Quinn Eastman

Stage fright: don’t get over it, get used to it

Stage fright: don’t get over it, get used to it, advises Emory neuroscientist Anwesha Banerjee in her recent talk at TEDx Decatur. