When dehydration strikes, part of the brain can swell, neural signaling can intensify, and doing monotonous tasks can get harder.

With the help of brain scans and a simple, repetitive task to test responsiveness, exercise physiologists at the Georgia Institute of Technology studied volunteer subjects who sweated a lot and did not hydrate. The fluid loss led most of the subjects to make more goofs on the task, and areas of participants’ brains showed conspicuous changes.

The researchers also found that even without dehydration, exertion and heat put a dent in test subjects’ performance, but water loss made the dent about twice as deep.

“We wanted to tease out whether exercise and heat stress alone have an impact on your cognitive function and study the effect of dehydration on top of that,” said Mindy Millard-Stafford, the study’s principal investigator and a professor in Georgia Tech’s School of Biological Sciences. “We found a two-step decline.”

Heat, strain, accident

The researchers hope that someday this kind of research will offer insights into how increased cognitive slipups in hot settings with strenuous labor and poor hydration may endanger occupational safety, especially around heavy machines or military hardware. The fuzzed cognition could also contribute to reduced performance in competitive sports.

“When I was just getting interested in this subject, my brother was doing an internship at a steel plant, where I visited him, and it was extremely hot,” said the study’s first author Matt Wittbrodt, a former graduate research assistant at Georgia Tech. “In addition, everyone had on layers of protective clothing. We want to figure out if we can help prevent accidents in those environments.”

Millard-Stafford and Wittbrodt, who is now a postdoctoral researcher at Emory University, published their study on Thursday, August 23, in the journal Physiological Reports. Their research was partly funded by The American College of Sports Medicine Foundation.

Brain ventricles expand

In the experiments, when participants exercised, sweated and drank water, fluid-filled spaces called ventricles in the center of their brains contracted. But with exertion plus dehydration, the ventricles did the opposite; they expanded.

Functional magnetic resonance imaging (fMRI) revealed the differences. Oddly, the ventricle expansion in dehydrated test subjects may not have had much to do with their deeper slumps in task performance.

“The structural changes were remarkably consistent across individuals,” said Millard-Stafford a past president of The American College of Sports Medicine. “But performance differences in the tasks could not be explained by changes in the size of those brain areas.”

Changes in neural firing patterns showed up during dehydration, too.

“The areas in the brain required for doing the task appeared to activate more intensely than before, and also, areas lit up that were not necessarily involved in completing the task,” Wittbrodt said. “We think the latter may be in response to the physiological state: the body signaling, ‘I’m dehydrated’.” 

Mind-numbing task

The task the subjects completed was mindless and repetitive.

For 20 straight minutes, they were expected to punch a button every time a yellow square appeared on a monitor. Sometimes the square appeared in a regular pattern, and sometimes it appeared randomly. The task was dull for a reason.

“It helped us to avoid the cognitive complexity behind elaborate tasks and strip cognition down to simple motor output,” Wittbrodt said. “It was designed to hit essential neural processing one would use to make straightforward, repetitive movements.”

Past studies have indicated that this kind of task reflects the neural processing involved in real-life motor functioning, especially in the repetition common in manual labor or military exercises. Such monotony can foster attention lapses that heat, strain, and fluid loss may exacerbate. 

Sweating for science

Thirteen volunteers performed the task on three separate occasions:

• Once after just relaxing and staying hydrated.
• Once after extended heat, exertion, and sweat but with drinking water during exercise.
• And once with heat, exertion, and sweat but without drinking water.

Even after just relaxing, task performance gradually slipped as the 20 minutes crept by. But under the subsequent stressors, average overall performance ratcheted down. A few of the volunteers did perform the task stalwartly under all imposed conditions.

The subjects completed the task in air-conditioned rooms and after a break from strenuous activity. In a real-world scenario, in which heat and toil are unrelenting, performance may collapse even further.

Overhydration also bad 

Going forward, the researchers would like to know if hydrating with electrolyte drinks might mitigate performance slumps even better than water did.

