Tuesday, December 12, 2023

New tool to analyze blood platelets holds major medical potential

Graphic image shows a blood clot forming in an artery. The white, spikey platelets are amid red and white blood cells. Activated platelets use their spkes like "arms" to grip onto one another and to stringy chains of proteins in the blood called fibrin, forming clumps that also bind up red and white blood cells.

By Carol Clark

A novel technique to test platelet function within a person’s blood sample is faster, easier and more precise than methods currently in use, an experimental study shows. 

Nature Biomedical Engineering published the research, led by scientists at Emory University. The researchers demonstrated the proof-of-concept for the technique, which provides the first detailed look at the molecular forces generated by activated platelets in patient blood samples. 

The study results show that the technology holds the potential to assess the effects of antiplatelet drugs on individuals and to gain a clearer picture of bleeding risks for patients undergoing cardiopulmonary bypass surgery. 

The technique requires only about a drop of blood to run tests, compared to the tablespoon needed for current assays. This ultrasensitivity may make the technology a valuable tool for the diagnosis of babies suffering from rare, congenital platelet disorders. 

The breakthrough is based on synthetic-DNA tension probes developed more than a decade ago in the laboratory of Khalid Salaita, professor in Emory’s Department of Chemistry and in the Wallace H. Coulter Department of Biomedical Engineering at Emory and Georgia Tech. 

‘A scientist’s dream’ 

The tension probes can detect cellular forces on the magnitude of just a few piconewtons, or about a billion times less than the weight of a paper clip. The researchers found a way to amplify the signal of the probes by tapping the power of an enzyme known as CRISPR-associated 12a. The mechanical signal is then detected using a plate-reader, a tool already routinely used in clinical testing. 

“This project started out of basic curiosity,” says Salaita, co-corresponding author. “We wanted to know whether we could measure the tiniest forces exerted by cells. It’s exciting that we are now building on this basic curiosity to develop diagnostic tools to help patients. It’s a scientist’s dream.” 

First author of the paper is Yuxin Duan, an American Heart Association postdoctoral fellow in the Salaita lab. 

Roman Sniecinski, a professor in Emory School of Medicine’s Department of Anesthesiology and a leading expert in the field of perioperative coagulation, is co-corresponding author of the paper.

“Platelet function in general is important and yet the current tools that we have to measure it are relatively primitive,” Sniecinski says. “This new technique offers an easier, faster and cheaper way to measure platelet function, while also providing us with key information that we didn’t have before.” 

Co-authors include: Fania Szlam, a senior associate in the Sniecinski lab; Yuesong Hu, a graduate student in the Salaita lab; Renhao Li, a professor in Emory School of Medicine’s Department of Pediatrics, Hematology/Oncology; Wenchun Chen, a postdoctoral fellow in Emory School of Medicine; and Yonggang Ke, an associate professor in the Coulter Department of Biomedical Engineering at Emory and Georgia Tech. 

The importance of platelets 

Platelets are colorless, disc-shaped blood-cell fragments whose job is to bind at the site of an injured blood vessel to stop the bleeding. In some cases, however, platelets may not function optimally. When platelets are weak, or less active than optimal, the blood may not clot properly leading to uncontrolled bleeding. But if platelets are “hyperactive” they may become too sticky and cause spontaneous blood clots that can lead to heart attack or stroke. 

Regulating platelet function is especially critical to people at higher risk for some conditions. Antiplatelet drugs, such as clopidogrel, ticagrelor and even aspirin, are among the most commonly prescribed medications in the United States. In some patients, however, these drugs may not work well and adjustments in doses or changing to another drug might better help prevent heart attacks. 

During cardiac surgery, platelet function becomes even more dysregulated. The operating-room team must perform a balancing act of making blood not clot during cardiopulmonary bypass, then using procoagulant interventions, including transfusions of platelets, to stop the bleeding when the surgical procedure is finished. This can be difficult because the use of the cardiopulmonary bypass machine can stress and weaken blood platelets. 

“For decades, people have written in the scientific literature about this problem of platelet dysfunction during cardiac surgery,” Sniecinski says, “but it’s really difficult to measure it with the tools that we’ve been using. And since we haven’t been able to measure platelet function well, that’s made it difficult to study it in effective ways.” 

‘A small part of the picture’ 

Aggregometry is a standard tool currently used to assess platelet function. It measures the speed and degree at which platelets in a blood sample clump together, or aggregate. 

“This data provides only a small part of the picture of platelet function and it’s not the most interesting part,” Sniecinski says. 

When a platelet gets activated, he explains, it changes its morphology and grows tiny pseudo “arms.” Platelets use these arms to grip onto chains of proteins in the blood called fibrinogen to form clots. 

“Aggregometry tells you that platelets are clumping together,” Sniecinski says. “But it doesn’t tell you about their level of activation — the amount of force they’re using to hold on to other coagulation proteins, as well as each other.” 

Amplifying the signal 

The Salaita lab is a leader in visualizing and measuring the mechanical forces applied by cells using tension probes made from synthetic strands of double-stranded DNA tethered to a surface. 

The double-strands of DNA can be programmed to bind to platelet cells. When the cells bind and apply force to the anchored DNA, the DNA splits into two strands, leaving one strand stuck to the surface. The resulting physical tug is converted into a fluorescent signal. 

A major challenge to reading this signal, however, is that these physical tugs are faint, fleeting and infrequent. They require a microscope to detect them. 

During the COVID-19 pandemic , the enzyme CRISPR 12a, or Cas12a, came to the fore as a diagnostic tool for SARS-CoV-2 virus. Bacteria use Cas12a to defend against phages, or viruses that attack bacteria. The Cas12a enzyme can be loaded with single-stranded “guide” RNA that is programmed to bind to a complementary single-stranded DNA. The enzyme then reacts to the single-stranded DNA by destroying other single-stranded DNA surrounding it. 

The Salaita lab decided to combine Cas12a with its tension probes to see if the enzyme would amplify the signal for the mechanical forces exerted by blood platelets. The lab developed what it calls the Mechano-Cas12a Assisted Tension Sensor, or MCATS. 

“It worked like gangbusters,” Salaita says. 

“Cas12a is quiet and inactive if it doesn’t see its target,” he explains. “But as soon as it sees a specific single-strand DNA, it goes bananas and starts destroying any single-stranded DNA it comes across. This activation generates a massive fluorescence signal output.” 

MCATS is precise and ultrasensitive, able to measure cellular traction forces generated by as few as 2,000 platelets within a sample. And the resulting signal is robust enough to measure via a conventional fluorometer — a tool commonly used in routine blood tests. 

MCATS also works with a plate reader, an instrument designed to handle dozens of samples simultaneously, for the kind of high-throughput readout needed to conduct research. 

Testing its clinical potential 

To test the efficacy of MCATS at measuring the activity of platelet function, the researchers drew blood samples from healthy volunteer donors. They first validated that the MCATS response was sensitive to the mechanical forces of platelets. 

They next added to the healthy blood samples different antiplatelet drugs, ranging from over-the-counter aspirin to a panel of different prescription medications. The MCATS results showed that the antiplatelet therapies reduced the mechanical activity of platelets by an amount similar to the reduction observed in aggregometry. 

The researchers also received permission to take blood samples for investigation from seven patients pre- and post-cardiopulmonary bypass surgery. The results showed that the MCATS readings for the platelet activity of each individual patient’s sample correlated to their likelihood to need platelet transfusions to minimize bleeding after surgery. 

The researchers are now enrolling participants in a prospective study to further explore MCATS as a diagnostic tool. People diagnosed with a platelet disorder will have their blood samples tested pre- and post-treatment to assess how well a therapy is working. 

“The bottom line is that MCATS is a whole new way to measure platelet function using a really tiny sample,” Sniecinski says. “It’s telling us something specific that we haven’t been able to measure before and that can give us a new way to understand what’s going on with platelet dysfunction and the best methods for controlling it.” 

“Blood work up gives you a basic readout of your health based on data like platelet count and metabolic concentrations,” Salaita adds. “Now we’re adding information about the mechanics of platelets. That’s like getting a whole new dial on your dashboard for monitoring your health.” 

Work on the current paper was funded by the National Institutes of Health, the National Science Foundation and the American Heart Association.


Tuesday, December 5, 2023

Building boom boosts malaria-carrying, invasive mosquito in Ethiopia

Sampling for mosquito larva in the water of a manmade pit at a construction site made of simple earth walls covered in plastic sheeting. 

A malaria-carrying mosquito that thrives in urban environments is moving into Africa where a construction boom may be one factor helping the newcomer feel at home.

Lancet Planetary Health published the findings on the ecology of the invasive Anopheles stephensi mosquito led by Gonzalo Vazquez-Prokopec, a professor in Emory University’s Department of Environmental Sciences. 

The invasion of stephensi poses a major threat to urban populations in Africa, where malaria has primarily been a rural disease. While most of the limited data available on stephensi in Africa has been gathered during the rainy season, this study focused on the city of Jigjiga in eastern Ethiopia during the peak of the dry season. 

Stephensi was first detected in Jigjiga in 2018 and has persisted there despite harsh dry seasons of around three rainless months. “We found that during this period of low-water availability, Anopheles stephensi is primarily exploiting habitats associated with construction,” says Vazquez-Prokopec, a leading expert in the disease ecology of urban mosquitos. 


Monday, November 20, 2023

Birds set foot near South Pole in Early Cretaceous, Australian tracks show

Emory's Anthony Martin, left, at the site of the discovery with Melissa Lowery, a local volunteer fossil hunter who was the first to spot most of the tracks. (Photo by Ruth Schowalter)

The discovery of 27 avian footprints on the southern Australia coast — dating back to the Early Cretaceous when Australia was still connected to Antarctica — opens another window onto early avian evolution and possible migratory behavior. 

PLOS ONE published the discovery of some of the oldest, positively identified bird tracks in the Southern Hemisphere, dated to between 120 million and 128 million years ago. 

“Most of the bird tracks and body fossils dating as far back as the Early Cretaceous are from the Northern Hemisphere, particularly from Asia,” says Anthony Martin, first author of the study and a professor in Emory University’s Department of Environmental Sciences. “Our discovery shows that there were many birds, and a variety of them, near the South Pole about 125 million years ago.” 

Read the full story here. 


Tell-toe toes point to oldest-known bird tracks from Australia 

Paleontologist explores a billion years of animals breaking up rocks, bones, shells and wood

Friday, November 10, 2023

NSF funds holistic approach to help farmers adapt to climate change

"There is already a lot of work on what climate change may mean for agriculture in general," says Emily Burchfield, Emory assistant professor of environmental sciences. "But what climate change means for an individual farm must be filtered through issues particular to that farm."

By Carol Clark

The National Science Foundation (NSF) awarded Emily Burchfield, Emory assistant professor of environmental sciences, $1.6 million to lead efforts to identify emerging pressures on agriculture in Georgia, Iowa and Ohio and to develop predictive models to help farmers and policymakers weather these changes. 

“In a nutshell, we’re trying to understand what climate change will mean for agriculture in these three states,” Burchfield says. “We’ll be integrating biophysical projections based on environmental data with insights gathered from farmers and agricultural experts.” 

The goal is to develop possible scenarios for the impacts of climate change — along with the evolving technical, socioeconomic and political landscapes in each state — for how and where crops could be grown over the next 30 to 40 years. The researchers will create a public, online tool to allow farmers and policymakers to explore the possible futures of agriculture at regional and state levels and to support their efforts to manage these scenarios. 

The grant is part of the NSF Dynamics of Integrated Socio-Environmental Systems Program (DISES). 

“Traditionally, the NSF has mainly split programs into the social sciences and the natural sciences but DISES is one of their newer programs that joins the two, looking at how nature affects people and people affect nature,” Burchfield says. “Coupling human and natural systems in theoretical frameworks allows us to take on some of the grand challenges that we’re facing, like climate change and food and water security.” 

Burchfield is principal investigator for the project, which also includes researchers from Arizona State University, Ohio State University and the University of Nebraska, Lincoln. 

A range of agricultural systems 

While the two main crops in both Iowa and Ohio are corn and soy, agriculture in Georgia is far more diverse. The state leads the nation in the production of peanuts, pecans, blueberries and spring onions and is also a leading producer of cotton, watermelon, peaches, cucumbers, sweet corn, bell peppers, tomatoes, cantaloupes, rye and cabbage. 

Agriculture contributes nearly $70 billion annually to Georgia’s economy and one in seven Georgians works in agriculture, forestry or related fields, according to the Georgia Farm Bureau. 

“Compared to other parts of the country, Georgia is incredibly diverse not just in terms of what is grown in the state but in terms of who grows it,” Burchfield says. “A lot of exciting changes are happening in the state — citrus production is moving into South Georgia. And the biggest organic farm east of the Mississippi is located in Georgia, producing carrots.” 

