Analyzing ways to help golden eagle populations weather wind-energy growth

"We are taking basic information about golden eagle ecology in the Anthropocene and developing it into predictive frameworks for how to protect them," says Eric Lonsdorf, Emory assistant professor of environmental sciences.

By Carol Clark

Wind energy is a major component of the U.S. clean-energy goals. Already one of the fastest growing and lowest-cost sources of electricity in the country, it is poised for even more rapid growth, according to the U.S. Department of Energy. 

Wind power, however, does not come without tradeoffs, including some negative impacts on wildlife. Throughout the United States, for example, it’s been estimated that as many as three golden eagles per wind farm are killed each year by wind turbines. 

“Renewable energy sources, including wind energy, are critical for us to achieve a net-zero emissions future,” says Eric Lonsdorf, assistant professor of environmental sciences at Emory University. “We need to address conflicts between renewable energy and wildlife conservation so that we can combat climate change while also limiting damage to biodiversity.” 

Lonsdorf and colleagues are developing data-driven methods to determine how much effort is needed to save golden eagles in order to offset the impact of wind turbines on their populations. 

The Journal of Wildlife Management recently published their latest model for calculating the benefit of one mitigation strategy — removal of large, road-killed animals that can lead to golden eagles getting hit by cars. 

Quantifying the benefits of natural capital

Lonsdorf is an expert in natural capital, or the quantifiable benefits that nature provides humans. He translates ecological principles and data into computer models that enable industry leaders and policymakers to better manage natural resources. 

Co-authors of the current study include James Gerber and Deepak Ray, from the University of Minnesota; Steven Slater, from HawkWatch International; and Taber Allison, from the Renewable Energy Wildlife Institute. 

The U.S. Fish and Wildlife Service (FWS) monitors golden eagle populations, which are protected through the Bald and Golden Eagle Protection Act and the Migratory Bird Treaty Act. Threats to golden eagles include loss of habitat and prey. 

Additional threats that are directly linked to human activities include illegal shootings, electrocution at power poles, lead poisoning from consuming parts of bullets in the entrails of deer carcasses discarded at the site of hunters’ kills, collisions with cars at sites where the birds are scavenging roadkill and collisions with the blades of a wind turbine. 

Across the western United States, hundreds of wind turbines have gone up in sage-brush flats that are part of golden eagles’ core habitat, and many more turbines are planned. In order to meet the permit requirements of the FWS, wind-energy companies must agree to mitigate their impact on the animals by offsetting the predicted number of golden eagles that will fly into their turbines each year. 

Currently, the only offset strategy approved by the FWS for wind-energy companies is to retrofit power poles to prevent golden eagles from becoming electrocuted. 

Adding empirical data

For the past five years, Lonsdorf and his colleagues have combined their expertise to develop a range of potential offset strategies for golden eagle fatalities. 

Their current paper — an updated model for golden eagle mortality due to vehicle collisions based on data from Wyoming — considered myriad factors such as the population density for golden eagles in the region, the number and size of deer roadkill carcasses expected and the traffic volume on the roads. The model also incorporated observational evidence of eagle-carcass roadside interactions obtained by motion-triggered cameras, data that was lacking in a previous model the researchers created. 

The addition of this empirical data allowed the researchers to make estimates for how long a golden eagle typically spends at a carcass, how the decay rate of the carcass affects the number of visits from eagles and the effects of seasonality on the scavenging behavior of the eagles. 

The model results suggest that carcass relocation is a viable golden eagle mitigation strategy that could save up to seven golden eagles annually in some Wyoming counties. On average, the model indicates that the prompt removal of four roadside carcasses would save at least one golden eagle. 

The researchers can make a user-friendly version of the prediction framework available to the FWS and wind-energy companies if the FWS decides to approve carcass removal as an eagle mortality offset strategy. 

“We’re taking basic information about golden eagle ecology in the Anthropocene and developing it into predictive frameworks for how to protect them,” Lonsdorf says. “As wind energy continues to grow, more mitigation strategies will likely be needed. Our goal is to provide scientific evidence for a portfolio of methods to help accomplish a zero-net loss of golden eagles from wind-energy facilities.” 

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Natural compound found in plants inhibits deadly fungi

A 3D illustration of the newly emerged species of fungus Candida auris, which is often drug-resistant and has a high mortality rate. (Dr_Microbe, Getty Images)

By Carol Clark

A new study finds that a natural compound found in many plants inhibits the growth of drug-resistant Candida fungi — including its most virulent species, Candida auris, an emerging global health threat. The journal ACS Infectious Diseases published the discovery led by scientists at Emory University. 

Laboratory-dish experiments showed that the natural compound, a water-soluble tannin known as PGG, blocks 90% of the growth in four different species of Candida fungi. The researchers also discovered how PGG inhibits the growth: It grabs up iron molecules, essentially starving the fungi of an essential nutrient. By starving the fungi rather than attacking it, the PGG mechanism does not promote the development of further drug resistance, unlike existing antifungal medications. 

Laboratory-dish experiments also showed minimal toxicity of PGG to human cells. 

“Drug-resistant fungal infections are a growing healthcare problem but there are few new antifungals in the drug-development pipeline,” says Cassandra Quave, senior author of the study and associate professor in Emory School of Medicine’s Department of Dermatology and the Center for the Study of Human Health. “Our findings open a new potential approach to deal with these infections, including those caused by deadly Candida auris.” 

C. auris is often multidrug-resistant and has a high mortality rate, leading the Centers for Disease Control and Prevention (CDC) to label it a serious global health threat. 

“It’s a really bad bug,” says Lewis Marquez, first author of the study and a graduate student in Emory’s molecular systems and pharmacology program. “Between 30 to 60% of the people who get infected with C. auris end up dying.” 

An emerging threat 

Candida is a yeast often found on the skin and in the digestive tract of healthy people. Some species, such as Candida albicans, occasionally grow out of control and cause mild infections in people. In more serious cases, Candida can invade deep into the body and cause infections in the bloodstream or organs such as the kidney, heart or brain. 

Immunocompromised people, including many hospital patients, are most at risk for invasive Candida infections, which are rapidly evolving drug resistance. 

In 2007, the new Candida species, C. auris, emerged in a hospital patient in Japan. Since then, C. auris has caused health care-associated outbreaks in more than a dozen countries around the world with more than 3,000 clinical cases reported in the United States alone. 

A ‘natural’ approach to drug discovery 

Quave is an ethnobotanist, studying how traditional people have used plants for medicine to search for promising new candidates for modern-day drugs. Her lab curates the Quave Natural Product Library, which contains 2,500 botanical and fungal natural products extracted from 750 species collected at sites around the world. 

“We’re not taking a random approach to identify potential new antimicrobials,” Quave says. “Focusing on plants used in traditional medicines allows us to hone in quickly on bioactive molecules.” 

Previously, the Quave lab had found that the berries of the Brazilian peppertree, a plant used by traditional healers in the Amazon for centuries to treat skin infections and some other ailments, contains a flavone-rich compound that disarms drug-resistant staph bacteria. Screens by the Quave lab had also found that the leaves of the Brazilian peppertree contain PGG, a compound that has shown antibacterial, anticancer and antiviral activities in previous research. 

A 2020 study by the Quave lab, for instance, found that PGG inhibited growth of Carbapenem-resistant Acinetobacter baumannii, a bacterium that infects humans and is categorized as one of five urgent threats by the CDC. 