“Blood plasma gets diluted with water replacement alone,” Millard-Stafford said. “If blood sodium -- plain old salt -- drops too much while water in the blood increases too much, that’s dangerous. It’s a condition known as water intoxication or hyponatremia.”

Ultra-endurance athletes who end up in the medical tent are sometimes suffering from dehydration but also sometimes from water intoxication. Just the right balance of water seems to be important for the brain.

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Also READ: As We Get Parched, Cognition Can Sputter

Georgia Tech’s Michael Sawka and Lewis Wheaton, and J. C. Mizelle of East Carolina University contributed to this study. Research was partly funded by The American College of Sports Medicine Foundation’s C. V. Gisolfi Doctoral Student Research Grant. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of The American College of Sports Medicine.

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More than an eon ago, the sun shone dimmer than it does today, but the Earth stayed warm due to a strong greenhouse gas effect, geoscience theory holds. Astronomer Carl Sagan coined this “the Faint Young Sun Paradox,” and for decades, researchers have searched for the right balance of atmospheric gases that could have kept early Earth cozy.

A new study led by the Georgia Institute of Technology suggests that nitrous oxide, known for its use as the dental sedative laughing gas, may have played a significant role.

The research team carried out experiments and atmospheric computer modeling that in detail substantiated an existing hypothesis about the presence of nitrous oxide (N2O), a powerful greenhouse gas, in the ancient atmosphere. Established research has already pointed to high levels of carbon dioxide and methane, but they may not have been plentiful enough to sufficiently keep the globe warm without the help of N2O.

Jennifer Glass, an assistant professor at Georgia Tech, and Chloe Stanton, formerly an undergraduate research assistant in the Glass lab at Georgia Tech, published the study in the journal Geobiology on Wednesday, August 22, 2018. Their work was funded by the NASA Astrobiology Institute. Stanton is now a graduate research assistant at the Pennsylvania State University.

No ‘boring billion’

The study focused on the middle of the Proterozoic Eon, over a billion years ago. The proliferation of complex life was still a few hundred million years out, and the pace of our planet’s evolution probably appeared deceptively slow.

“People in our field often refer to this middle chapter in Earth’s history roughly 1.8 to 0.8 billion years ago as the ‘boring billion’ because we classically think of it as a very stable period,” said Stanton, the study’s first author. “But there were many important processes affecting ocean and atmospheric chemistry during this time.”

Chemistry in mid-Proterozoic ocean was heavily influenced by abundant soluble ferrous iron (Fe2+) in oxygen-free deep waters.

Ancient iron key

“The ocean chemistry was completely different back then,” said Glass, the study’s principal investigator. “Today’s oceans are well-oxygenated, so iron rapidly rusts and drops out of solution. Oxygen was low in Proterozoic oceans, so they were filled with ferrous iron, which is highly reactive.”

In lab experiments, Stanton found that Fe2+ in seawater reacts rapidly with nitrogen molecules, especially nitric oxide, to yield nitrous oxide in a process called chemodenitrification. This nitrous oxide (N2O) can then bubble up into the atmosphere.

When Stanton plugged the higher fluxes of nitrous oxide into the atmospheric model, the results showed that nitrous oxide could have reached ten times today’s levels if mid-Proterozoic oxygen concentrations were 10 percent of those today. This higher nitrous oxide would have provided an extra boost of global warming under the Faint Young Sun.

Breathing laughing gas

Nitrous oxide could have also been what some ancient life breathed.

Even today, some microbes can breathe nitrous oxide when oxygen is low. There are many similarities between the enzymes that microbes use to breathe nitric and nitrous oxides and enzymes used to breathe oxygen. Previous studies have suggested that the latter evolved from the former two. 

The Georgia Tech model provides a plentiful source of nitrous oxide in ancient iron-rich seas for this evolutionary scenario. And prior to the Proterozoic, when oxygen was extremely low, early aquatic microbes could have already been breathing nitrous oxide.

“It’s quite possible that life was breathing laughing gas long before it began breathing oxygen,” Glass said. “Chemodenitrification might have supplied microbes with a steady source of it.”

Also READ: Cold Suns, Warm Exoplanets, and Methane Blankets

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The paper was co-authored by Chris Reinhard of Georgia Tech, James Kasting of the Pennsylvania State University, Nathaniel Ostrom and Joshua Haslun of Michigan State University, and Timothy Lyons of the University of California Riverside. The research was funded by grant NNA15BB03A from the NASA Astrobiology Institute. Findings, opinions, and conclusions are those of the authors and not necessarily of the NASA Astrobiology Program.

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Aug. 21, 2017, the first day of the school year: At noon the Georgia Tech campus morphs into a massive, festive solar-eclipse-watching party. Thousands sprawl on Tech Green and stand on roof tops to cheer the celestial event.

Meanwhile in Kentucky, James Boehm is part of an experiment by AT&T. The company is testing a device to enable Boehm – who has been blind since he was 13 – to experience the eclipse. The set-up includes a soundtrack, which “voices” the changes in temperature and brightness as the moon’s shadow covers the sun. That accompaniment came from researchers in the Georgia Tech Sonification Lab.

That story leads the first season of the College of Sciences’ podcast. The people who made the 2017 eclipse-watching party possible now offer another treat: ScienceMatters, a podcast celebrating discoveries and achievements – the “Wow” and “Aha” moments – of Georgia Tech scientists and mathematicians.

Season 1 is now available at sciencematters.gatech.edu. 

Continue here for the full story.

The new school year is a good time to remind ourselves to take care of our mental health.

Mental health problems are on the rise. A 2014 survey of college counseling services – cited by the American Psychological Association – found that clients with severe psychological problems went up to 52%, from 44% the year before. The survey noted increases in anxiety disorder, crises, psychiatric medication issues, and clinical depression.

The good news is that mental health awareness is growing and spreading. Also good news is the acceptance that mental health needs are real and addressing them is essential for self-care.

Last summer, a research group at the European Organization for Nuclear Research (CERN) asked physics Ph.D. student Andrea Welsh to share her experiences as a graduate student grappling with mental health concerns.

A mental health advocate, Welsh attracted attention outside of Georgia Tech after she wrote about the subject in Physics Today. She told the research group at CERN that graduate students have unique vulnerabilities. Yet her tips for managing mental health are universal.

The CERN research group was looking for someone who has experienced mental health problems, Welsh says. “That was important for representation.” By representation, Welsh means how people grappling with mental health appear to others.

In high school, Welsh recalls, she saw depictions of people with depression as sleeping all the time and unable to get out of bed. She wasn’t like that. Yes, she cried a lot, her weight fluctuated, she had periods of high energy and bouts of low energy, and she couldn’t concentrate. But she was functional, attending school.

Continue here for the full story.

The start of the school year can be discombobulating. Fortunately, many questions that come up are common from semester to semester.

Here, academic advisors in the College of Sciences share their answers to questions they’ve heard frequently from new and returning students during the first few days of a new semester.

Is it true that I shouldn’t take two lab classes in my first semester?
Your course load is a personal decision, best discussed with your academic advisor. That said, for some science majors, such as biology, we do recommend that students take two labs in their first semester to stay on track for timely progress through the degree.

How many credit hours should I take?
Again, the course load is a personal decision. Taking 12–14 credit hours during the first semester allows you to acclimate to the course work at Tech and to explore co- and extracurricular ways to take part in the campus community.

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For ants and robots operating in confined spaces like tunnels, having more workers does not necessarily mean getting more work done. Just as too many cooks in a kitchen get in each other’s way, having too many robots in tunnels creates clogs that can bring the work to a grinding halt.

