In the December 12, 2018 issue of the Proceedings of the Royal Society B, a multi-institutional team of researchers based at the University of Chicago Medicine take a novel and wide-ranging approach to understanding such speed-related gait transitions. The generally accepted approach has long focused on reducing locomotor costs, essentially finding the least taxing way to ramp up from one gait to a faster one without wasting energy.

The researchers, however, uncovered a different explanation. They chose to focus less on energy conservation and more on locomotor instability — in layman’s terms, reducing the risk of stumbling or toppling over. Their findings suggest that gait transitions represent “predictive, anticipatory switching of movements to minimize unstable dynamic states.”

“We found that gait transitions occur when the stability of a gait decreases so much that switching to a new gait improves stability,” said Michael Granatosky, PhD, lead author of the study and a post-doctoral student in the department of Organismal Biology and Anatomy at the University of Chicago. “The mammals and birds we studied tend to make gait transitions at critical points to provide a more rhythmic, less unstable locomotor state.”

These transitions, he added, can minimize “high inter-stride variation and unstable dynamic states, reducing the risk of inter-limb interference, such as tripping or falling.”

This wide-ranging study focused on gait transitions in nine animal models — seven mammals and two birds. The researchers started with Virginia opossums, tufted capuchins (“organ grinder” monkeys) and domestic dogs.

They subsequently found similar data on gait transitions in six additional species: American minks, Australian water rats, brush-tailed bettongs (small marsupials also known as rat kangaroos), ostriches, North American river otters and the Svalbard rock ptarmigan.

All of the initial animals — dogs, monkeys and opossums — were trained to exercise at a range of speeds on a treadmill within a plexiglass metabolic chamber. This familiarized the animals with the treadmills while improving their physical fitness. By the end of the training period, all of the animals could sustain six to ten minutes of vigorous running at “speeds required for metabolic movements.”

Once the training was completed, the researchers began testing. They monitored oxygen uptake, carbon-dioxide production, temperature, moisture levels, barometric pressure and air flow. Each animal ran in the chamber two to five times a day. From these metrics it was possible to determine the energetic costs of running at a particular speed.

These energetic costs were collected over a range of speeds during walking and running. Variations in stride cycle duration were collected for each speed interval.

Based on the data collected from this broad phylogenetic range of species, the authors determined that the assumptions of the energetic minimization hypothesis for gait transitions were rarely met.

Instead, most animals choose not to switch gaits when it was most energetically efficient. In this study, dogs, ptarmigans, ostriches and otters, showed no significant change in the energy cost of transport while switching from a walk to a faster mode. In contrast, almost all of the other species demonstrated high variability near gait transitions. They subsequently reduced variability after switching to a new more stable gait.

“Energy savings do not predict gait transition patterns,” the authors conclude. Instead, gait transitions “maintain dynamic stability across a range of speeds.”

“Our data,” the authors conclude, “suggest that gait transitions represent predictive, anticipatory switching of movement types to minimize high variability and avoid unstable dynamic states.” Birds and mammals, they added, appear to have evolved sensorimotor mechanisms for monitoring inter-stride stability during locomotion and for triggering gait transitions at critical levels of variation.

It was just about a year ago that Caltech scientists in the laboratory of Lulu Qian, assistant professor of bioengineering, announced they had used a technique known as DNA origami to create tiles that could be designed to self-assemble into larger nanostructures that carry predesigned patterns. They chose to make the world’s smallest version of the iconic Mona Lisa.

The feat was impressive, but the technique had a limitation similar to that of Leonardo da Vinci’s oil paints: Once the image was created, it could not easily be changed.

Now, the Caltech team has made another leap forward with the technology. They have created new tiles that are more dynamic, allowing the researchers to reshape already-built DNA structures. When Caltech’s Paul Rothemund (BS ’94) pioneered DNA origami more than a decade ago, he used the technique to build a smiley face. Qian’s team can now turn that smile into a frown, and then, if they want, turn that frown upside down. And they have gone even further, fashioning a microscopic game of tic-tac-toe in which players place their X’s and O’s by adding special DNA tiles to the board.

“We developed a mechanism to program the dynamic interactions between complex DNA nanostructures,” says Qian. “Using this mechanism, we created the world’s smallest game board for playing tic-tac-toe, where every move involves molecular self-reconfiguration for swapping in and out hundreds of DNA strands at once.”

Putting the Pieces Together

That swapping mechanism combines two previously developed DNA nanotechnologies. It uses the building blocks from one and the general concept from the other: self-assembling tiles, which were used to create the tiny Mona Lisa; and strand displacement, which has been used by Qian’s team to build DNA robots.

Both technologies make use of DNA’s ability to be programmed through the arrangement of its molecules. Each strand of DNA consists of a backbone and four types of molecules known as bases. These bases — adenine, guanine, cytosine, and thymine, abbreviated as A, T, C, and G — can be arranged in any order, with the order representing information that can be used by cells, or in this case by engineered nanomachines.

