

The study found that the genetic markers with the strongest effects on educational attainment could each only explain two one-hundredths of a percentage point (0.02 percent). To put that figure into perspective, it is known from earlier research that the SNP with the largest effect on human height accounts for about 0.40 percent of the variation.

Combining the two million examined SNPs, the SSGAC researchers were able to explain about 2 percent of the variation in educational attainment across individuals, and anticipate that this figure will rise as larger samples become available.

"We hope that our findings will eventually be useful for understanding biological processes underlying learning, memory, reading disabilities and cognitive decline in the elderly," said co-author Daniel Benjamin, a behavioral economist at Cornell who is a co-director of the SSGAC.

"Another contribution of our study is that it will strengthen the methodological foundations of social-science genetics," said David Cesarini, an NYU assistant professor at the Center for Experimental Social Science and the Center for Neuroeconomics, who also co-directs the SSGAC. "We used 125,000 individuals to conduct this study. Previous studies used far smaller samples, sometimes as small as 100 individuals and rarely more than 10,000. These small samples make sense under the assumption that individual genes have large effects. However, if genes have small effects, as our study shows, then sample sizes need to be very large to produce robust findings that will reliably replicate in other samples."

The researchers were careful to note that they have not discovered "the gene for education" or that these findings somehow imply that a person's educational attainment is determined at birth.

"For most outcomes that we study as social scientists, genetic influences are likely to operate through environmental channels that are modifiable," explained NYU sociologist Dalton Conley, one of the study's co-authors who also serves on the Advisory Board of the SSGAC. "We have now taken a small but important first step toward identifying the specific genetic variants that predict educational attainment. Armed with this knowledge, we can now begin to examine how other factors -- including public policy, parental roles, and economic status -- dampen or amplify genetic effects and ultimately devise better remedies to bolster educational outcomes." 

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IQ Predicted by Ability to Filter Visual Motion

A brief visual task can predict IQ, according to a new study. This surprisingly simple exercise measures the brain's unconscious ability to filter out visual movement. The study shows that individuals whose brains are better at automatically suppressing background motion perform better on standard measures of intelligence. The test is the first purely sensory assessment to be strongly correlated with IQ and may provide a non-verbal and culturally unbiased tool for scientists seeking to understand neural processes associated with general intelligence.

Intelligence is closely linked to a person's ability to filter out background movement, according to a new cognitive science study from the University of Rochester. (Credit: J. Adam Fenster, University of Rochester)

"Because intelligence is such a broad construct, you can't really track it back to one part of the brain," says Duje Tadin, a senior author on the study and an assistant professor of brain and cognitive sciences at the University of Rochester. "But since this task is so simple and so closely linked to IQ, it may give us clues about what makes a brain more efficient, and, consequently, more intelligent."

The unexpected link between IQ and motion filtering was reported online in the Cell Press journal Current Biology on May 23 by a research team lead by Tadin and Michael Melnick, a doctoral candidate in brain and cognitive sciences at the University of Rochester.

In the study, individuals watched brief video clips of black and white bars moving across a computer screen. Their sole task was to identify which direction the bars drifted: to the right or to the left. The bars were presented in three sizes, with the smallest version restricted to the central circle where human motion perception is known to be optimal, an area roughly the width of the thumb when the hand is extended. Participants also took a standardized intelligence test.

As expected, people with higher IQ scores were faster at catching the movement of the bars when observing the smallest image. The results support prior research showing that individuals with higher IQs make simple perceptual judgments swifter and have faster reflexes. "Being 'quick witted' and 'quick on the draw' generally go hand in hand," says Melnick.

But the tables turned when presented with the larger images. The higher a person's IQ, the slower they were at detecting movement. "From previous research, we expected that all participants would be worse at detecting the movement of large images, but high IQ individuals were much, much worse," says Melnick. That counter-intuitive inability to perceive large moving images is a perceptual marker for the brain's ability to suppress background motion, the authors explain. In most scenarios, background movement is less important than small moving objects in the foreground. Think about driving in a car, walking down a hall, or even just moving your eyes across the room. The background is constantly in motion.

The key discovery in this study is how closely this natural filtering ability is linked to IQ. The first experiment found a 64 percent correlation between motion suppression and IQ scores, a much stronger relationship than other sensory measures to date. For example, research on the relationship between intelligence and color discrimination, sensitivity to pitch, and reaction times have found only a 20 to 40 percent correlation. "In our first experiment, the effect for motion was so strong," recalls Tadin, "that I really thought this was a fluke."

So the group tried to disprove the findings from the initial 12-participant study conducted while Tadin was at Vanderbilt University working with co-author Sohee Park, a professor of psychology. They reran the experiment at the University of Rochester on a new cohort of 53 subjects, administering the full IQ test instead of an abbreviated version and the results were even stronger; correlation rose to 71 percent. The authors also tested for other possible explanations for their findings.

For example, did the surprising link to IQ simply reflect a person's willful decision to focus on small moving images? To rule out the effect of attention, the second round of experiments randomly ordered the different image sizes and tested other types of large images that have been shown not to elicit suppression. High IQ individuals continued to be quicker on all tasks, except the ones that isolated motion suppression. The authors concluded that high IQ is associated with automatic filtering of background motion.

"We know from prior research which parts of the brain are involved in visual suppression of background motion. This new link to intelligence provides a good target for looking at what is different about the neural processing, what's different about the neurochemistry, what's different about the neurotransmitters of people with different IQs," says Tadin.

The relationship between IQ and motion suppression points to the fundamental cognitive processes that underlie intelligence, the authors write. The brain is bombarded by an overwhelming amount of sensory information, and its efficiency is built not only on how quickly our neural networks process these signals, but also on how good they are at suppressing less meaningful information. "Rapid processing is of little utility unless it is restricted to the most relevant information," the authors conclude.

The researchers point out that this vision test could remove some of the limitations associated with standard IQ tests, which have been criticized for cultural bias. "Because the test is simple and non-verbal, it will also help researchers better understand neural processing in individuals with intellectual and developmental disabilities," says co-author Loisa Bennetto, an associate professor of psychology at the University of Rochester.