A study published August 17 in the journal Science shows that in fire ant colonies, a small number of workers does most of the digging, leaving the other ants to look somewhat less than industrious. For digging nest tunnels, this less busy approach gets the job done without ant traffic jams – ensuring smooth excavation flow. Researchers found that applying the ant optimization strategy to autonomous robots avoids mechanized clogs and gets the work done with the least amount of energy.

Optimizing the activity of autonomous underground robots could be useful for tasks such as disaster recovery, mining or even digging underground shelters for future planetary explorers. The research was supported by the National Science Foundation’s Physics of Living Systems program, the Army Research Office and the Dunn Family Professorship.

“We noticed that if you have 150 ants in a container, only 10 or 15 of them will actually be digging in the tunnels at any given time,” said Daniel Goldman, a professor in the School of Physics at the Georgia Institute of Technology. “We wanted to know why, and to understand how basic laws of physics might be at work. We found a functional, community benefit to this seeming inequality in the work environment. Without it, digging just doesn’t get done.”

By monitoring the activities of 30 ants that had been painted to identify each individual, Goldman and colleagues, including former postdoctoral fellow Daria Monaenkova and Ph.D. student Bahnisikha Dutta, discovered that just 30 percent of the ants were doing 70 percent of the work – an inequality that seems to keep the work humming right along. However, that is apparently not because the busiest ants are the most qualified. When the researchers removed the five hardest working ants from the nest container, they saw no productivity decline as the remaining 25 continued to dig.

Having a nest is essential to fire ants, and if a colony is displaced – by a flood, for instance – the first thing the ants will do upon reaching dry land is start digging. Their tunnels are narrow, barely wide enough for two ants to pass, a design feature hypothesized to give locomotion advantages in the developing vertical tunnels. Still, the ants know how to avoid creating clogs by retreating from tunnels already occupied by other workers – and sometimes by not doing anything much at all. 

To avoid clogs and maximize digging in the absence of a leader, robots built by Goldman’s master’s degree student Vadim Linevich were programmed to capture aspects of the dawdling and retreating ants. The researchers found that as many as three robots could work effectively in a narrow horizontal tunnel digging 3D printed magnetic plastic balls that simulated sticky soil. If a fourth robot entered the tunnel, however, that produced a clog that stopped the work entirely.

“When we put four robots into a confined environment and tried to get them to dig, they immediately jammed up,” said Goldman, who is the Dunn Family Professor in the School of Physics. “While observing the ants, we were surprised to see that individuals would sometimes go to the tunnel and if they encountered even a small amount of clog, they’d just turn around and retreat. When we put those rules into combinations with the robots, that created a good strategy for digging rapidly with low amounts of energy use per robot.”

Experimentally, the research team tested three potential behaviors for the robots, which they termed “eager,” “reversal” or “lazy.” Using the eager strategy, all four robots plunged into the work – and quickly jammed up. In the reversal behavior, robots gave up and turned around when they encountered delays reaching the work site. In the lazy strategy, dawdling was encouraged.

“Eager is the best strategy if you only have three robots, but if you add a fourth, that behavior tanks because they get in each other’s way,” said Goldman. “Reversal produces relatively sane and sensible digging. It is not the fastest strategy, but there are no jams. If you look at energy consumed, lazy is the best course.” Analysis techniques based on glassy and supercooled fluids, led by former Ph.D. student Jeffrey Aguilar, gave insight into how the different strategies mitigated and prevented clog-forming clusters.

To understand what was going on and experiment with the parameters, Goldman and colleagues – including Will Savoie, a Georgia Tech Ph.D. student, Research Assistant Hui-Shun Kuan and Professor Meredith Betterton from the Department of Physics at the University of Colorado Boulder – used computer modeling known as cellular automata that has similarities to the way in which traffic engineers model the movement of cars and trucks on a highway.