The Brazilian peppertree, an invasive weed in Florida, is a member of the poison ivy family. “PGG has popped up repeatedly in our laboratory screens of plant compounds from members of this plant family,” Quave says. “It makes sense that these plants, which thrive in really wet environments, would contain molecules to fight a range of pathogens.” 

Experimental results 

The Quave lab decided to test whether PGG would show antifungal activity against Candida. Laboratory-dish experiments demonstrated that PGG blocked around 90% of the growth in 12 strains from four species of Candida: C. albicans, multidrug-resistant C. auris and two other multidrug-resistant non-albicans Candida species. 

PGG is a large molecule known for its iron-binding properties. The researchers tested the role of this characteristic in the antifungal activity. 

“Each PGG molecule can bind up to five iron molecules,” Marquez explains. “When we added more iron to a dish, beyond the sequestering capacity of the PGG molecules, the fungi once again grew normally.” 

Dish experiments also showed that PGG was well-tolerated by human kidney, liver and epithelial cells. “Iron in human cells is generally not free iron,” Marquez says. “It is usually bound to a protein or is sequestered inside enzymes.” 

A potential topical treatment 

Previous animal studies on PGG have found that the molecule is metabolized quickly and removed from the body. Instead of an internal therapy, the researchers are investigating its potential efficacy as a topical antifungal. 

“If a Candida infection breaks out on the skin of a patient where a catheter or other medical instrument is implanted, a topical antifungal might prevent the infection from spreading and entering into the body,” Marquez says. 

As a next step, the researchers will test PGG as a topical treatment for fungal skin infections in mice. 

Meanwhile, Quave and Marquez have applied for a provisional patent for the use of PGG for the mitigation of fungal infections. 

“These are still early days in the research, but another idea that we’re interested in pursuing is the potential use of PGG as a broad-spectrum microbial,” Quave says. “Many infections from acute injuries, such as battlefield wounds, tend to be polymicrobial so PGG could perhaps make a useful topical treatment in these cases.” 

Scientists from the University of Toronto are co-authors of the paper, including Yunjin Lee, Dustin Duncan, Luke Whitesell and Leah Cowen. Whitesell and Cowen are co-founders and shareholders in Bright Angel Therapeutics, a platform company for development of antifungal therapeutics, and Cowen is a science advisor for Kapoose Creek, a company that harnesses the therapeutic potential of fungi. 

The work was supported by grants from the National Institutes of Health, National Center for Complementary and Integrative Health; the Jones Center at Ichauway, the CIHR Frederick Banting and Charles Best Canada Graduate Scholarship and the Canadian Institutes of Health Research Foundation. 

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NIH funds Emory center to advance cellular mechanics

"We are catalyzing the process of spreading our technology so that studying biomechanics becomes common and routine in biology," says Khalid Salaita, Emory professor of chemistry and director of the new Center for Molecular Mechanobiology.

By Carol Clark

The National Institutes of Health (NIH) awarded Emory University $5.6 million to establish a national center to advance pioneering technology for cellular mechanics. The center is directed by Khalid Salaita, Emory professor of chemistry, whose lab developed the first sensors for detecting cell-receptor forces at the molecular level. 

“We’ve been working on our molecular-force probes for more than a decade,” Salaita says. “We’ve demonstrated that these probes can be used to visualize, measure and map cellular forces down to the level of piconewtons. The center allows us to get this technology into the hands of end users — researchers in the biomedical sciences.” 

The Center for Molecular Mechanobiology encompasses labs from seven leading research institutions including: Children’s Hospital of Philadelphia, Dana-Farber Cancer Institute, Emory, Georgia Tech, Memorial Sloan Kettering, University of Utah and Vanderbilt University. 

The center members will use the molecular-force probes to investigate the biomechanics of processes such as the clotting of blood cells, the response of immune cells to an infection and the migration of cancer cells. Better understanding these processes may lead to the development of new treatments and therapies for a range of diseases and disorders. 

In addition to supplying the technology, the center will train researchers to use the molecular-force probes and help adapt the technology to answer specific biomedical research questions. 

“Working directly with the research community will help us to further refine and optimize the technology,” Salaita says. “We envision that measuring cellular forces will soon become part of the standard repertoire of biochemical techniques that scientists use to study living systems.” 

The center’s associate directors are Yonggan Ke (associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Emory and Georgia Tech) and Alexa Mattheyses (associate professor in the Department of Cell Developmental and Integrative Biology at the University of Alabama). 

The five-year award from the National Institute of General Medical Sciences is part of the NIH Biomedical Technology Optimization and Dissemination Centers program. The goal is to optimize and disseminate state-of-the-art, late-stage biomedical technologies. 

The first detailed view of mechanical forces

The Salaita lab works at the intersection of chemistry, biology and the physical sciences. It uses the building blocks of nature — nucleic acids — to create synthetic micro motors and probes for investigating fundamental questions of biology. 

The molecular-force probes, developed by the Salaita lab in 2011, provide the first detailed view of the mechanical forces on the surface of a cell. The technology can detect mechanical forces as fleeting as the blink of an eye and as faint as piconewtons — about one billionth the weight of a paperclip. 

The probes are made from strands of synthetic DNA tagged with fluorescence so that they function like molecular beacons, shining when they sense force. The technique is noninvasive, does not modify the cell and can be done with a standard fluorescence microscope. 

In 2014, the lab used the new method to demonstrate how adherent cells — the kind that form the architecture of all multicellular organisms — mechanically sense their environments, migrate and stick to things. 

In 2016, the molecular-force probes provided the first direct evidence for the mechanical forces of T cells, the security guards of the immune system. The lab’s experiments on T cells drawn from mice showed how they use a kind of mechanical “handshake” to test whether a cell they encounter is a friend or a foe. 

In 2017, the lab shined its molecular beacons on platelets, the cells in the blood whose job is to stop bleeding by sticking together to form clots and plug up a wound. That work revealed the key molecular forces on platelets that trigger the clotting process. 

In 2020, the lab and its collaborators combined advances in optical imaging with the molecular-force probes to capture forces at a resolution of 25 nanometers — far shorter than the length of a light wave. “That resolution is akin to being on the moon and seeing the ripples caused by raindrops hitting the surface of a lake on the Earth,” Salaita said at the time. 

Key technological goals 

The Center for Molecular Mechanobiology will build on this foundational work of the Salaita lab. It will focus on three key technological development goals:

• Optimizing the highest-resolution technique of the molecular-force probes so that it can be applied to a range of research questions. 

• Tagging cells based on their force level in order to use force as a marker to barcode cells and their receptors. The idea is to classify the mechanics of individual cells and then link these classifications to gene-expression levels to study the cause-and-effect relationships. 

• Amplifying the molecular-force signals to better understand the role of even the weakest forces involved in cellular mechanics, including those involved in the immune response. 

Researchers from throughout the country will come to the Center for Molecular Mechanobiology to receive hands-on training in the molecular-force probes and then return to their home labs to become ambassadors for the technology. 

“We’ll be adding a whole other layer of information for researchers working on everything from designing vaccines to cancer immunotherapy agents,” Salaita says. 

Decades ago, he points out, complicated techniques such as crystallography, PCR and mass spectrometry were not frequently used but have since become routine workhorses in the biomedical sciences. 

“We are catalyzing the process of spreading our technology so that studying biomechanics also becomes common and routine in biology,” Salaita says. “Molecular forces are a missing piece to understanding the way biology works.” 

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Buffalo slaughter left lasting impact on Indigenous peoples

"Bison were not just key to the economies of some Indigenous nations," says Emory economist Maggie Jones, co-author of the study. "The bison were also important cultural and spiritual symbols."