Bryan Harrison, a doctoral candidate in clinical and social psychology at the University of Rochester is also an author on the paper. The research was supported by grants from the National Institutes of Health.

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Bad Decisions Arise from Faulty Information, Not Faulty Brain Circuits

Making decisions involves a gradual accumulation of facts that support one choice or another. A person choosing a college might weigh factors such as course selection, institutional reputation and the quality of future job prospects.

Researchers have found that it might be the information rather than the brain's decision-making process that is to blame. The researchers report that erroneous decisions tend to arise from errors, or "noise," in the information coming into the brain rather than errors in how the brain accumulates information.

But if the wrong choice is made, Princeton University researchers have found that it might be the information rather than the brain's decision-making process that is to blame. The researchers report in the journal Science that erroneous decisions tend to arise from errors, or "noise," in the information coming into the brain rather than errors in how the brain accumulates information.

These findings address a fundamental question among neuroscientists about whether bad decisions result from noise in the external information -- or sensory input -- or because the brain made mistakes when tallying that information. In the example of choosing a college, the question might be whether a person made a poor choice because of misleading or confusing course descriptions, or because the brain failed to remember which college had the best ratings.

Previous measurements of brain neurons have indicated that brain functions are inherently noisy. The Princeton research, however, separated sensory inputs from the internal mental process to show that the former can be noisy while the latter is remarkably reliable, said senior investigator Carlos Brody, a Princeton associate professor of molecular biology and the Princeton Neuroscience Institute (PNI), and a Howard Hughes Medical Institute Investigator.

"To our great surprise, the internal mental process was perfectly noiseless. All of the imperfections came from noise in the sensory processes," Brody said. Brody worked with first author Bingni Brunton, now a postdoctoral research associate in the departments of biology and applied mathematics at the University of Washington; and Matthew Botvinick, a Princeton associate professor of psychology and PNI.

The research subjects -- four college-age volunteers and 19 laboratory rats -- listened to streams of randomly timed clicks coming into both the left ear and the right ear. After listening to a stream, the subjects had to choose the side from which more clicks originated. The rats had been trained to turn their noses in the direction from which more clicks originated.

The test subjects mostly chose the correct side but occasionally made errors. By comparing various patterns of clicks with the volunteers' responses, researchers found that all of the errors arose when two clicks overlapped, and not from any observable noise in the brain system that tallied the clicks. This was true in experiment after experiment utilizing different click patterns, in humans and rats.

The researchers used the timing of the clicks and the decision-making behavior of the test subjects to create computer models that can be used to indicate what happens in the brain during decision-making. The models provide a clear window into the brain during the "mulling over" period of decision-making, the time when a person is accumulating information but has yet to choose, Brody said.

"Before we conducted this study, we did not have a way of looking at this process without inserting electrodes into the brain," Brody said. "Now thanks to our model, we have an estimation of what is going on at each moment in time during the formation of the decision."

The study suggests that information represented and processed in the brain's neurons must be robust to noise, Brody said. "In other words, the 'neural code' may have a mechanism for inherent error correction," he said.

"The new work from the Brody lab is important for a few reasons," said Anne Churchland, an assistant professor of biological sciences at Cold Spring Harbor Laboratory who studies decision-making and was not involved in the study. "First, the work was very innovative because the researchers were able to study carefully controlled decision-making behavior in rodents. This is surprising in that one might have guessed rodents were incapable of producing stable, reliable decisions that are based on complex sensory stimuli.

"This work exposed some unexpected features of why animals, including humans, sometimes make incorrect decisions," Churchland said. "Specifically, the researchers found that errors are mostly driven by the inability to accurately encode sensory information. Alternative possibilities, which the authors ruled out, included noise associated with holding the stimulus in mind, or memory noise, and noise associated with a bias toward one alternative or the other."

The work was funded by the Howard Hughes Medical Institute, Princeton University and National Institutes of Health training grants.

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Small in Size, Big On Power: New Microbatteries the Most Powerful Yet

Though they be but little, they are fierce. The most powerful batteries on the planet are only a few millimeters in size, yet they pack such a punch that a driver could use a cellphone powered by these batteries to jump-start a dead car battery -- and then recharge the phone in the blink of an eye. 

The graphic illustrates a high power battery technology from the University of Illinois. Ions flow between three-dimensional micro-electrodes in a lithium ion battery. (Credit: Image courtesy of the Beckman Institute for Advanced Science and Technology)

Developed by researchers at the University of Illinois at Urbana-Champaign, the new microbatteries out-power even the best supercapacitors and could drive new applications in radio communications and compact electronics.

Led by William P. King, the Bliss Professor of mechanical science and engineering, the researchers published their results in the April 16 issue of Nature Communications.

"This is a whole new way to think about batteries," King said. "A battery can deliver far more power than anybody ever thought. In recent decades, electronics have gotten small. The thinking parts of computers have gotten small. And the battery has lagged far behind. This is a microtechnology that could change all of that. Now the power source is as high-performance as the rest of it."

With currently available power sources, users have had to choose between power and energy. For applications that need a lot of power, like broadcasting a radio signal over a long distance, capacitors can release energy very quickly but can only store a small amount. For applications that need a lot of energy, like playing a radio for a long time, fuel cells and batteries can hold a lot of energy but release it or recharge slowly.

"There's a sacrifice," said James Pikul, a graduate student and first author of the paper. "If you want high energy you can't get high power; if you want high power it's very difficult to get high energy. But for very interesting applications, especially modern applications, you really need both. That's what our batteries are starting to do. We're really pushing into an area in the energy storage design space that is not currently available with technologies today."

The new microbatteries offer both power and energy, and by tweaking the structure a bit, the researchers can tune them over a wide range on the power-versus-energy scale.

The batteries owe their high performance to their internal three-dimensional microstructure. Batteries have two key components: the anode (minus side) and cathode (plus side). Building on a novel fast-charging cathode design by materials science and engineering professor Paul Braun's group, King and Pikul developed a matching anode and then developed a new way to integrate the two components at the microscale to make a complete battery with superior performance.