“On highways, too few cars don’t provide much flow, while too many cars create a jam,” Goldman said. “There is an intermediate level where things are best, and that is called the fundamental diagram. From our modeling, we learned that the ants are working right at the peak of the diagram. The right mix of unequal work distributions and reversal behaviors has the benefit of keeping them moving at maximum efficiency without jamming.”

The ability to avoid clumping seems to meet a need that many systems have, Betterton noted. “The ants work in a sweet spot where they can dig quickly without too many clogs. We see the same physics in ant digging, simulation models, and digging by robots, which suggests that for groups of animals that need to excavate, avoiding clogs is crucial.”

The researchers used robots designed and built for the research, but they were no match for the capabilities of the ants. The ants are flexible and robust, able to squeeze past each other in confines that would cause the inflexible robots to jam. In some cases, the robots in Goldman’s lab even damaged each other while jostling into position for digging.

The research findings could be useful for space exploration where tunnels might be needed to quickly shield humans from approaching dust storms or other threats. “If you were a robot swarm on Mars and needed to dig deeply in a hurry to get away from dust storms, this strategy might help provide shelter without having perfect information about what everybody was doing,” Goldman explained. 

Beyond the potential robotics applications, the work provides insights into the complex social skills of ants and adds to the understanding of active matter. 

“Ants that live in complex subterranean environments have to develop sophisticated social rules to avoid the bad things that can happen when you have a lot of individuals in a crowded environment,” Goldman said. “We are also contributing to understanding the physics of task-oriented active matter, putting more experimental knowledge into phenomenon such as swarms.”

In addition to those already mentioned, the research included Michael Goodisman, associate professor in Georgia Tech’s School of Biological Sciences.

This research was supported by the National Science Foundation through grant numbers PoLS-0957659, PHY-1205878 and DMR-1551095 as well as a grant W911NF-13-1-0347 from the Army Research Office, and the National Academies Keck Futures Initiative. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation or Army Research Office.

CITATION: J. Aguilar, et. al., “Collective clog control: optimizing traffic flow in confined biological and robophysical excavation,” (Science 2018).

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A car accident leaves an aging patient with severe muscle injuries that won’t heal. Treatment with muscle stem cells from a donor might restore damaged tissue, but doctors are unable to deliver them effectively. A new method may help change this.

Researchers at the Georgia Institute of Technology engineered a molecular matrix, a hydrogel, to deliver muscle stem cells called muscle satellite cells (MuSCs) directly to injured muscle tissue in patients whose muscles don’t regenerate well. In lab experiments on mice, the hydrogel successfully delivered MuSCs to injured, aged muscle tissue to boost the healing process while protecting the stem cells from harsh immune reactions.

The method was also successful in mice with a muscle tissue deficiency that emulated Duchene muscular dystrophy, and if research progresses, the new hydrogel therapy could one day save the lives of people suffering from the disease.

Inflammatory war zone

Simply injecting additional muscle satellite cells into damaged, inflamed tissue has proven inefficient, in part because the stem cells encounter an immune system on the warpath.

“Any muscle injury is going to attract immune cells. Typically, this would help muscle stem cells repair damage. But in aged or dystrophic muscles, immune cells lead to the release a lot of toxic chemicals like cytokines and free radicals that kill the new stem cells,” said Young Jang, an assistant professor in Georgia Tech’s School of Biological Sciences and one of the study’s principal investigators.

Only between 1 and 20 percent of injected MuSCs make it to damaged tissue, and those that do, arrive there weakened. Also, some tissue damage makes any injection unfeasible, thus the need for new delivery strategies. 

“Our new hydrogel protects the stem cells, which multiply and thrive inside the matrix. The gel is applied to injured muscle, and the cells engraft onto the tissues and help them heal,” said Woojin Han, a postdoctoral researcher in Georgia Tech’s School of Mechanical Engineering and the paper’s first author.