While California currently produces the bulk of the nation’s produce, that state is facing significant challenges for water availability, Burchfield notes. “Georgia has a unique opportunity to expand its fresh-produce production to help meet future demand,” she says. “We want to provide farmers the resources they need to capitalize on such trends.” 

Building tools for the future of farming 

Burchfield’s research combines spatial-temporal social and environmental data to understand the future of food security in the United States, including the consequences of a changing climate. 

For the current project, the researchers will draw from available climate, soil and land-use data to create biophysical models for how changes in climate will affect where and how particular crops can be grown. These models will be integrated with data gathered from surveys and focus groups conducted with agricultural experts, climatologists and farmers working the land throughout Georgia, Iowa and Ohio. 

The project aims to get input from a diverse range of farmers growing different crops and using different management practices. 

“There is already a lot of work on what climate change may mean for agriculture in general,” Burchfield says. “But what climate change means for an individual farm must be filtered through issues particular to that farm. So many dimensions that matter deeply to farmers are not included in policy discussions about agriculture.” 

Farmers will be asked what information and resources they need to sustain their operations and to adapt to climate change. “We want to understand the vision that farmers have for the future of their farms,” Burchfield says. “What would they would like to see happen? What do they see as the barriers and bridges to achieving that vision?” 

The public, online tool that the researchers develop will include interactive maps for crop forecasts by region. It will also provide information to guide policymakers and to help farmers adapt to the changes ahead. 

“It’s impossible to accurately say exactly what’s going to happen in the future,” Burchfield says. “But combining biophysical data with an understanding of the technical, economic and political changes emerging in each of these states, along with the expertise of our farmers, will allow us to forecast trends for how suitable particular regions will be for growing certain crops. The bottom line is we are pulling together the best information available to give a sense of the emergent opportunities in the state for agriculture as well as the emergent challenges.” 


Emory breaking new ground for climate-smart agriculture

Climate change on course to hit U.S. Corn Belt especially hard

Thursday, November 9, 2023

New antimicrobial shuts down bacterial growth without harming human cells

Graphic shows how the KKL-55 molecule (in red) inhibits trans-translation, a process that bacteria cells use for quality control during protein synthesis.

By Carol Clark

Scientists have shown how a molecule with broad-spectrum antibiotic activity works by disabling a process vital to bacterial growth without affecting the normal functioning of human cells. mBio, a journal of the American Society for Microbiology, published the work, led by researchers at Emory University and Pennsylvania State University. 

The molecule, known as KKL-55, is one of a suite of recently identified molecules that interfere with a key bacterial mechanism known as trans-translation, essentially shutting down the ability of bacteria to grow. 

“We’re opening a promising pathway for the development of new antibiotics to treat drug-resistant infections,” says Christine Dunham, co-corresponding author of the paper and a professor in Emory’s Department of Chemistry and the Emory Antibiotic Resistance Center. 

Kenneth Keiler, a professor in the Department of Biochemistry and Molecular Biology at Pennsylvania State, is co-corresponding author of the paper. 

First authors are Ha An Nguyen, who did the work as an Emory chemistry PhD candidate and has since graduated and works at Memorial Sloan Kettering, and Neeraja Marathe, a graduate student at Pennsylvania State. 

A growing global threat 

Antimicrobial-resistant infections have long been a public health threat. The situation grew even worse during the COVID-19 pandemic with increased antibiotic use and less prevention actions, according to the U.S. Centers for Disease Control and Prevention (CDC). 

The CDC estimates that at least 2.8 million antimicrobial-resistant infections continue to occur in the United States each year, killing more than 35,000 people. Globally, the World Health Organization projects that these infections will cause up to 10 million deaths annually by 2050 if new antibiotics are not developed. 

While antibiotics can save lives, any time they are used they can also contribute to the problem of resistance. Bacteria keep evolving new weapons as a defense against drugs, even as scientists work on developing new strategies to disarm bacteria. 

Cross-toxicity, or harmful effects on humans, is another key drawback of some of the drugs used in a last-ditch effort to kill antibiotic-resistant bacteria. 

Avoiding cross-toxicity 

Dunham and Keiler are avoiding the problem of cross-toxicity by focusing on the inhibition of a mechanism unique to bacteria — trans-translation. This mechanism is vital to the proper functioning of the bacterial ribosome. 