With so much power, the batteries could enable sensors or radio signals that broadcast 30 times farther, or devices 30 times smaller. The batteries are rechargeable and can charge 1,000 times faster than competing technologies -- imagine juicing up a credit-card-thin phone in less than a second. In addition to consumer electronics, medical devices, lasers, sensors and other applications could see leaps forward in technology with such power sources available.

"Any kind of electronic device is limited by the size of the battery -- until now," King said. "Consider personal medical devices and implants, where the battery is an enormous brick, and it's connected to itty-bitty electronics and tiny wires. Now the battery is also tiny."

Now, the researchers are working on integrating their batteries with other electronics components, as well as manufacturability at low cost.

"Now we can think outside of the box," Pikul said. "It's a new enabling technology. It's not a progressive improvement over previous technologies; it breaks the normal paradigms of energy sources. It's allowing us to do different, new things."

The National Science Foundation and the Air Force Office of Scientific Research supported this work. King also is affiliated with the Beckman Institute for Advanced Science and Technology; the Frederick Seitz Materials Research Laboratory; the Micro and Nanotechnology Laboratory; and the department of electrical and computer engineering at the U. of I.

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Brain Development Is Guided by Junk DNA That Isn't Really Junk

Specific DNA once dismissed as junk plays an important role in brain development and might be involved in several devastating neurological diseases, UC San Francisco scientists have found.

UCSF researchers have uncovered a role in brain development and in neurological disease for little appreciated molecules called long noncoding RNA. In this image, fluorescent dyes track the presence of the RNA molecules and the genes they affect in the developing mouse brain. (Credit: Image courtesy of Alexander Ramos)

Their discovery in mice is likely to further fuel a recent scramble by researchers to identify roles for long-neglected bits of DNA within the genomes of mice and humans alike.

While researchers have been busy exploring the roles of proteins encoded by the genes identified in various genome projects, most DNA is not in genes. This so-called junk DNA has largely been pushed aside and neglected in the wake of genomic gene discoveries, the UCSF scientists said.

In their own research, the UCSF team studies molecules called long noncoding RNA (lncRNA, often pronounced as "link" RNA), which are made from DNA templates in the same way as RNA from genes.

"The function of these mysterious RNA molecules in the brain is only beginning to be discovered," said Daniel Lim, assistant professor of neurological surgery, a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, and the senior author of the study, published online April 11 in the journal Cell Stem Cell.

Alexander Ramos, a student enrolled in the MD/PhD program at UCSF and first author of the study, conducted extensive computational analysis to establish guilt by association, linking lncRNAs within cells to the activation of genes.

Ramos looked specifically at patterns associated with particular developmental pathways or with the progression of certain diseases. He found an association between a set of 88 long noncoding RNAs and Huntington's disease, a deadly neurodegenerative disorder. He also found weaker associations between specific groups of long noncoding RNAs and Alzheimer's disease, convulsive seizures, major depressive disorder and various cancers.

"Alex was the team member who developed this new research direction, did most of the experiments, and connected results to the lab's ongoing work," Lim said. The study was mostly funded through Lim's grant - a National Institutes of Health (NIH) Director's New Innovator Award, a competitive award for innovative projects that have the potential for unusually high impact.

Unlike messenger RNA, which is transcribed from the DNA in genes and guides the production of proteins, lncRNA molecules do not carry the blueprints for proteins. Because of this fact, they were long thought to not influence a cell's fate or actions.

Nonetheless, lncRNAs also are transcribed from DNA in the same way as messenger RNA, and they, too, consist of unique sequences of nucleic acid building blocks.

Evidence indicates that lncRNAs can tether structural proteins to the DNA-containing chromosomes, and in so doing indirectly affect gene activation and cellular physiology without altering the genetic code. In other words, within the cell, lncRNA molecules act "epigenetically" -- beyond genes -- not through changes in DNA.

The brain cells that the scientists focused on the most give rise to various cell types of the central nervous system. They are found in a region of the brain called the subventricular zone, which directly overlies the striatum. This is the part of the brain where neurons are destroyed in Huntington's disease, a condition triggered by a single genetic defect.

Ramos combined several advanced techniques for sequencing and analyzing DNA and RNA to identify where certain chemical changes happen to the chromosomes, and to identify lncRNAs on specific cell types found within the central nervous system. The research revealed roughly 2,000 such molecules that had not previously been described, out of about 9,000 thought to exist in mammals ranging from mice to humans.

In fact, the researchers generated far too much data to explore on their own. The UCSF scientists created a website through which their data can be used by others who want to study the role of lncRNAs in development and disease.

"There's enough here for several labs to work on," said Ramos, who has training grants from the California Institute for Regenerative Medicine (CIRM) and the NIH.

"It should be of interest to scientists who study long noncoding RNA, the generation of new nerve cells in the adult brain, neural stem cells and brain development, and embryonic stem cells," he said.

Other co-authors who worked on the study include UCSF postdoctoral fellows Aaron Diaz, PhD, Abhinav Nellore, PhD, Michael Oldham, PhD, Jun Song, PhD, Ki-Youb Park, PhD, and Gabriel Gonzales-Roybal, PhD; and MD/PhD student Ryan Delgado. Additional funders of the study included the Sontag Foundation and the Sandler Foundation.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. 
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Human Genome Project Marks 10th Anniversary

This month marks the 10-year anniversary of the Human Genome Project, a 13-year international effort to determine the sequence of the 3 billion "letters" in a human being's DNA.

The $3 billion project, led by the U.S. Department of Energy and the National Institutes of Health, began in 1990 and was completed on April 14, 2003. In the decade since then, scientists have achieved many important milestones in using genomic discoveries to advance medical knowledge.

Sequencing technology has vastly improved in recent years. Sequencing the first human genome cost about $1 billion and took 13 years to complete; today it costs about $3,000 to $5000 and takes just one to two days.

Probing genome function

But just knowing the sequence would be meaningless without a way to interpret it. So researchers found ways to study the genome’s function, by sequencing the genomes of 135 other organisms and surveying the global variation among human genomes.

Researchers compared the genome sequences of other animals, such as chimpanzees and platypuses, as well as other eurkaryotic organisms (those whose cells have a nucleus), such as yeast and flat worms. From this comparison, scientists could identify stretches of DNA that have remained largely unchanged over the course of evolution. Five to 8 percent of the human genome has been unchanged for thousands of years.