Han, Jang and Andres Garcia, the study’s other principal investigator, published their results on August 15, 2018, in the journal Science Advances. The National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health funded the research.

Hydrogel: watery nets

Hydrogels often start out as water-based solutions of molecular components that resemble crosses, and other components that make the ends of the crosses attach to each other. When the components come together, they fuse into molecular nets suspended in water, resulting in a material with the consistency of a gel. 

If stem cells or a drug are mixed into the solution, when the net, or matrix, forms, it ensnares the treatment for delivery and protects the payload from death or dissipation in the body. Researchers can easily and reliably synthesize hydrogels and also custom-engineer them by tweaking their components, as the Georgia Tech researchers did in this hydrogel. 

“It physically traps the muscle satellite cells in a net, but the cells also grab onto chemical latches we engineered into the net,” Han said.

This hydrogel’s added latches, which bond with proteins protruding from stem cells’ membranes, not only increase the cells’ adhesion to the net but also hinder them from committing suicide. Stem cells tend to kill themselves when they’re detached and free-floating. 

The chemical components and the cells are mixed in solution then applied to the injured muscle, where the mixture sets to a matrix-gel patch that glues the stem cells in place. The gel is biocompatible and biodegradable.

“The stem cells keep multiplying and thriving in the gel after it is applied,” Jang said. “Then the hydrogel degrades and leaves behind the cells engrafted onto muscle tissue the way natural stem cells usually would be.”

Stem cell breakdown

In younger, healthier patients, muscle satellite cells are part of the natural healing mechanism.

“Muscle satellite cells are resident stem cells in your skeletal muscles. They live on muscle strands like specks, and they’re key players in making new muscle tissue,” Han said.

“As we age, we lose muscle mass, and the number of satellite cells also decreases. The ones that are left get weaker. It’s a double whammy,” Jang said. “At a very advanced age, a patient stops regenerating muscle altogether.”

“With this system we engineered, we think we can introduce donor cells to enhance the repair mechanism in injured older patients,” Han said. “We also want to get this to work in patients with Duchene muscular dystrophy.”

“Duchene muscular dystrophy is surprisingly frequent,” Jang said. “About 1 in 3,500 boys get it. They eventually get respiratory defects that lead to death, so we hope to be able to use this to rebuild their diaphragm muscles.”

If the method goes to clinical trials, researchers will likely have to work around the potential for donor cell rejection in human patients.

Also READ: Punching Cancer with RNA Knuckles Wrapped in Hydrogel

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The following researchers coauthored the paper: Shannon Anderson, Mahir Mohiuddin, Shadi Nakhai, and Eunjung Shin from Georgia Tech; Isabel Freitas Amaral, and Ana Paula Pêgo from the University of Porto in Portugal, and Daniela Barros from Georgia Tech and the University of Porto. The research was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (awards # R21AR072287 and R01AR062368). Any opinions, findings and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect views of the National Institutes of Health.

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By Michael Evans, Freshman Chemistry Laboratory Coordinator, School of Chemistry and Biochemistry

This summer, 43 Georgia Tech students, four teaching assistants, and six faculty members crossed the Atlantic to participate in the Biomolecular Engineering, Science, and Technology (BEST) Study Abroad Program in Lyon, France.

Since the program began in 2012, it has attracted more than 170 students. While in Lyon, students took courses in chemistry, biology, or French at Lyon’s École Supérieure de Chimie Physique Électronique (CPE). They interacted with French students and faculty at CPE, sharing the spirit and culture of Georgia Tech with their hosts.  

Ferguson Beardsley appreciated the program’s mix of science and culture. “The BEST Program not only challenged me by placing me in another country; I also learned how to balance learning inside the classroom with learning outside of CPE,” said the second-year chemical engineering major. “It was the perfect experience to learn chemistry in a different cultural environment.”

This year, the program was sold out. College of Sciences majors made up 72% of the cohort; women made up 79%.