By Carol Clark

The mass slaughter of North American bison by settlers of European descent is a well-known ecological disaster. An estimated eight million bison roamed the United States in 1870, but just 20 years later fewer than 500 of the iconic animals remained. 

The mass slaughter provided a brief economic boon to some newly arriving settlers, hunters and traders of the Great Plains who sold the hides and bones for industrial uses. In contrast, Indigenous peoples whose lives depended on the bison suffered a devastating economic shock — one that still reverberates in these communities today, an economic study finds. 

The Review of Economic Studies published the findings by economists at Emory University, the University of Toronto and the University of Victoria. The researchers quantified both the immediate and long-term economic impacts of the loss of the bison on Indigenous peoples whose lives depended on the animals. 

 

Changes in the average height of bison-related people is one striking example of the fallout. Adult height across a population is one proxy of wealth and health given that it can be impacted by nutrition and disease, particularly early in development. 

Bison-reliant Indigenous men stood around six feet tall on average, or about an inch taller than Indigenous men who were not bison-reliant. 

“They were among the tallest people in the world in the mid-19th century,” says Maggie Jones, assistant professor of economics at Emory University and a co-author of the paper. “But after the rapid near-extinction of the bison, the height of the people born after the slaughter also rapidly declined.” 

Within one generation, the average height of Indigenous peoples most impacted by the slaughter dropped by more than an inch. 

“That’s a major drop, but given the magnitude of the economic shock it’s not necessarily surprising,” Jones says. 

By the early 20th century, the paper shows, the child-mortality rate of bison-dependent Indigenous nations was 16 percentage points higher and the probability of a working-age male reporting an occupation was 19 percentage points lower compared with Indigenous nations that were never reliant on bison. 

And income per capita remained 25% lower, on average, for bison-reliant nations compared to other nations through the latter half of the 20th century to today. The persistent gap could not be explained by differences in factors such as agricultural productivity, self-governance or application of the Dawes Act of 1887, which authorized the breakup of reservation land into small allotments parceled out for individual ownership. 

The researchers find that limited access to credit was one factor that curtailed the ability of some bison-reliant nations to adjust economically following the near-extinction of the bison. 

“One role of economists is to provide quantitative evidence that people can turn to when trying to design more effective policies,” Jones says. “By providing data that benchmarks disparities among bison-reliant people and the sources and evolution of these disparities, we hope to support efforts to improve the situation.” 

The paper’s other co-authors are economists Donn Feir (University of Victoria) and Rob Gillezeau (University of Toronto). 

Jones’ economic research focus includes history, labor and education. She uses quantitative tools from these areas to better understand the persistence of socioeconomic inequalities between groups in North America. 

The economic effects of the bison slaughter are an overlooked piece of the history of Indigenous peoples that she and her co-authors decided to investigate. 

For more than 10,000 years, bison served as the primary source of the livelihood for many Native Americans in regions of the Great Plains, the Northwest and the Rocky Mountains. Along with nutrition, the animals provided hides for clothing, lodging and blankets as well as bones for tools and implements. Nearly every part of the animal was used, including the brains to obtain grease for tanning hides and the stomach for creating bags and water containers. 

Evidence suggests that bison-reliant Indigenous societies enjoyed living standards comparable to, or in some cases better than, their European contemporaries. 

A gradual decline of the bison population started with the introduction of the horse and the arrival of Europeans. By 1870, however, mass slaughter of the animals began. Factors that drove the kill-off included the completion of the transcontinental railroad, improvements in European tanning technology that made bison hides more desirable and encouragement by the U.S. Army to eliminate the animals to help in their efforts to force Indigenous peoples onto reservations. 

In some regions, the bison was eliminated in a little more than a decade. Jones and her co-authors describe the slaughter as one of the largest and most rapid losses of a critical industry in North American history. 

“Centuries of human capital were built around the use of the bison, and within 10 to 20 years this economic underpinning disappeared,” Jones says. “And many channels of economic adjustment were cut off for Indigenous populations.” 

Indigenous people were forced onto reservations, their movements were restricted and they were not allowed to become citizens of the United States until 1924, the authors note. 

Among the sources Jones and her colleagues drew on to quantify the impacts of the bison slaughter are data collected by anthropologists and published in the 15-volume Smithsonian Handbook on Native American Populations. 

The economists defined nearly 24 Indigenous nations as “exposed to the slaughter,” based on geographic location and whether bison served as their primary food source. 

In their quantitative analysis of bison-reliant nations with Indigenous nations that were not bison-reliant, they controlled for factors such as differences in self-governance status of communities, differences in forms of agricultural productivity and the suitability of the land for agricultural production, the effects of the Dust Bowl and differential application of the Dawes Act. 

To measure the persistent effects of the bison’s decline on economic outcomes, the researchers drew from several sources: the Bureau of Indian Affairs (beginning in 1945), the U.S. Census (1980, 1990, 2000) and American Community Surveys (2007-2012 and 2015-2019). 

The data showed that the income of formerly bison-reliant nations remained 25% lower than those of other Indigenous nations through 2019. 

The researchers find relatively more favorable trajectories for bison-reliant communities that were located nearer to financial institutions in 1870 when the mass slaughter of the bison began. 

“Proximity to a bank and access to credit appeared to be one important factor to help alleviate some of the financial hardship generated by the bison’s decline,” Jones says. “Many Indigenous communities are still located in banking deserts. That makes it more difficult to adjust to any kind of hardship that comes your way.” 

The researchers are now exploring the potential role of psychological trauma on the economic outcomes of bison-reliant nations. 

“Bison were not just key to the economies of some Indigenous nations,” Jones says. “The bison were also important cultural and spiritual symbols. You would expect a psychological impact when they were ripped away. That’s an important part of the story that this paper didn’t get to tell.”

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Biologist gets the scoop on squash bug poop

The tell-tale gut: Tagging different strains of bacteria in different fluorescent colors allows the researchers to determine what strain an insect carries in its gut. (Jason Chen)

By Carol Clark

The squash bug carries a gut bacterium that is essential for the bug’s development into an adult. But when they hatch from their eggs, squash bug nymphs do not have the bacteria in their systems. That left scientists who study the interplay between insects and their internal microbes wondering: How do the nymphs acquire these essential microbes? 

Jason Chen, an Emory University graduate student in the Department of Biology, stumbled upon a clue one evening in the lab. 

He had finished up experiments on some adult squash bugs whose Caballeronia bacteria he had tagged with a red fluorescent protein. The bugs were housed in a plastic box with pieces of paper towel inside as bedding. He tossed some nymphs inside the container just as a place to hold them while he cleaned up for the day. 

“When I came back to turn the lights out, I noticed that all the nymphs had flocked around one of the poop spots left on a paper towel by the adults,” Chen says. “Normally nymphs wander around a lot but they had all stopped around this poop. They were transfixed by it. I wondered what that behavior meant.” 

He eventually checked the nymphs under a microscope and saw that their guts lit up with the same red fluorescence as the adults. More experiments confirmed the finding — nymph squash bugs eat the feces of adults to acquire the bacteria they need to grow. 

Current Biology published the discovery, which may offer insights for improved methods to control the squash bug, a significant agricultural pest. 

Read more about the discovery here.

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Images of enzyme in action reveal secrets of antibiotic-resistant bacteria

A series of images captured through cryoelectron microscopy shows how a bacterial enzyme modifies a ribosome. (Pacific Northwest Center for Cryo-EM)

By Carol Clark

Bacteria draw from an arsenal of weapons to combat the drugs intended to kill them. Among the most prevalent of these weapons are ribosome-modifying enzymes. These enzymes are growing increasingly common, appearing worldwide in clinical samples in a range of drug-resistant bacteria. 