One of the more surprising findings is how little of the human genome (only 1.5 percent) actually encodes proteins, the molecular building blocks that perform most of the critical functions inside cells.

To probe this mystery, more than 400 researchers from 32 labs worldwide created the ENCyclopedia Of DNA Elements (ENCODE) consortium. In 2012, they published many important findings about how the human genome functions. These include locations in the genome that may be genetic "switches" to turn genes on and off, as well as demonstrating that more than 80 percent of the genome that was once called "junk DNA" actually does serve a function.

Other research has focused on measuring the variation among human genomes. Preliminary studies during the Human Genome Project indicated that human genomes differ by just one-tenth of a percent. Investigating the limited variation that does exist is key to understanding human health and disease.

In sickness and in health
The first catalog of human genome variation was the International HapMap Project, which compared the genomes of people from Europe, China, Japan and Africa. Biotech companies have used findings from this project and its follow-on, the 1000 Genomes Project, to study populations with and without diseases, in the hope of identifying genetic variants associated with disease. Such genome-wide association studies have resulted in the identification of thousands of variants that can influence a person's likelihood of developing a disease.

As a result of these studies, the U.S. Food and Drug Administration now requires that the labels of more than 100 drugs include information about certain genetic markers, so doctors can tailor their prescriptions based on a patient's genetic makeup.

In the 10 years since the Human Genome Project was completed, researchers have made big strides in using genomic information in diagnosing and treating cancer. For instance, the breast cancer drug trastuzumab (Herceptin) only works for women with tumors of a certain type known as "HER-2 positive." Similarly, the lung cancer drugs gefitinib (Iressa) and erlotinib (Tarceva) are only effective for patients whose tumors have so-called "EGFR" mutations.

Mutations in only 53 genes were linked to disease when the genome project began, whereas more than 2,900 genes are today.

But scientists have a long way to go in understanding the human genome and how it can be used for improving human health. The rise of personalized genomics and changes in the ways health information is collected and used are prompting a new era in medicine, which brings both challenges and opportunities.

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What Happens in the Brain to Make Music Rewarding?

A new study reveals what happens in our brain when we decide to purchase a piece of music when we hear it for the first time. The study, conducted at the Montreal Neurological Institute and Hospital -- The Neuro, McGill University and published in the journal Science on April 12, pinpoints the specific brain activity that makes new music rewarding and predicts the decision to purchase music.

A new study reveals what happens in our brain when we decide to purchase a piece of music when we hear it for the first time. (Credit: © Warren Goldswain / Fotolia)

Participants in the study listened to 60 previously unheard music excerpts while undergoing functional resonance imaging (fMRI) scanning, providing bids of how much they were willing to spend for each item in an auction paradigm. "When people listen to a piece of music they have never heard before, activity in one brain region can reliably and consistently predict whether they will like or buy it, this is the nucleus accumbens which is involved in forming expectations that may be rewarding," says lead investigator Dr. Valorie Salimpoor, who conducted the research in Dr. Robert Zatorre's lab at The Neuro and is now at Baycrest Health Sciences' Rotman Research Institute. "What makes music so emotionally powerful is the creation of expectations. Activity in the nucleus accumbens is an indicator that expectations were met or surpassed, and in our study we found that the more activity we see in this brain area while people are listening to music, the more money they are willing to spend."

The second important finding is that the nucleus accumbens doesn't work alone, but interacts with the auditory cortex, an area of the brain that stores information about the sounds and music we have been exposed to. The more a given piece was rewarding, the greater the cross-talk between these regions. Similar interactions were also seen between the nucleus accumbens and other brain areas, involved in high-level sequencing, complex pattern recognition and areas involved in assigning emotional and reward value to stimuli.

In other words, the brain assigns value to music through the interaction of ancient dopaminergic reward circuitry, involved in reinforcing behaviours that are absolutely necessary for our survival such as eating and sex, with some of the most evolved regions of the brain, involved in advanced cognitive processes that are unique to humans.

"This is interesting because music consists of a series of sounds that when considered alone have no inherent value, but when arranged together through patterns over time can act as a reward, says Dr. Robert Zatorre, researcher at The Neuro and co-director of the International Laboratory for Brain, Music and Sound Research. "The integrated activity of brain circuits involved in pattern recognition, prediction, and emotion allow us to experience music as an aesthetic or intellectual reward."

"The brain activity in each participant was the same when they were listening to music that they ended up purchasing, although the pieces they chose to buy were all different," adds Dr. Salimpoor. "These results help us to see why people like different music -- each person has their own uniquely shaped auditory cortex, which is formed based on all the sounds and music heard throughout our lives. Also, the sound templates we store are likely to have previous emotional associations."

An innovative aspect of this study is how closely it mimics real-life music-listening experiences. Researchers used a similar interface and prices as iTunes. To replicate a real life scenario as much as possible and to assess reward value objectively, individuals could purchase music with their own money, as an indication that they wanted to hear it again. Since musical preferences are influenced by past associations, only novel music excerpts were selected (to minimize explicit predictions) using music recommendation software (such as Pandora, Last.fm) to reflect individual preferences.

The interactions between nucleus accumbens and the auditory cortex suggest that we create expectations of how musical sounds should unfold based on what is learned and stored in our auditory cortex, and our emotions result from the violation or fulfillment of these expectations. We are constantly making reward-related predictions to survive, and this study provides neurobiological evidence that we also make predictions when listening to an abstract stimulus, music, even if we have never heard the music before. Pattern recognition and prediction of an otherwise simple set of stimuli, when arranged together become so powerful as to make us happy or bring us to tears, as well as communicate and experience some of the most intense, complex emotions and thoughts.

Listen to the music excerpts used in the study: http://www.zlab.mcgill.ca/science2013/

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3-D Printer Can Build Synthetic Tissues

A custom-built programmable 3D printer can create materials with several of the properties of living tissues, Oxford University scientists have demonstrated.