The program included excursions to locations of interest: the Pasteur Institute in Paris, CERN, the winemaking Beaujolais region, and a fragrance and personal care chemical company in the Provence region. Students also visited caves in the Ardeche region, which contain some of the world’s best preserved examples of prehistoric art.

Faculty included Cameron Tyson, program director; Jennifer Leavey and Brian Hammer, from the School of Biological Sciences, and Pamela Pollet and myself from the School of Chemistry and Biochemistry

It was my first time with the program. I was particularly struck by the visit to Grenoble and the nearby French Alps.

Grenoble’s cable car takes passengers from the city to the Grenoble Bastille. Overlooking the city, the old military fortress is now home to a museum, restaurant, and monument to the famous French geologists of the Alps. The Bastille is also the trailhead for hiking trails to Mount Jalla, a peak in the foothills of the French Alps. Near the summit is a monument to the mountain troops of France. Lookouts along the trail give breathtaking views of the city below.

In Paris, the group visited the resting place of French royalty, at the Cathedral of St. Denis, near the end of the no. 13 Métro line. The church contains the remains of most of the French kings and queens. Unlike Westminster Abbey in London, this church is far from the center of Paris. It evokes the image of a detached and elitist French aristocracy.

Smiling down on the unassuming sarcophagi of Marie Antoinette and Louis XVI is as satisfying as it sounds! The crypt beneath the church includes an ancient Roman cemetery containing the remains of St. Denis himself.

The BEST Study Abroad Program will resume in summer 2019. For additional information, see the BEST Lyon website or Facebook page.

Tucked away inside cell membranes, a molecular butcher does the bidding of healthy cells but also of disease agents. It has been operating out of clear view, but researchers just shined a mighty spotlight on it.

The butcher is a common enzyme called presenilin, which chops lengthy protein building blocks down to useable shorter lengths. It resides in membrane spaces that evade ready experimental detection, but in a new study, researchers at the Georgia Institute of Technology and Oak Ridge National Laboratory (ORNL) have illuminated presenilin using a neutron beam produced by the world's most powerful research nuclear reactor.

Presenilin is one of many mysterious protein structures residing in our cell membranes, where they are essential to life.

“One-third of our genome goes to work to encode intramembrane proteins,” said Raquel Lieberman, an associate professor in Georgia Tech’s School of Chemistry and Biochemistry. “Some of them are huge and do super complex biochemistry.”

Presenilin is an enzyme, more particularly an intramembrane protease. There are four classes of these, and they are needed, among other things, for: Alerting to and defending against infectors, and cell differentiation and development.

If the latter two go wrong, that can lead to cancer.

Grainy neutron mugshot

Now, the researchers have gotten their first figurative mugshot of an intramembrane protein, the presenilin. Technically speaking, the researchers worked with a presenilin cousin found in microbes -- M. marisnigri intramembrane aspartyl protease or MmIAP -- but here we will use presenilin and MmIAP interchangeably for simplicity’s sake.

The measurement was low-resolution but revealed enough to establish that the protein structure is more simply put together than previously believed, and that surprised the scientists.

“Our sample shows that this is a monomer all by itself,” Lieberman said. “We were expecting a dimer or a trimer.” That means it was made up of one long strand, mostly coiled up like a spring, instead of doubled-up or tripled-up curly strands.

Presenilin (MmIAP) is armed with two chemical knives, aspartates, that reliably make cuts on peptides, subunits that make up proteins. And a second new study by the same researchers illuminated how the cleaving works.

Anybody’s peptide butcher

Presenilin can trim peptides into building blocks helpful to its own cells, or whittle bad peptide chunks that end up in amyloid-beta plaque, a suspect in Alzheimer’s disease. Or presenilin can aid and abate hepatitis C viruses by carving components it needs to reproduce.

Understanding how presenilin works could one day prove useful to medical research. “If you could find a way to interfere with it selectively, you could stop the spread of hepatitis C in the body,” Lieberman said.

The researchers, led by Lieberman and neutron scattering scientist Volker Urban from ORNL, published the revelations of the neutron scattering on February 6, 2018, in Biophysical Journal. The new insights into presenilin functioning are to officially publish in March in the Journal of Biological Chemistry but the study is currently available online without embargo. First authors were Swe-Htet Naing of Georgia Tech and Ryan Oliver of Oak Ridge.

Research was funded by the National Science Foundation, the National Institutes of Health, and the U.S. Department of Energy.

Herding hydrophobic hiders

By going to the High Flux Isotope Reactor (HFIR), the scientists were reaching for the big gun to make presenilin (MmIAP) come out of hiding.

HFIR’s neutron beams were cooled to minus 253 degrees Celsius (minus 424 degrees Fahrenheit) to slow the neutrons down, so they could probe molecular features of the biological samples.

Presenilin and other intramembrane proteins warrant such proverbial desperate measures. They live in a lipid environment and hate water about the way cats do, and that’s a problem for researchers studying them.

“When you have proteins that are not soluble in water, you’re in trouble,” Lieberman said. “The usual techniques to analyze them become very, very difficult, if not impossible. And when you chemically bootstrap these proteins to be able use these water-soluble methods, you have really poor chances of seeing the protein’s actual structure that performs its function.”

Form follows function

Images derived from water-based analytical methods in Lieberman’s lab have not completely jibed with presenilin’s function. For one, the enzyme’s cutting surfaces have been too far apart. The neutron beam’s revelations indicated a form that seemed more logical.

“Our shape was tighter, and made more sense with presenilin’s function in its natural setting in the membrane,” Lieberman said.

The presenilin (MmIAP) samples examined at the HFIR were suspended in a solution friendly to the hydrophobic protein. Ironically, presenilin and other intramembrane proteases often hydrolyze peptides, in other words, they add water to them.

“These proteases are confined to the lipid cell membrane where there is no water. Since water is required for hydrolysis, it has to come from outside the membrane,” Lieberman said. “How that happens is yet another mystery that needs uncovering.”

Robust, reliable cleavers

The precision and consistency, with which the presenilin homologue MmIAP cleaved peptides, impressed the researchers.

“When we used a model synthetic peptide, it cleaved only at very specific positions on the peptide,” Lieberman said. “When we switched to a real biological peptide, it also cleaved very exactly.”

The researchers put the presenilin through various mutations, which had little to no effect on its cleaving abilities. That could mean that its baseline functioning is nearly immune to genetic interference.

On a chilling note, when the researchers observed the microbial presenilin cousin, MmIAP, cutting amyloid-beta precursor peptides, it always made the chop in a way notorious for amyloid’s association with Alzheimer’s disease.

“We never saw the cut that made what is typically viewed as the ‘good’ amyloid, A-beta-40,” Lieberman said. “We only saw cuts that led to the ‘bad’ amyloid, A-beta-42.”

More research would be needed to explain why that happened; if the same is true for presenilin in human cell membranes, and also if some regulator prevents the creation or accumulation of so much bad amyloid in healthy cells.

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Kevin Weiss from Oak Ridge National Laboratory coauthored the study in Biophysical Journal. Sibel Kalyoncu, David Smalley, Hyojung Kim, Xingjian Tao, Josh George, Alex Jonke, Ryan Oliver, and Matthew Torres coauthored the study in the Journal of Biological Chemistry. Research was funded by the National Science Foundation’s Division of Molecular and Cellular Biosciences (grant 0845445), and the National Institutes of Health (grant R01GM112662 and R01GM118744). Neutron scattering research conducted at the Bio-SANS instrument, a DOE Office of Science, Office of Biological and Environmental Research resource, used resources at the High Flux Isotope Reactor, a DOE Office of Science, Scientific User Facility operated by the Oak Ridge National Laboratory. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the sponsors.