The second property of DNA that makes it useful for building nanostructures is that the A, T, C, and G bases have a natural tendency to pair up with their counterparts. The A base pairs with T, and C pairs with G. By extension, any sequence of bases will want to pair up with a complementary sequence. For example, ATTAGCA will want to pair up with TAATCGT.

However, a sequence can also pair up with a partially matching sequence. If ATTAGCA and TAATACC were put together, their ATTA and TAAT portions would pair up, and the nonmatching portions would dangle off the ends. The more closely two strands complement each other, the more attracted they are to each other, and the more strongly they bond.

To picture what happens in strand displacement, imagine two people who are dating and have several things in common. Amy likes dogs, hiking, movies, and going to the beach. Adam likes dogs, hiking, and wine tasting. They bond over their shared interest in dogs and hiking. Then another person comes into the picture. Eddie happens to like dogs, hiking, movies, and bowling. Amy realizes she has three things in common with Eddie, and only two in common with Adam. Amy and Eddie find themselves strongly attracted to each other, and Adam gets dumped — like a displaced DNA strand.

Eddie and Amy have more in common and their bond is stronger. As in DNA strand displacement, Amy leaves with Eddie

The other technology, self-assembling tiles, is more straightforward to explain. Essentially, the tiles, though all square in shape, are designed to behave like the pieces of a jigsaw puzzle. Each tile has its own place in the assembled picture, and it only fits in that spot.

In creating their new technology, Qian’s team imbued self-assembling tiles with displacement abilities. The result is tiles that can find their designated spot in a structure and then kick out the tile that already occupies that position. Whereas Eddie merely bonded with one person, causing another to be kicked to the curb, the tiles are more like an adopted child who connects so strongly with a new family that they take the title of “favorite” away from biological offspring.

“In this work, we invented the mechanism of tile displacement, which follows the abstract principle of strand displacement but occurs at a larger scale between DNA origami structures,” says Qian’s former graduate student Philip Petersen (PhD ’18), lead author of the study. “This is the first mechanism that can be used to program dynamic behaviors in systems of multiple interacting DNA origami structures.”

Let’s Play

To get the tic-tac-toe game started, Qian’s team mixed up a solution of blank board tiles in a test tube. Once the board assembled itself, the players took turns adding either X tiles or O tiles to the solution. Because of the programmable nature of the DNA they are made from, the tiles were designed to slide into specific spots on the board, replacing the blank tiles that had been there. An X tile could be designed to only slide into the lower left-hand corner of the board, for example. Players could put an X or and O in any blank spot they wanted by using tiles designed to go where they wanted. After six days of riveting gameplay, player X emerged victorious.

Obviously, no parents will be rushing out to buy their children a tic-tac-toe game that takes almost a week to play, but tic-tac-toe is not really the point, says Grigory Tikhomirov, senior postdoctoral scholar and co-first author of the study. The goal is to use the technology to develop nanomachines that can be modified or repaired after they have already been built.

“When you get a flat tire, you will likely just replace it instead of buying a new car. Such a manual repair is not possible for nanoscale machines,” he says. “But with this tile displacement process we discovered, it becomes possible to replace and upgrade multiple parts of engineered nanoscale machines to make them more efficient and sophisticated.”

Video: https://www.youtube.com/watch?v=UJveJUVrWZA

“The huge bodies that we see in most dinosaurs must have gotten really hot in warm Mesozoic climates,” said Jason Bourke, Assistant Professor at the New York Institute of Technology College of Osteopathic Medicine at Arkansas State and lead author of the study. “Brains don’t like that, so we wanted to see if there were ways to protect the brain from cooking. It turns out the nose may be the key.”

Bourke and the team used CT scanning and a powerful engineering approach called computational fluid dynamics to simulate how air moved through the nasal passages of two different ankylosaur species, the hippo-sized Panoplosaurus and larger rhino-sized Euoplocephalus, to test how well ankylosaur noses transferred heat from the body to the inhaled air.

“A decade ago, my colleague Ryan Ridgely and I published the discovery that ankylosaurs had insanely long nasal passages coiled up in their snouts,” said study co-author Lawrence Witmer, professor at the Ohio University Heritage College of Osteopathic Medicine. “These convoluted airways looked like a kid’s ‘crazy-straw!’ It was completely unexpected and cried out for explanation. I was thrilled when Jason took up the problem as part of his doctoral research in our lab.”

“This project is an excellent example of how advances in CT scanning, 3-D reconstruction, imaging, and computational fluid dynamics modeling can be used in biological research to test long-standing hypotheses,” said Kathy Dickson, a program officer at the National Science Foundation that funded the research. “From these new images and models, fossils can provide further insight into extinct organisms like the ankylosaur — in this case, offering an explanation of how unusual features actually function physiologically.”

Smell may be a primary function of the nose, but noses are also heat exchangers, making sure that air is warmed and humidified before it reaches our delicate lungs. To accomplish this effective air conditioning, birds and mammals, including humans, rely on thin curls of bone and cartilage within their nasal cavities called turbinates, which increase the surface area, allowing for air to come into contact with more of the nasal walls. “Ankylosaurs didn’t have turbinates, but instead made their noses very long and twisty,” said Bourke.