A custom-built programmable 3D printer can create materials with several of the properties of living tissues, Oxford University scientists have demonstrated: Droplet network c.500 microns across with electrically conductive pathway between electrodes mimicking nerve. (Credit: Oxford University/G Villar)

The new type of material consists of thousands of connected water droplets, encapsulated within lipid films, which can perform some of the functions of the cells inside our bodies.

These printed 'droplet networks' could be the building blocks of a new kind of technology for delivering drugs to places where they are needed and potentially one day replacing or interfacing with damaged human tissues. Because droplet networks are entirely synthetic, have no genome and do not replicate, they avoid some of the problems associated with other approaches to creating artificial tissues -- such as those that use stem cells.

The team report their findings in this week's Science.

'We aren't trying to make materials that faithfully resemble tissues but rather structures that can carry out the functions of tissues,' said Professor Hagan Bayley of Oxford University's Department of Chemistry, who led the research. 'We've shown that it is possible to create networks of tens of thousands connected droplets. The droplets can be printed with protein pores to form pathways through the network that mimic nerves and are able to transmit electrical signals from one side of a network to the other.'

Each droplet is an aqueous compartment about 50 microns in diameter. Although this is around five times larger than living cells the researchers believe there is no reason why they could not be made smaller. The networks remain stable for weeks.

'Conventional 3D printers aren't up to the job of creating these droplet networks, so we custom built one in our Oxford lab to do it,' said Professor Bayley. 'At the moment we've created networks of up to 35,000 droplets but the size of network we can make is really only limited by time and money. For our experiments we used two different types of droplet, but there's no reason why you couldn't use 50 or more different kinds.'

The unique 3D printer was built by Gabriel Villar, a DPhil student in Professor Bayley's group and the lead author of the paper.

The droplet networks can be designed to fold themselves into different shapes after printing -- so, for example, a flat shape that resembles the petals of a flower is 'programmed' to fold itself into a hollow ball, which cannot be obtained by direct printing. The folding, which resembles muscle movement, is powered by osmolarity differences that generate water transfer between droplets.

Gabriel Villar of Oxford University's Department of Chemistry said: 'We have created a scalable way of producing a new type of soft material. The printed structures could in principle employ much of the biological machinery that enables the sophisticated behaviour of living cells and tissues.'

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Biological Transistor Enables Computing Within Living Cells

When Charles Babbage prototyped the first computing machine in the 19th century, he imagined using mechanical gears and latches to control information. ENIAC, the first modern computer developed in the 1940s, used vacuum tubes and electricity. Today, computers use transistors made from highly engineered semiconducting materials to carry out their logical operations.

Artist's rendering of cells. (Credit: © Jezper / Fotolia)

And now a team of Stanford University bioengineers has taken computing beyond mechanics and electronics into the living realm of biology. In a paper to be published March 28 in Science, the team details a biological transistor made from genetic material -- DNA and RNA -- in place of gears or electrons. The team calls its biological transistor the "transcriptor."

"Transcriptors are the key component behind amplifying genetic logic -- akin to the transistor and electronics," said Jerome Bonnet, PhD, a postdoctoral scholar in bioengineering and the paper's lead author.

The creation of the transcriptor allows engineers to compute inside living cells to record, for instance, when cells have been exposed to certain external stimuli or environmental factors, or even to turn on and off cell reproduction as needed.

"Biological computers can be used to study and reprogram living systems, monitor environments and improve cellular therapeutics," said Drew Endy, PhD, assistant professor of bioengineering and the paper's senior author.

The biological computer

In electronics, a transistor controls the flow of electrons along a circuit. Similarly, in biologics, a transcriptor controls the flow of a specific protein, RNA polymerase, as it travels along a strand of DNA.

"We have repurposed a group of natural proteins, called integrases, to realize digital control over the flow of RNA polymerase along DNA, which in turn allowed us to engineer amplifying genetic logic," said Endy.

Using transcriptors, the team has created what are known in electrical engineering as logic gates that can derive true-false answers to virtually any biochemical question that might be posed within a cell.

They refer to their transcriptor-based logic gates as "Boolean Integrase Logic," or "BIL gates" for short.

Transcriptor-based gates alone do not constitute a computer, but they are the third and final component of a biological computer that could operate within individual living cells.

Despite their outward differences, all modern computers, from ENIAC to Apple, share three basic functions: storing, transmitting and performing logical operations on information.

Last year, Endy and his team made news in delivering the other two core components of a fully functional genetic computer. The first was a type of rewritable digital data storage within DNA. They also developed a mechanism for transmitting genetic information from cell to cell, a sort of biological Internet.

It all adds up to creating a computer inside a living cell.

Boole's gold

Digital logic is often referred to as "Boolean logic," after George Boole, the mathematician who proposed the system in 1854. Today, Boolean logic typically takes the form of 1s and 0s within a computer. Answer true, gate open; answer false, gate closed. Open. Closed. On. Off. 1. 0. It's that basic. But it turns out that with just these simple tools and ways of thinking you can accomplish quite a lot.

"AND" and "OR" are just two of the most basic Boolean logic gates. An "AND" gate, for instance, is "true" when both of its inputs are true -- when "a" and "b" are true. An "OR" gate, on the other hand, is true when either or both of its inputs are true.

In a biological setting, the possibilities for logic are as limitless as in electronics, Bonnet explained. "You could test whether a given cell had been exposed to any number of external stimuli -- the presence of glucose and caffeine, for instance. BIL gates would allow you to make that determination and to store that information so you could easily identify those which had been exposed and which had not," he said.

By the same token, you could tell the cell to start or stop reproducing if certain factors were present. And, by coupling BIL gates with the team's biological Internet, it is possible to communicate genetic information from cell to cell to orchestrate the behavior of a group of cells.

"The potential applications are limited only by the imagination of the researcher," said co-author Monica Ortiz, a PhD candidate in bioengineering who demonstrated autonomous cell-to-cell communication of DNA encoding various BIL gates.

Building a transcriptor

To create transcriptors and logic gates, the team used carefully calibrated combinations of enzymes -- the integrases mentioned earlier -- that control the flow of RNA polymerase along strands of DNA. If this were electronics, DNA is the wire and RNA polymerase is the electron.

"The choice of enzymes is important," Bonnet said. "We have been careful to select enzymes that function in bacteria, fungi, plants and animals, so that bio-computers can be engineered within a variety of organisms."

On the technical side, the transcriptor achieves a key similarity between the biological transistor and its semiconducting cousin: signal amplification.

With transcriptors, a very small change in the expression of an integrase can create a very large change in the expression of any two other genes.

To understand the importance of amplification, consider that the transistor was first conceived as a way to replace expensive, inefficient and unreliable vacuum tubes in the amplification of telephone signals for transcontinental phone calls. Electrical signals traveling along wires get weaker the farther they travel, but if you put an amplifier every so often along the way, you can relay the signal across a great distance. The same would hold in biological systems as signals get transmitted among a group of cells.

"It is a concept similar to transistor radios," said Pakpoom Subsoontorn, a PhD candidate in bioengineering and co-author of the study who developed theoretical models to predict the behavior of BIL gates. "Relatively weak radio waves traveling through the air can get amplified into sound."

Public-domain biotechnology

To bring the age of the biological computer to a much speedier reality, Endy and his team have contributed all of BIL gates to the public domain so that others can immediately harness and improve upon the tools.

"Most of biotechnology has not yet been imagined, let alone made true. By freely sharing important basic tools everyone can work better together," Bonnet said.

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New Light On Possible 'Fifth Force of Nature'

In a breakthrough for the field of particle physics, Professor of Physics Larry Hunter and colleagues at Amherst College and The University of Texas at Austin have established new limits on what scientists call "long-range spin-spin interactions" between atomic particles. These interactions have been proposed by theoretical physicists but have not yet been seen. Their observation would constitute the discovery of a "fifth force of nature" (in addition to the four known fundamental forces: gravity, weak, strong and electromagnetic) and would suggest the existence of new particles, beyond those presently described by the Standard Model of particle physics.

This picture depicts the long-range spin-spin interaction (blue wavy lines) in which the spin-sensitive detector on Earth’s surface interacts with geoelectrons (red dots) deep in Earth’s mantle. The arrows on the geoelectrons indicate their spin orientations, opposite that of Earth’s magnetic field lines (white arcs). (Credit: Illustration: Marc Airhart (University of Texas at Austin) and Steve Jacobsen (Northwestern University).)

The new limits were established by considering the interaction between the spins of laboratory fermions (electrons, neutrons and protons) and the spins of the electrons within Earth. To make this study possible, the authors created the first comprehensive map of electron polarization within Earth induced by the planet's geomagnetic field.

Hunter -- along with emeritus Amherst physics professor Joel Gordon; postdoctoral fellow Stephen Peck; student researcher Daniel Ang '15; and Jung-Fu "Afu" Lin, associate professor of geosciences at UT Austin -- co-authored a paper about their work that appears in this week's issue of the journal Science. The highly interdisciplinary research relies on geophysics, atomic physics, particle physics, mineral physics, solid-state physics and nuclear physics to reach its conclusions.

The paper describes how the team combined a model of Earth's interior with a precise map of the planet's geomagnetic field to produce a map of the magnitude and direction of electron spins throughout Earth. Their model was based in part on insights gained from Lin's studies of spin transitions at the high temperatures and pressures of Earth's interior.

Every fundamental particle (every electron, neutron and proton, to be specific), explained Hunter, has the intrinsic atomic property of "spin." Spin can be thought of as a vector -- an arrow that points in a particular direction. Like all matter, Earth and its mantle -- a thick geological layer sandwiched between the thin outer crust and the central core -- are made of atoms. The atoms are themselves made up of electrons, neutrons and protons that have spin. Earth's magnetic field causes some of the electrons in the mantle's minerals to become slightly spin-polarized, meaning the directions in which their spins point are no longer completely random, but have some net orientation.

Earlier experiments, including one in Hunter's laboratory, explored whether their laboratory spins prefer to point in a particular direction. "We know, for example, that a magnetic dipole has a lower energy when it is oriented parallel to the geomagnetic field and it lines up with this particular direction -- that is how a compass works," he explained. "Our experiments removed this magnetic interaction and looked to see if there might be some other interaction that would orient our experimental spins. One interpretation of this 'other' interaction is that it could be a long-range interaction between the spins in our apparatus, and the electron spins within the Earth, that have been aligned by the geomagnetic field. This is the long-range spin-spin interaction we are looking for."

So far, no experiment has been able to detect any such interaction. But in Hunter's paper, the researchers describe how they were able to infer that such so-called spin-spin forces, if they exist, must be incredibly weak -- as much as a million times weaker than the gravitational attraction between the particles. At this level, the experiments can constrain "torsion gravity" -- a proposed theoretical extension of Einstein's Theory of General Relativity. Given the high sensitivity of the technique Hunter and his team used, it may provide a useful path for future experiments that will refine the search for such a fifth force. If a long-range spin-spin force is found, it not only would revolutionize particle physics but might eventually provide geophysicists with a new tool that would allow them to directly study the spin-polarized electrons within Earth.

"If the long-range spin-spin interactions are discovered in future experiments, geoscientists can eventually use such information to reliably understand the geochemistry and geophysics of the planet's interior," said Lin.

Possible future discoveries aside, Hunter said that he was pleased that this particular project enabled him to work with Lin. "When I began investigating spin transitions in the mantle, all of the literature led to him," he explained. "I was thrilled that he was interested in the project and willing to sign on as a collaborator. He has been a good teacher and has had enormous patience with my ignorance about geophysics. It has been a very fruitful collaboration."

Lin had his own take: "The most rewarding and surprising thing about this project was realizing that particle physics could actually be used to study the deep Earth."

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Using 3-D Printing and Injectable Molds, Bioengineered Ears Look and Act Like the Real Thing

Cornell bioengineers and physicians have created an artificial ear -- using 3-D printing and injectable molds -- that looks and acts like a natural ear, giving new hope to thousands of children born with a congenital deformity called microtia.

A 3-D printer in Weill Hall deposits cells encapsulated in a hydrogel that will develop into new ear tissue. The printer takes instructions from a file built from 3-D photographs of human ears taken with a scanner in Rhodes Hall. (Credit: Lindsay France/University Photography)

In a study published online Feb. 20 in PLOS One, Cornell biomedical engineers and Weill Cornell Medical College physicians described how 3-D printing and injectable gels made of living cells can fashion ears that are practically identical to a human ear. Over a three-month period, these flexible ears grew cartilage to replace the collagen that was used to mold them.

"This is such a win-win for both medicine and basic science, demonstrating what we can achieve when we work together," said co-lead author Lawrence Bonassar, associate professor of biomedical engineering.

The novel ear may be the solution reconstructive surgeons have long wished for to help children born with ear deformity, said co-lead author Dr. Jason Spector, director of the Laboratory for Bioregenerative Medicine and Surgery and associate professor of plastic surgery at Weill Cornell in New York City.

"A bioengineered ear replacement like this would also help individuals who have lost part or all of their external ear in an accident or from cancer," Spector said. Replacement ears are usually constructed with materials that have a Styrofoam-like consistency, or sometimes, surgeons build ears from a patient's harvested rib. This option is challenging and painful for children, and the ears rarely look completely natural or perform well, Spector said.

To make the ears, Bonassar and colleagues started with a digitized 3-D image of a human subject's ear, and converted the image into a digitized "solid" ear using a 3-D printer to assemble a mold.

This Cornell-developed, high-density gel is similar to the consistency of Jell-o when the mold is removed. The collagen served as a scaffold upon which cartilage could grow.

The process is also fast, Bonassar added: "It takes half a day to design the mold, a day or so to print it, 30 minutes to inject the gel, and we can remove the ear 15 minutes later. We trim the ear and then let it culture for several days in nourishing cell culture media before it is implanted."

The incidence of microtia, which is when the external ear is not fully developed, varies from almost 1 to more than 4 per 10,000 births each year. Many children born with microtia have an intact inner ear, but experience hearing loss due to the missing external structure.

Spector and Bonassar have been collaborating on bioengineered human replacement parts since 2007. The researchers specifically work on replacement human structures that are primarily made of cartilage -- joints, trachea, spine, nose -- because cartilage does not need to be vascularized with a blood supply in order to survive.

"Using human cells, specifically those from the same patient, would reduce any possibility of rejection," Spector said.

He added that the best time to implant a bioengineered ear on a child would be when they are about 5 or six 6 old. At that age, ears are 80 percent of their adult size. If all future safety and efficacy tests work out, it might be possible to try the first human implant of a Cornell bioengineered ear in as little as three years, Spector said.

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Chinese Medicine Yields Secrets: Atomic Mechanism of Two-Headed Molecule Derived from Chang Shan, a Traditional Chinese Herb

The mysterious inner workings of Chang Shan -- a Chinese herbal medicine used for thousands of years to treat fevers associated with malaria -- have been uncovered thanks to a high-resolution structure solved at The Scripps Research Institute (TSRI).

Scripps Research Institute scientists have determined a molecular 
 structure that helps explain how the Chinese herbal medicine 
Chang Shan works. (Credit: Image courtesy of the Schimmel lab.)

Described in the journal Nature this week, the structure shows in atomic detail how a two-headed compound derived from the active ingredient in Chang Shan works. Scientists have known that this compound, called halofuginone (a derivative of the febrifugine), can suppress parts of the immune system -- but nobody knew exactly how.

The new structure shows that, like a wrench in the works, halofuginone jams the gears of a molecular machine that carries out "aminoacylation," a crucial biological process that allows organisms to synthesize the proteins they need to live. Chang Shan, also known as Dichroa febrifuga Lour, probably helps with malarial fevers because traces of a halofuginone-like chemical in the herb interfere with this same process in malaria parasites, killing them in an infected person's bloodstream.

"Our new results solved a mystery that has puzzled people about the mechanism of action of a medicine that has been used to treat fever from a malaria infection going back probably 2,000 years or more," said Paul Schimmel, PhD, the Ernest and Jean Hahn Professor and Chair of Molecular Biology and Chemistry and member of The Skaggs Institute for Chemical Biology at TSRI. Schimmel led the research with TSRI postdoctoral fellow Huihao Zhou, PhD.

Halofuginone has been in clinical trials for cancer, but the high-resolution picture of the molecule suggests it has a modularity that would make it useful as a template to create new drugs for numerous other diseases.

The Process of Aminoacylation and its Importance to Life

Aminoacylation is a crucial step in the synthesis of proteins, the end products of gene expression. When genes are expressed, their DNA sequence is first read and transcribed into RNA, a similar molecule. The RNA is then translated into proteins, which are chemically very different from DNA and RNA but are composed of chains of amino acid molecules strung together in the order called for in the DNA.

Necessary for this translation process are a set of molecules known as transfer RNAs (tRNAs), which shuttle amino acids to the growing protein chain where they are added like pearls on a string. But before the tRNAs can move the pearls in place, they must first grab hold of them.

Aminoacylation is the biological process whereby the amino acid's pearls are attached to these tRNA shuttles. A class of enzymes known as aminoacyl-tRNA synthetases is responsible for attaching the amino acids to the tRNAs, and Schimmel and his colleagues have been examining the molecular details of this process for years. Their work has given scientists insight into everything from early evolution to possible targets for future drug development.

Over time what has emerged as the picture of this process basically involves three molecular players: a tRNA, an amino acid and the aminoacyl-tRNA synthetase enzyme that brings them together. A fourth molecule called ATP is a microscopic form of fuel that gets consumed in the process.

The new work shows that halofuginone gets its potency by interfering with the tRNA synthetase enzyme that attaches the amino acid proline to the appropriate tRNA. It does this by blocking the active site of the enzyme where both the tRNA and the amino acid come together, with each half of the halofuginone blocking one side or the other.

Interestingly, said Schimmel, ATP is also needed for the halofuginone to bind. Nothing like that has ever been seen in biochemistry before.

"This is a remarkable example where a substrate of an enzyme (ATP) captures an inhibitor of the same enzyme, so that you have an enzyme-substrate-inhibitor complex," said Schimmel.