Now scientists have captured the first images of one important class of these enzymes in action. The images show how the enzymes latch onto a particular site on the bacterial ribosome and squeeze it like a pair of tweezers to extract an RNA nucleotide and alter it. 

The Proceedings of the National Academy of Sciences (PNAS) published the findings, led by scientists at Emory University. The advanced technique of cryoelectron microscopy made the ultra-high-resolution, three-dimensional snapshots possible. 

“Seeing is believing,” says Christine Dunham, Emory professor of chemistry and co-corresponding author of the paper. “The minute you see biological structures interacting in real life at the atomic level it’s like solving a jigsaw puzzle. You see how everything fits together and you get a clearer idea of how things work.” 

The insights may lead to the design of new antibiotic therapies to inhibit the drug-resistance activities of RNA methyltransferase enzymes. These enzymes transfer a small hydrocarbon known as a methyl group from one molecule to another, a process known as methylation. 

“Methylation is one of the smallest chemical modifications in biology,” says Graeme Conn, professor of biochemistry in Emory’s School of Medicine and co-corresponding author of the paper. “But this tiny modification can fundamentally change biology. In this case, it confers resistance that allows bacteria to evade an entire class of antibiotics.” 

Both Conn and Dunham are also members of the Emory Antibiotic Resistance Center. 

First author of the paper is Pooja Srinivas, who did the work as a PhD candidate in Emory’s graduate program in molecular and systems pharmacology. She has since graduated and is now a postdoctoral fellow at the University of Washington. 

Understanding the ribosome 

Dunham is a leading expert on the ribosome — an elaborate structure that operates like a factory within a cell to manufacture proteins. Proteins are the machines that make cells run while nucleic acids such as DNA and RNA store the blueprints for life. The ribosome is made mostly of RNA, which does not just store information but can also act as an enzyme, catalyzing chemical reactions. 

One goal of Dunham’s lab is to find ways to manipulate bacterial ribosomes to make them more susceptible to antimicrobials. If an antimicrobial successfully inactivates bacterial ribosomes, that shuts down the manufacturing of proteins essential for bacterial growth and survival. 

The idea is to exploit differences in human cellular ribosomes and bacterial ribosomes, so that only the bacteria is targeted by an antimicrobial drug. 

Antimicrobials, however, need to get past bacterial defenses. 

“It’s like a molecular arms race,” Dunham explains. Bacteria keep evolving new weapons as a defense against drugs, while scientists evolve new strategies to disarm bacteria. 

Enzymes that modify the ribosome 

Conn is a leading expert in the bacterial defense weapons known as ribosomal RNA methyltransferase enzymes. This family of enzymes was originally discovered in soil bacteria. They are now increasingly found in bacterial infections in people and animals, making these infections harder to treat. 

“They keep turning up more and more often in clinical samples of some nasty bacterial pathogens in different parts of the world,” Conn says. 

The enzymes can drive deadly drug-resistance in pathogens such as E. coli, Salmonella, Klebsiella pneumoniae, Pseudomonas aeruginosa and Enterobacteriaceae. The enzymes add a methyl group at a specific site on the bacterial ribosome. That addition blocks the ability of a class of antibiotics known as aminoglycosides to bind and cause their antibacterial action. 

For the PNAS paper, the researchers focused on a culprit within this family of enzymes known as ribosomal RNA methyltransferase C, or RmtC. 

A complicated enzyme 

For decades, researchers have relied on a technique known as X-ray crystallography to reveal the atomic details of how molecular machines work when the molecules are arranged in a crystal. 

In 2015, for example, Dunham’s lab obtained precise pictures through X-ray crystallography of how an enzyme known as HigB rips up RNA to inhibit growth of the bacteria. By restraining the growth of the bacteria that makes it, HigB establishes a dormant “persister cell” state that makes the bacteria tolerant to antibiotics. 

The secrets of how the RmtC enzyme interacts with the ribosome, however, eluded X-ray crystallography. 

“RmtC is much more complicated,” Dunham explains. “It’s an interesting enzyme from a basic science perspective because it looks so different from others.” 

A resolution revolution 

Recent advances in cryoelectron microscopy opened the door to zooming in on the complex mechanisms of RmtC. 

Cryoelectron microscopy does not require crystallization to reveal the structures of molecules and how they interact. Instead, liquid samples are frozen rapidly to form a glassy matrix. The glassy matrix retains the three-dimensional structure of molecules and protects them from deterioration by the intense electron beam. 

Meisam Nosrati, a former postdoctoral fellow in the Conn lab and a co-author of the PNAS paper, prepared samples of RmtC interacting with part of an E. coli ribosome. He tapped the expertise of co-author Lindsay Comstock, a chemist at Wake Forest University who developed a technique to trap and stabilize the enzyme in the needed position. 

Nosrati then froze the samples on a tiny grid and sent them to the Pacific Northwest Center for Cryo-EM for imaging. 

As a graduate student in the Dunham lab, Pooja Srinivas then analyzed and interpreted the microscopy dataset. She used computer algorithms to stitch together thousands of individual images. 

The result turned the images into a flipbook that revealed the complicated structure of RmtC in action. 

“The enzyme latches on like a pincer to the ribosome,” Dunham explains. “It tightens its grip until it squeezes out a nucleotide from the interior of an RNA helix. It then chemically modifies that nucleotide.” 

The enzyme is exquisitely specific about where it binds to the ribosome, a huge macromolecule made up of 50 different proteins and 6,000 different RNA nucleotides. 

The researchers used biochemistry techniques to validate that what they observed matched previous findings for how RmtC makes bacteria resistant to aminoglycoside antimicrobials that target the ribosome. 

Strategies for new therapies 

The researchers are now trying to develop new ways to counter the effects of RmtC and related enzymes based on the new information. 

“Knowledge of the shape of the enzyme as its performs its chemical reaction gives us new targets to inhibit its effects,” Conn says. “For instance, we could target the pincer action of the enzyme to try to prevent it from squeezing and binding to the ribosome. We now know that the enzyme forms a pocket on its surface where a small molecule might sit to block this action.” 

Additional co-authors of the PNAS paper are Natalia Zelinskaya and Debayan Dey, research scientists in the Conn lab. Funding for the work was provided by the National Institutes of Health and the Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease Award. 

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Physicists open new path to exotic form of superconductivity

"Everything we learn about the world has potential applications," says Emory physicist Luiz Santos, senior author of the paper.

By Carol Clark

Physicists have identified a mechanism for the formation of oscillating superconductivity known as pair-density waves. Physical Review Letters published the discovery, which provides new insight into an unconventional superconductive state seen in certain materials, including high-temperature superconductors. 

“We discovered that structures known as Van Hove singularities can produce modulating, oscillating states of superconductivity,” says Luiz Santos, assistant professor of physics at Emory University and senior author of the study. “Our work provides a new theoretical framework for understanding the emergence of this behavior, a phenomenon that is not well understood.” 

First author of the study is Pedro Castro, an Emory physics graduate student. Co-authors include Daniel Shaffer, a postdoctoral fellow in the Santos group, and Yi-Ming Wu from Stanford University. 

The work was funded by the U.S. Department of Energy’s Office of Basic Energy Sciences. 

The puzzle of superconductivity 

Santos is a theorist who specializes in condensed matter physics. He studies the interactions of quantum materials — tiny things such as atoms, photons and electrons — that don’t behave according to the laws of classical physics. 

Superconductivity, or the ability of certain materials to conduct electricity without energy loss when cooled to a super-low temperature, is one example of intriguing quantum behavior. The phenomenon was discovered in 1911 when Dutch physicist Heike Kamerlingh Onnes showed that mercury lost its electrical resistance when cooled to 4 Kelvin or minus 371 degrees Fahrenheit. That’s about the temperature of Uranus, the coldest planet in the solar system. 

It took scientists until 1957 to come up with an explanation for how and why superconductivity occurs. At normal temperatures, electrons roam more or less independently. They bump into other particles, causing them to shift speed and direction and dissipate energy. At low temperatures, however, electrons can organize into a new state of matter. 

“They form pairs that are bound together into a collective state that behaves like a single entity,” Santos explains. “You can think of them like soldiers in an army. If they are moving in isolation they are easier to deflect. But when they are marching together in lockstep it’s much harder to destabilize them. This collective state carries current in a robust way.” 

A holy grail of physics 

Superconductivity holds huge potential. In theory, it could allow for electric current to move through wires without heating them up, or losing energy. These wires could then carry far more electricity, far more efficiently. 

“One of the holy grails of physics is room-temperature superconductivity that is practical enough for everyday-living applications,” Santos says. “That breakthrough could change the shape of civilization.”

Many physicists and engineers are working on this frontline to revolutionize how electricity gets transferred. 

Meanwhile, superconductivity has already found applications. Superconducting coils power electromagnets used in magnetic resonance imaging (MRI) machines for medical diagnostics. A handful of magnetic levitation trains are now operating in the world, built on superconducting magnets that are 10 times stronger than ordinary electromagnets. The magnets repel each other when the matching poles face each other, generating a magnetic field capable of levitating and propelling a train. 

The Large Hadron Collider, a particle accelerator that scientists are using to research the fundamental structure of the universe, is another example of technology that runs through superconductivity. 

Superconductivity continues to be discovered in more materials, including many that are superconductive at higher temperatures.  

An accidental discovery 

One focus of Santos’ research is how interactions between electrons can lead to forms of superconductivity that cannot be explained by the 1957 description of superconductivity. An example of this so-called exotic phenomenon is oscillating superconductivity, when the paired electrons dance in waves, changing amplitude. 

In an unrelated project, Santos asked Castro to investigate specific properties of Van Hove singularities, structures where many electronic states become close in energy. Castro’s project revealed that the singularities appeared to have the right kind of physics to seed oscillating superconductivity. 

That sparked Santos and his collaborators to delve deeper. They uncovered a mechanism that would allow these dancing-wave states of superconductivity to arise from Van Hove singularities. 

“As theoretical physicists, we want to be able to predict and classify behavior to understand how nature works,” Santos says. “Then we can start to ask questions with technological relevance.” 

Some high-temperature superconductors — which function at temperatures about three times as cold as a household freezer — have this dancing-wave behavior. 

The discovery of how this behavior can emerge from Van Hove singularities provides a foundation for experimentalists to explore the realm of possibilities it presents. 

“I doubt that Kamerlingh Onnes was thinking about levitation or particle accelerators when he discovered superconductivity,” Santos says. “But everything we learn about the world has potential applications.” 

Related:

Chemists crack complete quantum nature of water 

New evidence for a unifying theory of granular physics

Merck Prize boosts work on air sensor for pandemic pathogens

"There is a need for viral-detecting devices for public indoor air spaces as we enter an era when pandemics will likely become more common," says Emory chemist Khalid Salaita.

Merck KGaA, Darmstadt, Germany, awarded its 2023 Future Insight Prize to Khalid Salaita, professor of chemistry at Emory University. The award comes with $540,000 to fund the next phase of research into an air sensor that can continuously monitor indoor spaces for pathogens that can cause pandemics. 

“I’m extremely thankful to receive the Future Insight Prize as this enables us to continue our path toward an early-warning system for emerging threats,” Salaita says. “Our research sets the stage for fully automated detection of airborne pathogens without human intervention or sample processing.” 

The Merck Future Insight Prize recognizes groundbreaking ideas to solve some of the world’s most pressing challenges in health, nutrition and energy. 

The Salaita lab’s sensor, a rolling micro-motor called “Rolosense,” holds the potential to help mitigate, or even prevent, a pandemic. 

Read the full story here.

Biophysicists reveal how three proteins interact to fine-tune cellular movement

Graduate student Heidi Ulrichs created this cartoon to illustrate previous theories that thee enzymes could not all "dance" together on the end of an actin filament. The filament (in blue) is shown with the enzymes, in pink, gold and green, engaged in a kind of "sibling rivalry." The Emory physicists discovered that, in fact, the three enzymes could simultaneously work together on the end of an actin filament.
 

By Carol Clark

A single human cell teems with as many 100,000 different proteins. Actin is one of the most abundant and essential of them all. This protein forms into filaments that help make up the skeleton of cells, giving them shape. And as the actin filaments elongate, they work like muscles, pushing against the inner membrane of a cell to move it forward. 

Three other proteins are known to drive the activities of actin. One class of protein assembles individual actin molecules into actin filaments, another causes the filaments to stop growing and a third disassembles filaments. 

Biophysicists at Emory University, however, have discovered an even more complex and nuanced view of how these three proteins together influence actin dynamics. Nature Communications published the findings, showing how these proteins sometimes shift from solo or duet acts to perform as a trio, allowing them to fine-tune the activity of actin filaments. 

The discovery opens another window onto the dynamics of cellular movement, which is key to processes ranging from stem-cell differentiation and wound healing to the development of diseases such as cancer. 

“We found that while these three proteins do one thing when working on their own, they do a completely different thing when the other two proteins join them,” says Shashank Shekhar, Emory assistant professor of physics and cell biology, and senior author of the study. “It gets really complex, very fast.” 

“No one had looked at all of these proteins interacting at once on actin,” adds Heidi Ulrichs, co-first author of the study and an Emory PhD candidate in biochemistry, cell and developmental biology. “Our paper is the first report of all three of them occupying the same barbed end of an actin filament.” 

Ulrichs worked closely on the project with Ignas Gaska, a postdoctoral fellow in the Shekkhar lab who is co-first author of the paper. 

Building on previous research 

Research into how proteins act individually on actin is relatively well-characterized. 

A polymerase protein, such as formin, drives elongation of actin. Formin positions itself at the end of an actin filament, grabs onto free-floating actin molecules and stacks them up one by one to keep growing the end. 

Depolymerase proteins, such as twinfilin, are another class of proteins that influence actin. Twinfilin works like a lint roller, binding to the end of a filament and peeling away one molecule at a time. Twinfilin can repeat the process to disassemble the actin filament entirely. 

Proteins known as cappers can stop the elongation and disassembling of the filaments. A capper attaches to the end of an actin filament and covers it like a hat, blocking activity by the other proteins. 

This knowledge was built up by isolating one protein at a time to study how it influences actin. More recent studies have also shown simultaneous interactions between twinfilin and capping proteins. 

A new approach using advanced technology 

For the current study, the researchers wanted to explore whether formin, twinfilin and the capping protein could all three act simultaneously on actin. 

“An actin filament end is really tiny, just five nanometers across,” Shekhar explains. “One thought was that there just isn’t enough real estate available for three proteins to work on a single actin filament at once.” 

The Shekhar lab is one of only a handful in the world using the highly specialized technique of microfluidics-assisted total internal reflection fluorescence microscopy (mf-TIRF) to study how the actin cytoskeleton remodels itself. 

Cells are packed with thousands of proteins moving around, performing different functions, making it impossible to track all of them. Researchers must isolate the proteins of interest and study them outside of a cellular system, by introducing them to a microfluidic system on a microscope slide. 

The mf-TIRF technology allows the Shekhar Lab to attach fluorescent orbs to single protein molecules so that researchers can better observe what these molecules are doing through a microscope. 

In experiments, the researchers tagged molecules of actin, formin, twinfilin and the capping protein with four different colors that emitted fluorescent light. They then introduced actin to the microfluidic system and added the other proteins one at a time. 

Establishing a new paradigm 

The results startled them. 

When twinfilin, the protein that breaks apart an actin filament, was added in the presence of both formin and the capping protein, twinfilin actually worked to speed up the process of filament elongation. 

“That’s counterintuitive, which is cool,” Ulrichs says. “Doing science you get surprised all the time.” 

Twinfilin alone could not join formin on the end of the actin filament. However, when the capping protein was also present, all three could simultaneously work together on the tiny surface of the actin filament. 

Shekhar compares the effects of all three proteins working together to a knob that allows for more precise control of a process. 

“Our findings establish a new paradigm in which the three proteins work in concert to fine-tune how fast or slowly actin filaments are formed,” he says. The dynamics of how the three proteins interact with actin is fundamental to teasing apart the complex mysteries of how cells function normally and what happens when something goes wrong. 

“We’re building up knowledge, step by step, study by study, on the dynamics of what’s happening inside of a cell,” Ulrichs says. 

Related:

How protein assemblies drive cell movement 

'Firefly' imaging zooms in on the forces within us

A medical entomologist battles bubonic plague in Madagascar

"There are 48 different species of fleas in Madagascar, but only a handful of them are found in a human environment," says Adelaide Miarinjara, an expert in the ecology of plague transmission.

Madagascar is famous for its biodiversity and unique wildlife, especially lemurs. Less well known is that it’s a hot spot for bubonic plague. The island nation off the southeast coast of Africa is one of the last places where large outbreaks of human plague happen regularly. 

Adelaide Miarinjara, who grew up in Madagascar, is now a medical entomologist and a postdoctoral fellow at Emory. Her project, unraveling some of the many mysteries surrounding plague, spans the lab of Thomas Gillespie, Emory professor of environmental sciences, and the Pasteur Institute. 

“I chose not to study lemurs,” Miarinjara says. “So many people are already doing that. The animals that I work with, rats and fleas, are not nearly as charismatic. But learning about them may lead to better policies to prevent people getting plague.” 

“As a microbiologist, Adelaide is extremely creative,” Gillespie says. “She’s developed whole new protocols for studying fleas that are allowing her to zero in on unanswered questions.”

Read more about her work here.

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Madagascar: An Island on the Brink

Valuing Natural Capital Vital to Avoid the Next Pandemic

New book eyes Earth's excavators, from microbes to elephants and dinosaurs

Anthony Martin in Emory's Lullwater Forest with the trunk of a pine tree carved up by beetles. Some species of beetles chew through wood to create tunnels where they lay their eggs. (Photo by Ruth Schowalter)

The ordinary person looks at Stone Mountain and sees a solid, unmovable monolith. Emory paleontologist Anthony Martin, who thinks in geologic time, sees something more akin to a giant sugar cube. 

Ever since the crystalized mass of igneous-born minerals rose from deep underground, pushed by the upwelling of magma that formed the Blue Ridge Mountains around 350 million years ago, the giant rock’s flanks have faced continuous assault — and not just from weather and water. 

Stone Mountain “is fighting a battle against life, and life is winning,” Martin writes in the preface of his new book, “Life Sculpted: Tales of the Animals, Plants and Fungi That Drill, Break and Scrape to Shape the Earth.” 

The University of Chicago Press recently published “Life Sculpted," marking the fifth book during the past 10 years by Martin, professor of practice in Emory’s Department of Environmental Sciences. 

Read more here. 

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'Love hormone' guides young songbirds in choice of 'voice coach'

Zebra finches are highly social birds and will press a lever in order to hear a recording of another Zebra finch singing. (Photo by Carlos Rodríguez-Saltos)

By Carol Clark

Oxytocin, the so-called “love hormone,” plays a key role in the process of how a young zebra finch learns to sing by imitating its elders, suggests a new study by neuroscientists at Emory University. Scientific Reports published the findings, which add to the understanding of the neurochemistry of social learning. 

“We found that the oxytocin system is involved from an early age in male zebra finches learning song,” says Natalie Pilgeram, first author of the study and an Emory PhD candidate in psychology. “It’s basic science that may lead to insights into the process of vocal learning across the animal kingdom, including humans.” 

“Our results suggest that the neurochemistry of early social bonds, particularly during language learning, may be relevant in studies of autism,” adds Donna Maney, a professor of neuroscience in Emory’s Department of Psychology and senior author of the study. 

Young male zebra finches learn to sing by listening to an adult male tutor that they choose to pay close attention to, normally their biological father or a “foster” father who nurtures them. This social process holds some similarities for how children learn to speak, making the birds a laboratory model for the neural underpinnings of social vocal learning. 

In the current paper, the researchers show how oxytocin, a hormone essential to social bonding, influences young finches exposed only to the songs of unfamiliar males. In experiments, blocking the young birds’ oxytocin receptors while they listened to a male biased the birds against that male’s song. Instead they preferred to listen to and eventually learn the song of a male they heard when their oxytocin receptors were allowed to function normally. 

The paper builds on previous work by the Maney lab regarding the hormonal and genetic influences on social behavior. Her lab is working with researchers at the Marcus Autism Center in Atlanta to maximize any potential translational impact of its research findings. 

Finding their voice 

Zebra finches are highly social birds. In the wild they nest together in large colonies. Only adult males sing, primarily to court females. 

From the time they hatch, the males begin listening for song, and memorizing particular songs, even before they can actually sing one. “Up until around day 50, they are making little cheeps and warbles, what we call ‘subsong,’” Pilgeram explains. “It’s similar to human infants who begin to babble at around six months without actually talking.” 

During this sensitive listening phase, a male zebra finch pays closest attention to the song of its father, even though it can hear other adult males nearby. 

In a laboratory environment, research shows that if a biological father is removed from a cage before a male hatches and then substituted with a “foster father” that they can interact with, the young male will prefer the song of the foster father over other males it can hear. The young males demonstrate this preference by pressing levers that allow them to hear playback of different songs. 

Learning from their environment 

“The young birds have got to learn all that they can from their environment,” Pilgeram says. “Just as during human development, the birds pay the closest attention to their immediate caregivers, on whom they rely for everything.” 

Around day 50, the young male finches enter puberty and what is called the “plastic song phase.” During this time, they practice their song motor skills and actively try to produce song. Although they begin to shift their attention away from their fathers and show a preference for hearing songs of other males, each young male still practices dad’s tune. 

By day 100, most male zebra finches are fully singing their father’s song. They have reached adulthood and their tune has “crystalized” into the song that they will sing for the rest of their lives. 

In previous research, the Maney lab found that the stronger the preference a male zebra finch shows for its father’s song during the early listening phase, the more closely its crystalized adult song will mimic that of the father. 

The role of oxytocin 

For the current paper, the researchers wanted to test whether the oxytocin system played a role in that preference. 

The research centered on male juvenile zebra finches hatched in the lab. At day four, the fathers were removed from each of the youngsters’ cages so they were raised only by their mothers. The cages were enclosed in chambers that prevented the young birds from hearing song from other birds housed nearby. 

Beginning at day 27 in a young bird’s life, it was exposed to a series of tutoring sessions by two different adult male tutors that it had never heard. The tutor’s cage was placed next to the cage of the young bird, or pupil. When it was exposed to one of the tutors, the pupil was given a substance that blocked its oxytocin receptors from activating. When the young bird was exposed to the other tutor it received a control substance that allowed its oxytocin receptors to function normally. 

After completing a series of tutoring sessions, the pupils were presented with two different levers they could press in their cages. Pressing one lever was more likely to play the song they heard when their oxytocin receptors were blocked. The other lever was more likely to play the song they heard with normally functioning oxytocin. 

The results showed that early in their development, the juveniles favored the song that they heard when their oxytocin was not blocked. 

Building on past findings 

“We also found that when their oxytocin was not blocked, the birds’ developmental milestones fit the same data curve as in our previous research,” Maney says. “They showed an early preference for the song of one tutor, then switched to preferring the other song during puberty.” 

The preference flattened out as they began singing the song of their chosen tutor, she adds. And the stronger the preference that they showed for the chosen tutor’s song during the early listening phase, the more closely their own adult song resembled that of the chosen tutor. 

The researchers also noted behavioral differences in the way the pupils and tutors interacted. With normally functioning oxytocin, a pupil pecked more often at the wall of its cage facing the tutor and more often preened in a fashion known to be associated with focused listening in the birds, compared to when its oxytocin was blocked. 

“Our results suggest that the oxytocin system is involved in how an animal decides where to focus its attention very early in its life,” Pilgeram says. 

Co-authors of the study include Carlos Rodríguez-Saltos, who received his doctorate from Emory and is now at Illinois State University; postdoctoral fellow Nicole Baran; research technicians Matthew Davis and Erik Iverson; and Emory undergraduates Sumin Lee, Emily Kim and Aditya Bhise. 

The work was funded by the National Science Foundation and the Silvio O. Conte Center for Oxytocin and Social Cognition. 

Related:

How a single gene drives aggression in songbirds 

Songbird data yields new theory for learning sensorimotor skills

As the worm turns: New twists in behavioral association theories

The researchers conducted experiments on C. elegans, a roundworm with just 300 neurons, that offers a simple laboratory model for studying how an animal learns.

By Carol Clark

Physicists have developed a dynamical model of animal behavior that may explain some mysteries surrounding associative learning going back to Pavlov’s dogs. The Proceedings of the National Academy of Sciences (PNAS) published the findings, based on experiments on a common laboratory organism, the roundworm C. elegans. 

“We showed how learned associations are not mediated by just the strength of an association, but by multiple, nearly independent pathways — at least in the worms,” says Ilya Nemenman, an Emory professor of physics and biology whose lab led the theoretical analyses for the paper. “We expect that similar results will hold for larger animals as well, including maybe in humans.” 

“Our model is dynamical and multi-dimensional,” adds William Ryu, an associate professor of physics at the Donnelly Centre at the University of Toronto, whose lab led the experimental work. “It explains why this example of associative learning is not as simple as forming a single positive memory. Instead, it’s a continuous interplay between positive and negative associations that are happening at the same time.” 

First author of the paper is Ahmed Roman, who worked on the project as an Emory graduate student and is now a postdoctoral fellow at the Broad Institute. Konstaintine Palanski, a former graduate student at the University of Toronto, is also an author. 

The conditioned reflex

More than 100 years ago, Ivan Pavlov discovered the “conditioned reflex” in animals through his experiments on dogs. For example, after a dog was trained to associate a sound with the subsequent arrival of food, the dog would start to salivate when it heard the sound, even before the food appeared. 

About 70 years later, psychologists built on Pavlov’s insights to develop the Rescorla-Wagner model of classical conditioning. This mathematical model describes conditioned associations by their time-dependent strength. That strength increases when the conditioned stimulus (in Pavlov dog’s case the sound) can be used by the animal to decrease the surprise in the arrival of the unconditioned response (the food). 

Such insights helped set the stage for modern theories of reinforcement learning in animals, which in turn enabled reinforcement learning algorithms in artificial intelligence systems. But many mysteries remain, including some related to Pavlov’s original experiments. 

After Pavlov trained dogs to associate the sound of a bell with food he would then repeatedly expose them to the bell without food. During the first few trials without food, the dogs continued to salivate when the bell rang. If the trials continued long enough, the dogs “unlearned” and stopped salivating in response to the bell. The association was said to be “extinguished.” 

Pavlov discovered, however, that if he waited a while and then retested the dogs, they would once again salivate in response to the bell, even if no food was present. Neither Pavlov nor more recent associative-learning theories could accurately explain or mathematically model this spontaneous recovery of an extinguished association. 

Teasing out the puzzle

Researchers have explored such mysteries through experiments with C. elegans. The one-millimeter roundworm only has about 1,000 cells and 300 of them are neurons. That simplicity provides scientists with a simple system to test how the animal learns. At the same time, C. elegans’ neural circuitry is just complicated enough to connect some of the insights gained from studying its behavior to more complex systems. 

Earlier experiments have established that C. elegans can be trained to prefer a cooler or warmer temperature by conditioning it at a certain temperature with food. In a typical experiment, the worms are placed in a petri dish with a gradient of temperatures but no food. Those trained to prefer a cooler temperature will move to the cooler side of the dish, while the worms trained to prefer a warmer temperature go to the warmer side. 

But what exactly do these result mean? Some believe that the worms crawl toward a particular temperature in expectation of food. Others argue that the worms simply become habituated to that temperature, so they prefer to hang out there even without a food reward. 

The puzzle could not be resolved due to a major limitation of many of these experiments — the lengthy amount of time it takes for a worm to traverse a nine-centimeter petri dish in search of the preferred temperature. 

Measuring how learning changes over time

Nemenman and Ryu sought to overcome this limitation. They wanted to develop a practical way to precisely measure the dynamics of learning, or how learning changes over time. 

Ryu’s lab used a microfluidic device to shrink the experimental model of nine-centimeter petri dishes into four-millimeter droplets. The researchers could rapidly run experiments on hundreds of worms, each worm encased within its individual droplet. 

“We could observe in real time how a worm moved across a linear gradient of temperatures,” Ryu says. “Instead of waiting for it to crawl for 30 minutes or an hour, we could much more quickly see which side of the droplet, the cold side or the warm side, that the worm preferred. And we could also follow how its preferences changed with time.” 

Their experiments confirmed that if a worm is trained to associate food with a cooler temperature it will move to the cooler side of the droplet. Over time, however, with no food present, this memory preference seemingly decays. 

“We found that suddenly the worms wanted to spend more time on the warm side of the droplet,” Ryu says. “That’s surprising because why would the worms develop a different preference and even avoidance of the temperature they had come to associate with food?” 

Eventually the worm begins moving back and forth between the cooler and warmer temperatures. The researchers hypothesized that the worm does not simply forget the positive memory of food associated with cooler temperatures but instead starts to negatively associate the cooler side with no food. That spurs it to head for the warmer side. Then as more time passes, it begins to form a negative association of no food with the warmer temperature, which combined with the residual positive association to the cold, makes it migrate back to the cooler one. 

“The worm is always learning, all the time,” Ryu explains. “There is an interplay between the drive of a positive association and a negative association that causes it to start oscillating between cold and warm.” 

'It's like when you lose your keys'

Nemenman’s team developed theoretical equations to describe the interactions over time between the two independent variables — the positive, or excitatory, association that drives a worm toward one temperature and the negative, or inhibitory, association that drives it away from that temperature. 

