Simulation  

Researchers using computer simulations have revealed a key mechanism in the replication process of influenza A.  The work may help defend against future deadly pandemics.

Treating influenza relies on drugs, such as Amantadine, that are becoming less effective due evolution of the virus. Now University of Chicago scientists have published computational results that may give drug designers the insight they need to develop the next generation of effective influenza treatment.

“It’s very hard to design a drug if you don’t understand how the disease functions,” said Gregory Voth, the Haig P. Papazian Distinguished Service Professor in Chemistry. Voth and three co-authors offer new insights into the disease’s functioning in the Proceedings of the National Academy of Sciences.

Amantadine is a bulky organic compound originally designed to treat influenza A by blocking proton flow through the M2 channel, one of the few proteins that are targets for antiviral therapies. “The proton flow is essential for influenza viral replication,” said Voth, who also is director of the Center for Multiscale Theory and Simulation. Unfortunately, subsequent mutations in different forms of the flu have changed the ability of Amantadine to bind to the M2 protein. “There’s a big, worldwide push to find new drugs that will block this or other influenza proteins,” Voth said.

"Computer simulation, when done very well, with all the right physics, reveals a huge amount of information that you can’t get otherwise."

The UChicago team conducted extensive multiscale simulations of proton permeation, a critical step in viral replication, through the M2 channel from influenza A. The simulations enabled them to visualize this process at three interconnected scales, from the electronic (the smallest), to the molecular (intermediate) to the mesoscopic (the largest). The capability of the technique was demonstrated by last year’s Nobel Prize in Chemistry, which was awarded to three scientists “for the development of multiscale models for complex chemical systems.”

“Computer simulation, when done very well, with all the right physics, reveals a huge amount of information that you can’t get otherwise,” Voth said. “In principle, you could do these calculations with potential drug targets and see how they bind and if they are, in fact, effective.”

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The flow of protons through the watery M2 channel is a complex process, one involving many phenomena, including the making and breaking of chemical bonds. Scientists have attempted to simulate this process computationally for more than 20 years to understand how it works, but only now has the feat been achieved. No other experimental or simulation technique is capable of examining the proton flow process in such detail.

Scientists have, however, succeeded in experimentally producing mutations of different parts of the M2 protein. The UChicago team’s simulations of the protein’s dynamics not only agree with those experimental data, which validates the results, but also explains the effects of these mutations, one of which is a dominant cause of drug resistance.

To reach such significant conclusions, the UChicago team tapped the power of four high-performance computer clusters. Principal among these was the Midway high-performance computing cluster at the University’s Research Computing Center. The Midway cluster worked various aspects of the problem continually for an entire year under the watchful guidance of Ruibin Liang, a graduate student in chemistry and the study’s lead author.

But the team also needed clusters at the Texas Advanced Computing Center at the University of Texas at Austin, the San Diego Supercomputer Center at the University of San Diego, and the Department of Defense High Performance Computing Center in Vicksburg, Miss.

“This was a huge amount of work, so I used every resource available. Professor Voth devoted a lot of machine time to this project,” Liang said.

More work lies ahead for Voth and his team, including trying to make the simulation process run more quickly, explaining the effects of drug resistant mutations, and targeting other forms of influenza. According the Liang, the stage has been set and the work is underway to reveal the proton permeation mechanism in influenza B, another form of the flu that has a different M2 channel and is entirely resistant to drugs like Amantidine.


SOURCE  University of Chicago

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 Bionics  

New research at the University of Chicago is laying the groundwork for touch-sensitive prosthetic limbs that one day could convey real-time sensory information to amputees via a direct interface with the brain.

DARPA-funded research at the University of Chicago is laying the groundwork for touch-sensitive prosthetic limbs that one day could convey real-time sensory information to amputees via a direct interface with the brain.

The research, published early online in the Proceedings of the National Academy of Sciences, marks an important step toward new technology that, if implemented successfully, would increase the dexterity and clinical viability of robotic prosthetic limbs.

“To restore sensory motor function of an arm, you not only have to replace the motor signals that the brain sends to the arm to move it around, but you also have to replace the sensory signals that the arm sends back to the brain,” said the study’s senior author, Sliman Bensmaia, PhD, assistant professor in the Department of Organismal Biology and Anatomy at the University of Chicago. “We think the key is to invoke what we know about how the brain of the intact organism processes sensory information, and then try to reproduce these patterns of neural activity through stimulation of the brain.”

Bensmaia’s research is part of Revolutionizing Prosthetics, a multi-year Defense Advanced Research Projects Agency (DARPA) project that seeks to create a modular, artificial upper limb that will restore natural motor control and sensation in amputees. Managed by the Johns Hopkins University Applied Physics Laboratory, the project has brought together an interdisciplinary team of experts from academic institutions, government agencies and private companies.