The article, "ATP-Directed Capture of Bioactive Herbal-Based Medicine on Human tRNA Synthetase," by Huihao Zhou, Litao Sun, Xiang-Lei Yang and Paul Schimmel was published in the journal Nature on Dec. 23, 2012.

This work was supported by the National Institutes of Health through grants #GM15539, #23562 and #88278 and by a fellowship from the National Foundation for Cancer Research.

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Strange Behavior: New Study Exposes Living Cells to Synthetic Protein

One approach to understanding components in living organisms is to attempt to create them artificially, using principles of chemistry, engineering and genetics. A suite of powerful techniques -- collectively referred to as synthetic biology -- have been used to produce self-replicating molecules, artificial pathways in living systems and organisms bearing synthetic genomes.

The depletion of ATP in cells of the bacterium Escherichia coli causes them to transition to a filamentous state and form dense lipid structures known as endoliposomes. The structures can be clearly observed in these transmission electron micrographs of increasing magnification. (Credit: Image courtesy of Arizona State University)

In a new twist, John Chaput, a researcher at Arizona State University's Biodesign Institute and colleagues at the Department of Pharmacology, Midwestern University, Glendale, AZ have fabricated an artificial protein in the laboratory and examined the surprising ways living cells respond to it.

"If you take a protein that was created in a test tube and put it inside a cell, does it still function," Chaput asks. "Does the cell recognize it? Does the cell just chew it up and spit it out?" This unexplored area represents a new domain for synthetic biology and may ultimately lead to the development of novel therapeutic agents.

The research results, reported in the advanced online edition of the journal ACS Chemical Biology, describe a peculiar set of adaptations exhibited by Escherichia coli bacterial cells exposed to a synthetic protein, dubbed DX. Inside the cell, DX proteins bind with molecules of ATP, the energy source required by all biological entities.

"ATP is the energy currency of life," Chaput says. The phosphodiester bonds of ATP contain the energy necessary to drive reactions in living systems, giving up their stored energy when these bonds are chemically cleaved. The depletion of available intracellular ATP by DX binding disrupts normal metabolic activity in the cells, preventing them from dividing, (though they continue to grow).

After exposure to DX, the normally spherical E. coli bacteria develop into elongated filaments. Within the filamentous bacteria, dense intracellular lipid structures act to partition the cell at regular intervals along its length. These unusual structures, which the authors call endoliposomes, are an unprecedented phenomenon in such cells.

"Somewhere along the line of this filamentation, other processes begin to happen that we haven't fully understood at the genetic level, but we can see the results phenotypically," Chaput says. "These dense lipid structures are forming at very regular regions along the filamented cell and it looks like it could be a defense mechanism, allowing the cell to compartmentalize itself." This peculiar adaptation has never been observed in bacterial cells and appears unique for a single-celled organism.

Producing a synthetic protein like DX, which can mimic the elaborate folding characteristics of naturally occurring proteins and bind with a key metabolite like ATP is no easy task. As Chaput explains, a clever strategy known as mRNA display was used to produce, fine-tune and amplify synthetic proteins capable of binding ATP with high affinity and specificity, much as a naturally occurring ATP-binding protein would.

First, large libraries of random sequence peptides are formed from the four nucleic acids making up DNA, with each strand measuring around 80 nucleotides in length. These sequences are then transcribed into RNA with the help of an enzyme -- RNA polymerase. If a natural ribosome is then introduced, it attaches to the strand and reads the random sequence RNA as though it was a naturally-occurring RNA, generating a synthetic protein as it migrates along the strand. In this way, synthetic proteins based on random RNA sequences can be generated.

Exposing the batch of synthetic proteins to the target molecule and extracting those that bind can then select for ATP-binding proteins. But as Chaput explains, there's a problem: "The big question is how do you recover that genetic information? You can't reverse transcribe a protein back into DNA. You can't PCR amplify a protein. So we have to do all these molecular biology tricks."

The main trick involves an earlier step in the process. A molecular linker is chemically attached to the RNA templates, such that each RNA strand forms a bond with its newly translated protein. The mRNA-protein hybrids are exposed to selection targets (like ATP) over consecutive rounds of increasing stringency. After each round of selection, those library members that remain bound to the target are reverse-transcribed into cDNA (using their conveniently attached RNA messages), and then PCR amplified.

In the current study, E. coli cells exposed to DX transitioned into a filamentous form, which can occur naturally when such cells are subject to conditions of stress. The cells display low metabolic activity and limited cell division, presumably owing to their ATP-starved condition.

The study also examined the ability of E. coli to recover following DX exposure. The cells were found to enter a quiescent state known as viable but non-culturable (VBNC), meaning that they survived ATP sequestration and returned to their non-filamentous state after 48 hours, but lost their reproductive capacity. Further, this condition was difficult to reverse and seems to involve a fundamental reprogramming of the cell.

In an additional response to DX, the filamentous cells form previously undocumented structures, which the authors refer to as endoliposomes. These dense lipid concentrations, spanning the full width of the filamented E. coli, segment the cells into distinct compartments, giving the cells a stringbean-like appearance under the microscope.

The authors speculate that this adaptation may be an effort to maintain homeostasis in regions of the filamentous cell, which have essentially been walled off from the intrusion of ATP-depleting DX. They liken endoliposomes to the series of water-tight compartments found in submarines which are used to isolate damaged sections of the ship and speculate that DX-exposed cells are partitioning their genetic information into regions where it can be safely quarantined. Such self-compartmentalization is known to occur in some eukaryotic cells, but has not been previously observed in prokaryotes like E. coli.

The research indicates that there is still a great deal to learn about bacterial behavior and the repertoire of responses available when such cells encounter novel situations, such as an unfamiliar, synthetic protein. The study also notes that many infectious agents rely on a dormant state, (similar to the VBNC condition observed in the DX-exposed E. coli), to elude detection by antibiotics. A better understanding of the mechanisms driving this behavior could provide a new approach to targeting such pathogens.

The relative safety of E. coli as a model organism for study may provide a fruitful tool for more in-depth investigation of VBNC states in pathogenic organisms. Further, given ATP's central importance for living organisms, its suppression may provide another avenue for combating disease. One example would be an engineered bacteriophage capable of delivering DX genes to pathogenic organisms.

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