“The side that the worm gravitates toward depends on when exactly you take the measurements,” Nemenman explains. “It’s like when you lose your keys you may check the desk where you usually keep them first. If you don’t see them there right away, you run around different places looking for them. If you still don’t find them, you go back to the original desk figuring you just didn’t look hard enough.” 

The researchers repeated the experiments under different conditions. They trained the worms at different starting temperatures and starved them for different durations before testing their temperature preference, and the worms’ behaviors were correctly predicted by the equations. 

They also tested their hypothesis by genetically modifying the worms, knocking out the insulin-like signaling pathway known to serve as a negative association pathway. 

“We perturbed the biology in specific ways and when we ran the experiments, the worm’s behavior changed as predicted by our theoretical model,” Nemenman says. “That gives us more confidence that the model reflects the underlying biology of learning, at least in C. elegans.” 

The researchers hope that others will test their model in studies of larger animals across species. 

“Our model provides an alternative quantitative model of learning that is multi-dimensional,” Ryu says. “It explains results that are difficult, or in some cases impossible, for other theories of classical conditioning to explain.” 

Related:

Physicists develop theoretical model for neural activity of mouse brain

Machine learning used to understand and predict dynamics of worm behavior

Hidden 'super spreaders' spur dengue fever transmission

A NASA satellite image shows Iquitos, Peru, nestled in the Amazon Basin, on the banks of the Amazon River and surrounded by smaller rivers, lakes and lagoons.

By Carol Clark

For mosquito-borne diseases such as dengue fever, the abundance of the insects in places where people gather has long served as the main barometer for infection risk. A new study, however, suggests that the number of “hidden” infections tied to a place, or cases of infected people who show no symptoms, is the key indicator for dengue risk. 

PNAS Nexus published the research led by scientists at Emory University, which drew from six years of data collected in the Amazonian city of Iquitos, Peru. 

The results found that 8% of human activity spaces in the study accounted for more than half of infections during a dengue outbreak. And these “super spreader” spaces were associated with a predominance of asymptomatic cases, or 74% of all infections. 

“Our findings show that any public health intervention that focuses on responding to symptomatic cases of dengue is going to fail to control an outbreak,” says Gonzalo Vazquez-Prokopec, first author of the study and an Emory associate professor of environmental sciences. “Symptomatic cases represent only the tip of the iceberg.” 

Co-authors of the research include Uriel Kitron, Emory professor of environmental sciences; Lance Waller, professor of biostatistics and bioinformatics at Emory’s Rollins School of Public Health; and scientists from University of California-Davis, Tulane University, San Diego State University, University of Notre Dame, North Carolina State University and the U.S. Naval Medical Research Unit in Lima, Peru. 

'What matters is where you went'

Dengue fever is caused by a virus transmitted by the bite of a female Aedes aegypti mosquito. When the insect takes a blood meal from a human infected with dengue, the virus begins replicating within the mosquito. The virus may then spread to another person that the mosquito bites days later. 

This species of mosquito feeds exclusively on human blood, has a limited flight range of about 100 meters and thrives in sprawling urban areas of the tropics and subtropics. Its preferred habitat is inside homes, where it rests on the backs of furniture and at the bases of walls. Even the little bit of water held by an upturned bottle cap can serve as a nursery for its larvae. 

Vazquez-Prokopec is pioneering new mosquito-borne disease interventions, including tapping spatiotemporal data to track, predict and control outbreaks of pathogens transmitted by Aedes aegypti. The mosquito spreads the Zika, chikungunya and yellow fever viruses in addition to dengue. 

Around 500,000 cases of dengue occur annually around the world, according to the World Health Organization. The disease is caused by four distinct but closely related serotypes of the dengue virus. Infected people may have some immunity that prevents them from experiencing any noticeable effects while others may be severely debilitated for a week or more by symptoms such as extreme aches and pains, vomiting and rashes. Dengue hemorrhagic fever, the most severe form of the disease, causes an estimated 25,000 deaths annually worldwide. 

Iquitos, a city of nearly 500,000 people on the edge of the Amazon rainforest in Peru, is a dengue hotspot. For more than a decade, Vazquez-Prokopec and colleagues have mapped patterns of human mobility and dengue spread in Iquitos. 

“For diseases that are directly spread from one person to another, like COVID-19, what matters is who you were near,” he says. “But in the case of dengue, what matters most is where you went.” 

Tracking hidden cases

For the current study, the researchers wanted to determine the role of asymptomatic cases. People without symptoms may continue to go about their daily routines, unknowingly infecting any mosquitoes that bite them, which can then later spread the virus to more people. 

The study involved 4,600 people in two different neighborhoods. They were surveyed three times a week about their mobility. This data was used to map “activity spaces,” such as residences, churches and schools. 

The study participants were also regularly surveilled to determine if they experienced any dengue symptoms. Blood analyses confirmed a total of 257 symptomatic cases of dengue during the six-year study period. That led to investigations of other participants whose activity spaces overlapped with the symptomatic cases. More than 2,000 of these location-based contacts were confirmed by blood tests to have dengue infections and more than half of them reported not having any noticeable symptoms. 

A cascade of circumstances

The results pinpointed the role of asymptomatic “super spreaders” in a dengue outbreak. A small number of the activity spaces, or 8%, were linked to more than half of the infections and most of the cases associated with those places were asymptomatic. 

The comprehensive, one-of-a-kind study broke down the virus infections by serotype and measured the amount of mosquitoes in the activity spaces. 

“We found that the mosquito numbers in a location alone is not a predictor of the risk of infection,” Vazquez-Prokopec says. 

Instead, risk prediction for a location requires a cascade of circumstances: a high number of asymptomatic cases frequenting the location combined with high levels of mosquitos and high numbers of people who are not immune to the particular serotype of dengue virus that is circulating. 

“That’s the complicated nature of this virus,” Vazquez-Prokopec says. “We have underestimated the role of asymptomatic cases in spreading dengue.” 

Generally, about 50 to 70% of dengue cases are asymptomatic, making detection by public health officials impractical, and the current study reveals that asymptomatic cases are tied to a third of transmission. 

“The lesson is that we need to focus on prevention of dengue outbreaks,” Vazquez-Prokopec says. “The interventions for dengue for decades have been reactive. Simply reacting by closing a net around reported cases of the disease, however, will fail to contain an outbreak because that’s missing the super spreaders.” 

The study was funded by the U.S. National Institute of Allergy and Infectious Diseases, Bill and Melinda Gates Foundation, University of Notre Dame, Defense Threat Reduction Agency, Military Infectious Disease Research Program and the Armed Forces Health Surveillance Branch Global Emerging Infections Systems research program. 

Related:

Tapping big data to target a tiny predator 

Mapping dengue hot spots pinpoints risks for Zika and chikungunya 

Mutant mosquitoes make insecticide-resistance monitoring key to control Zika

Atlanta Science Festival expands your horizons

Rae Wynn-Grant admires a bear cub after tagging it. "I hope that I can play a small role in helping people see that science is a space where anyone can find belonging," she says.

"Science has quite literally taken me around the world," says Rae Wynn-Grant, an Emory alumna and wildlife biologist whose field research has spanned six continents.

"But you don't have to physically travel to be a great scientist," she adds. "I want people to know that there are many different ways that science can expand your horizons." 

Wynn-Grant returns to Atlanta as a featured speaker to launch this year's Atlanta Science Festival, set for March 10-25. The festival is bigger and more expansive than ever with more than 150 events and an overarching theme: Where will science take you?

Read more about the festival here.