Bensmaia and his colleagues at the University of Chicago are working specifically on the sensory aspects of these limbs. In a series of experiments with monkeys, whose sensory systems closely resemble those of humans, they indentified patterns of neural activity that occur during natural object manipulation and then successfully induced these patterns through artificial means.

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The first set of experiments focused on contact location, or sensing where the skin has been touched. The animals were trained to identify several patterns of physical contact with their fingers. Researchers then connected electrodes to areas of the brain corresponding to each finger and replaced physical touches with electrical stimuli delivered to the appropriate areas of the brain. The result: The animals responded the same way to artificial stimulation as they did to physical contact.

Next the researchers focused on the sensation of pressure. In this case, they developed an algorithm to generate the appropriate amount of electrical current to elicit a sensation of pressure. Again, the animals’ response was the same whether the stimuli were felt through their fingers or through artificial means.

Finally, Bensmaia and his colleagues studied the sensation of contact events. When the hand first touches or releases an object, it produces a burst of activity in the brain. Again, the researchers established that these bursts of brain activity can be mimicked through electrical stimulation.

The result of these experiments is a set of instructions that can be incorporated into a robotic prosthetic arm to provide sensory feedback to the brain through a neural interface. Bensmaia believes such feedback will bring these devices closer to being tested in human clinical trials.

“The algorithms to decipher motor signals have come quite a long way, where you can now control arms with seven degrees of freedom. It’s very sophisticated. But I think there’s a strong argument to be made that they will not be clinically viable until the sensory feedback is incorporated,” Bensmaia said. “When it is, the functionality of these limbs will increase substantially.”



SOURCE  University of Chicago via Newswise

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 Evolution  

A research team led by a University of Chicago scientist has discovered two key mutations that sparked a hormonal revolution 500 million years ago.

Evolution, it seems, sometimes jumps instead of crawls.

A research team led by a University of Chicago scientist has discovered two key mutations that sparked a hormonal revolution 500 million years ago.

In a feat of "molecular time travel," the researchers resurrected and analyzed the functions of the ancestors of genes that play key roles in modern human reproduction, development, immunity and cancer. By re-creating the same DNA changes that occurred during those genes' ancient history, the team showed that two mutations set the stage for hormones like estrogen, testosterone and cortisol to take on their crucial present-day roles.

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"Changes in just two letters of the genetic code in our deep evolutionary past caused a massive shift in the function of one protein and set in motion the evolution of our present-day hormonal and reproductive systems," said Joe Thornton, PhD, professor of human genetics and ecology & evolution at the University of Chicago, who led the study.

"If those two mutations had not happened, our bodies today would have to use different mechanisms to regulate pregnancy, libido, the response to stress, kidney function, inflammation, and the development of male and female characteristics at puberty," Thornton said.

The findings were published online in the Proceedings of the National Academy of Sciences.

Understanding how the genetic code of a protein determines its functions would allow biochemists to better design drugs and predict the effects of mutations on disease. Thornton said the discovery shows how evolutionary analysis of proteins' histories can advance this goal, Before the group's work, it was not previously known how the various steroid receptors in modern species distinguish estrogens from other hormones.

The team, which included researchers from the University of Oregon, Emory University and the Scripps Research Institute, studied the evolution of a family of proteins called steroid hormone receptors, which mediate the effects of hormones on reproduction, development and physiology. Without receptor proteins, these hormones cannot affect the body's cells.

Thornton's group traced how the ancestor of the entire receptor family—which recognized only estrogens—evolved into descendant proteins capable of recognizing other steroid hormones, such as testosterone, progesterone and the stress hormone cortisol.

To do so, the group used a gene "resurrection" strategy. They first inferred the genetic sequences of ancient receptor proteins, using computational methods to work their way back up the tree of life from a database of hundreds of present-day receptor sequences. They then biochemically synthesized these ancient DNA sequences and used molecular assays to determine the receptors' sensitivity to various hormones.

Thornton's team narrowed down the time range during which the capacity to recognize non-estrogen steroids evolved, to a period about 500 million years ago, before the dawn of vertebrate animals on Earth. They then identified the most important mutations that occurred during that interval by introducing them into the reconstructed ancestral proteins. By measuring how the mutations affected the receptor's structure and function, the team could re-create ancient molecular evolution in the laboratory.

They found that just two changes in the ancient receptor's gene sequence caused a 70,000-fold shift in preference away from estrogens toward other steroid hormones. The researchers also used biophysical techniques to identify the precise atomic-level mechanisms by which the mutations affected the protein's functions. Although only a few atoms in the protein were changed, this radically rewired the network of interactions between the receptor and the hormone, leading to a massive change in function.

"Our findings show that new molecular functions can evolve by sudden large leaps due to a few tiny changes in the genetic code," Thornton said. He pointed out that, along with the two key changes in the receptor, additional mutations, the precise effects of which are not yet known, were necessary for the full effects of hormone signaling on the body to evolve.


SOURCE  University of Chicago

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