When the researchers compared their findings to data from living animals, they discovered that the dinosaurs’ noses were just as efficient at warming and cooling respired air. “This was a case of nature finding a different solution to the same problem,” said Bourke.

Just how long were these nasal passages? In Panoplosaurus, they were a bit longer than the skull itself and in Euoplocephalus they were almost twice as long as the skull, which is why they’re coiled up in the snout. To see if nasal passage length was the reason for this efficiency, Bourke ran alternative models with shorter, simpler nasal passages that ran directly from the nostril to the throat, as in most other animals. The results clearly showed that nose length was indeed the key to their air-conditioning ability. “When we stuck a short, simple nose in their snouts, heat-transfer rates dropped over 50 percent in both dinosaurs. They were less efficient and didn’t work very well,” said Bourke.

Another line of evidence that these noses were air conditioners that helped cool the brain came from analyses of blood flow.

“When we reconstructed the blood vessels, based on bony grooves and canals, we found a rich blood supply running right next to these convoluted nasal passages,” said Ruger Porter, lecturer at the Ohio University Heritage College of Osteopathic Medicine and one of the study’s co-authors. “Hot blood from the body core would travel through these blood vessels and transfer their heat to the incoming air. Simultaneously, evaporation of moisture in the long nasal passages cooled the venous blood destined for the brain.”

So why the need for such effective heat exchangers? The large bodies of Panoplosaurus and Euoplocephalus were really good at retaining heat, which is good for staying warm, but bad when the animals need to cool off. This heat-shedding problem would have put them at risk of overheating even on cloudy days. In the absence of some protective mechanism, the delicate neural tissue of the brain could be damaged by the hot blood from the body core.

“Sure, their brains were almost comically small,” Bourke said. “But they’re still their brains and needed protection.”

The complicated nasal airways of these dinosaurs were acting as radiators to cool down the brain with a constant flow of cooled venous blood, allowing them to keep a cool head at all times. This natural engineering feat also may have allowed the evolution of the great sizes of so many dinosaurs.

“When we look at the nasal cavity and airway in dinosaurs, we find that the most elaborate noses are found in the large dinosaur species, which suggests that the physiological stresses of large body size may have spurred some of these anatomical novelties to help regulate brain temperatures,” Witmer said.

The next step for the researchers is to examine other dinosaurs to determine when this nasal enlargement happened.

“We know that large dinosaurs had these crazy airways, but at exactly what size did this happen?” Bourke said. “Was this elaboration gradual as body size increased, or is there a threshold size where a run-of-the-mill nose can no longer do the job? We just don’t know yet.”

The research was funded by National Science Foundation (NSF) grants to Witmer (part of the Visible Interactive Dinosaur Project) and an NSF fellowship to Bourke, as well as by the Ohio University Heritage College of Osteopathic Medicine.

“Currently, encryption is done with mathematical algorithms that are called one-way functions,” said Saptarshi Das, assistant professor of engineering science and mechanics, Penn State. “These are easy to create in one direction, but very difficult to do in the opposite direction.”

An example of this is multiplying two prime numbers. Assuming the original numbers are very large, reverse engineering from the result becomes very time and computer-resource heavy.

“However, now that computers are becoming more powerful and quantum computing is on the horizon, using encryption that relies on its effectiveness because it is monumentally time consuming to decrypt won’t fly anymore,” Das said.

Only truly random encryption keys are unclonable and not capable of being reverse-engineered because there is no pattern or formula in the process. Even so-called random number generators are really pseudo-random number generators.

“We need to go back to nature and identify real random things,” said Das. “Because there is no mathematical basis for many biological processes, no computer can unravel them.”

The researchers, who also included Akhil Dodda, graduate student in engineering science and mechanics; Akshay Wali, graduate student in electrical engineering; and Yang Wu, postdoctoral fellow in engineering science and mechanics, looked at human T cells. They photographed a random, 2-dimensional array of T cells in solution and then digitized the image by creating pixels on the image and making the T cell pixels “ones” and the empty spaces “zeros.”

“When we started there were a few papers out using nanomaterials,” said Dodda. “However, they weather (nanomaterials) out of the material and are stationary.”

Living cells, regardless of the type, can be kept around for a long time and because they move constantly, can be photographed repeatedly to create new encryption keys.

“We need a lot of keys because the population of the world is 7 billion,” said Das. “Each person will generate a megabyte of data every second by 2020.”

Besides encryption keys for personal computers, the keys are also needed for medical, financial and business data, and much more. If something is hacked or malfunctions, this method would also allow rapid replacement of the encryption key.

“It is very difficult to reverse-engineer these systems,” said Dodda. “Not being able to reverse-engineer these keys is an area of strength.”

The researchers are currently using 2,000 T cells per encryption key. The team reports in a recent issue of Advanced Theory and Simulations that even if someone knows the key generation mechanism, including cell type, cell density, key generation rate and key sampling instance, it is impossible for anyone to breach the system. It is simply not possible from that information to bust the encryption.

“We need something secure, and biological species-encrypted security systems will keep our data safe and secure everywhere and anytime,” said Wali.

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