Keiler, a molecular geneticist and biochemist, first identified trans-translation in bacteria and is an expert in how it functions. Dunham, a structural biologist, is an expert in the human ribosome. She uses advanced biochemistry and structural biology techniques to understand the mechanics of molecular interactions. 

“Our individual areas of expertise mesh well for this project,” Dunham says. “By collaborating, we are able to take the science further, faster.” 

A cellular protein factory 

The ribosome is an elaborate macromolecular machine within a cell that operates like a factory 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. 

In a human cell, messenger RNA (mRNA), containing the instructions for manufacturing a protein, originates in the nucleus. While still in the nucleus, mRNA undergoes an elaborate quality-control process. It must pass inspection before getting exported to translate the information it contains into a protein. 

“A lot of mRNAs have defects,” Dunham says. “Human cells have efficient ways to test mRNAs and ultimately remove the defective ones.” 

Bacterial cells, however, have no nucleus or organized center for quality control. 

“Bacteria wants to grow, grow and grow, which requires the ribosome to make a lot of proteins,” Dunham says. “But when mRNA has defects, there is little to no quality control. When the ribosome encounters a defective mRNA protein, synthesis gets stalled.” 

The trans-translation process “rescues” ribosomes stalled due to such defects, in order to maintain proper protein synthesis and cell viability in bacteria. 

How KKL-55 works 

Using a high-throughput screening process, the Keiler lab has identified dozens of molecules that inhibit trans-translation in bacteria. 

For the current paper, the researchers focused on understanding how one of these molecules, KKL-55, performs this trick. They used the high-powered structural biology technique of X-ray crystallography to capture KKL-55 in action as it interacted with a protein required for translation. 

The results showed how KKL-55 blocks trans-translation by binding to elongation factor thermos-unstable (EF-Tu). EF-Tu is a protein that interacts with transfer RNA molecules, which play a key role in protein synthesis, and also transfer-messenger RNA, an RNA molecule required for the trans-translation pathway. 

“We got lucky,” Dunham says. “There are dozens of steps involved in the process that KKL-55 could have inhibited and we might have had to test for each one. But the results are clear-cut. It shuts down trans-translation right at the beginning by preventing EF-Tu from binding to tmRNA.” 

Determining the mechanism by which a molecule works to inhibit bacteria is a critical step toward developing a new antibiotic for clinical use. The next step is to test the efficacy of KKL-55 to treat a bacterial infection in a mouse model. 

In 2021, the research team published their finding that a group of trans-translation inhibitors known as acylaminooxadiazoles clear multiple-drug-resistant Neisseria gonorrhoeae infection in mice after a single oral dose. That work is now advancing to clinical trials. 

Dozens more trans-translation inhibitors await the team’s investigation. Each represents a potential new weapon to help humans stay on top in the arms race with drug-resistant bacteria. 

Co-authors of the current paper include Alexandra Nagy (a former National Institutes of Health FIRST Institutional Research and Academic Career Development postdoctoral fellow at Emory who is now at Earlham College); as well as John Alumasa and Michael Vazquez (both from Pennsylvania State University). The work was funded by the National Institutes of Health, the National Institute of General Medical Sciences. 


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

Biochemist Dunham shifts the frame on proteins

Monday, October 23, 2023

Emory breaking new ground for climate-smart agriculture in the Southeast

"Our project is unique in that it focuses on the Southern Piedmont and an often under served piece of our food system, but one that is vital to providing us the nutrients we need — the vegetable sector," says Emily Burchfield, assistant professor of environmental sciences.

Three Emory University researchers received $5,100,000 as part of a United States Department of Agriculture (USDA) project to help measure and promote climate-smart practices that support small-scale, diversified vegetable farmers in the Southern Piedmont. A plateau below the Appalachian Mountains and above the coastal plain, the Southern Piedmont is a banana-shaped region spanning a bit of eastern Alabama, up across part of northern Georgia and into North and South Carolina and Virginia. 

Emory is one of 12 organizations involved in the $25 million project, headed by the Rodale Institute and titled “Quantifying the Potential to Reduce Greenhouse Gas Emissions and Increase Carbon Sequestration by Growing and Marketing Climate-Smart Commodities in the Southern Piedmont.” 

The five-year project is part of the USDA’s Partnerships for Climate-Smart Commodities initiative. “This effort will increase the competitive advantage of U.S. agriculture both domestically and internationally, build wealth that stays in rural communities and support a diverse range of producers and operation types,” USDA Secretary Tom Vilsack says of the initiative. 

The Emory team encompasses three faculty from the Department of Environmental Sciences: Emily Burchfield, Eri Saikawa and Debjani Sihi. 

• Burchfield combines spatial-temporal social and environmental data to understand the future of food security in the United States. 

• Saikawa is an atmospheric chemist who models global soil nitrous oxide emissions and quantifies soil greenhouse gas fluxes. 

• Sihi is an environmental biogeochemist who researches soil organic matter dynamics and greenhouse gas emissions from natural and managed systems. 

Read more here.


Climate change on course to hit U.S. corn belt especially hard

Diverse land cover boosts yields for major U.S. crops, study finds 

Soil quality critical to help some U.S. crops weather climate change

Thursday, October 19, 2023

Math trio makes new points about size of the smallest triangle

"It's a very rich area, to study tiny, small-scale shapes and uncover what the math hidden there can tell us," says Emory mathematician Cosmin Pohoata.

By Carol Clark

Think of a square dotted with points. Now imagine the smallest triangle that could be made by connecting three of those points. That’s the Heilbronn triangle problem in a nutshell. 

“The problem is very easy to state and can sound frivolous,” says Cosmin Pohoata, a theoretical mathematician and Emory assistant professor of mathematics “When I have conversations with non-math friends, they often ask me why we should study problems like this. The beauty of them is that they are often more complex than they seem. They can have unexpected connections that open new doors for understanding all sorts of phenomena.” 
Pohoata and two MIT graduate students, Alex Cohen and Dimitrii Zakharov, recently opened some of those new doors. They completed a new proof for the Heilbronn triangle problem that shows that the smallest triangle in a confined space is much smaller than was previously realized, breaking a record that stood for 40 years. 
Their proof, available online, is submitted to the Journal of the American Mathematical Society and is already making waves in the math world. 

“I think it’s a stunning result,” Anthony Carbery, a mathematician at the University of Edinburgh, told Qanta Magazine. And Thomas Bloom of the University of Oxford told Qanta that he expects the new proof to “prompt a renaissance” of progress on the triangle problem. 
“What makes the proof special to me,” Pohoata says, “is the way that we connected the triangle problem to different areas of math. In particular, harmonic analysis, the study of how waves interact with one another and projection theory, or the behavior of fractals under projections.” 

A graphic representation of the Heilbronn triangle problem.

The making of a mathematician 

Pohoata loved math from the time he was a small child growing up in Romania. He cites an elementary school teacher, who encouraged his love for numbers and patterns, as one key influence. 

In middle school he began competing in International Mathematical Olympiads (IMO). Romania is the original home of the IMO, which dates back to 1959, making it the oldest of the International Science Olympiads. Today more than 100 countries compete in the annual event. 

“I thought I knew a lot about math because the problems in class had been so easy for me,” Pohoata recalls. “When I started competing in the Olympiads, I began to realize how little I knew and how much math was out there to learn.” 

He began to think about math as a career. “It’s quite fun to get to think about problems that interest you,” he says. 

Pohoata attended Princeton as an undergraduate, got his PhD at the California Institute of Technology and taught at Yale before joining Emory this fall. 

Patterns in points and lines 

As a theoretical mathematician, Pohoata focuses his research on three specialized fields: Discrete geometry, additive number theory and extremal combinatorics. 

Extremal combinatorics examines how large or small finite objects such as graphs can be, if placed under certain restrictions. For centuries, it seemed like an esoteric endeavor. 

“The breadcrumbs to extremal combinatorics trace back to ancient Greece,” Pohoata says, “but the field didn’t really come alive until the late 20th century with the rise of computers and the internet. Graphs are at the heart of many things to do with computer science and the internet.” 

Facebook “friend” networks, for example, are large collections of data that are essentially graphs. “You can think of people in the world as points on paper and then draw arrows connecting the ones who are friends,” Pohoata explains. “Then you can look at basic questions underlying these structures. If you have at least seven points do you always have triangles? When do you see a big cluster of connected vertices? Are there areas of the world that are less connected than others?” 

Real-life problems, like how to make algorithms run faster, fuel interest in studying problems about graphs and related areas. 

“As a theorist, I’m driven simply by the math behind shapes and the beauty of them,” Pohoata says, “but I do get excited when I hear that some math breakthrough has been used in a cool way to help with a practical problem.” 

The human side of math 

“I wasn’t interested in the history of math when I first started out,” Pohoata says. “Why learn the progression of results if you have the latest result?” 

But when he taught an introductory course to number theory, it forced him to look more closely at the history of the greats and trace the chronology of events. “I started realizing that you can get many new ideas by following the progress of the past rather than just focusing on the latest thing,” he says. “And I personally learn better when I follow the story of the people in the history of math. You feel the math differently, too, when you put yourself in someone else’s shoes.” 

Pohoata’s interest in the Heilbronn triangle problem inspired him to delve deeper into the work of Klaus Roth, a German-British mathematician who won math’s highest honor, the Fields Medal. “Roth does elegant math that has inspired a lot of activity,” Pohoata says. 

In 1951, Roth developed a strategy for finding the smallest possible triangle within the parameters of the Heilbronn triangle problem, or its so-called “upper bound.” Austrian mathematician Wolfgang Schmidt pushed the upper bound further in a paper published in 1972. That inspired Roth to jump back into the game. Roth further improved the result by Schmidt, just a few months after Schmidt’s breakthrough. 

A tiny problem 

“Roth and Schmidt had a kind of rivalry to see who could come up with the best recipe to find even smaller triangles,” Pohoata says. “They were writing beautiful papers, improving on each other’s work. I learned a lot by studying them.” 

In 1980, a trio of mathematicians — Komlos, Pintz and Szemeredi — pushed the envelope even further, finding a new upper bound to the Heilbronn triangle problem. 

While the problem in its simplest form can be thought of as dots and lines drawn on paper, the mathematicians are working with triangles far too tiny to be “seen” without special tools. 

“You can think of these triangles as microscopic,” Pohoata says. “We’re talking about billions of points crammed within a confined space.” 

Just as scientists keep making improvements in microscopy to get an ever more detailed view of the tiniest parts of a living system or of distant galaxies imperceptible to human eyes on Earth, theoretical mathematicians create tools to get closer and sharper views of the math underlying the universe and everything in it. 

Making connections 

Pohoata had pondered the Heilbronn triangle problem for several months with Zakharov. He met Cohen last year in a chance encounter at MIT, where he had traveled to give a presentation. 

“When math people get together, they like to talk about recent problems on their minds,” he says. “We were excited to learn that we were taking similar approaches to the Heilbronn triangle problem. And that we were all stuck in the same place.” 

The trio decided to join forces. Unlike many of their math heroes of the past, who communicated across distances by letter, they exchanged ideas in real time through Zoom and the Discord instant-messaging platform. 

“Math research is becoming more of a social experience as the world has become more connected,” Pohoata says. “Technology facilitates collaboration.” 

Rather than a single, euphoric eureka moment, he describes the process of creating their 40-page proof as a series of smaller insights. “There are many moving pieces to this proof and each one had to come together,” Pohoata explains. “There was a lot of going back and forth to get all the pieces to fit. You can think of it like putting together a really complex Lego structure.” 

Ultimately, their breakthrough revealed new connections between the Heilbronn triangle problem and other areas of mathematics, including harmonic analysis and fractals — figures that are similar and keep repeating one another at smaller and smaller scales. 

Pohoata and his two MIT colleagues are continuing to work on explaining this web of connections in more detail. “It’s a very rich area, to study tiny, small-scale shapes and uncover what the math hidden there can tell us,” Pohoata says. “What makes math fascinating is that it’s the language for how things work in the world.” 


Wednesday, September 20, 2023

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.” 


Valuing 'natural capital' vital to avoid next pandemic, global experts warn

International trade bans on endangered species tend to help mammals but hurt reptiles

Wednesday, September 13, 2023

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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Friday, September 8, 2023

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.” 


‘Firefly’ imaging method makes cellular forces visible

Chemists reveal the force within you

T cells use ‘handshakes’ to sort friends from foes

New methods reveal the mechanics of blood clotting

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Friday, August 25, 2023

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.”


Wednesday, August 23, 2023

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.


Antibiotic used on food crops affects bumblebee behavior

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Thursday, August 10, 2023

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. 


Biochemist Dunham shifts the frame on proteins 

New molecule found in chestnut trees disarms dangerous staph bacteria

Monday, August 7, 2023

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.” 


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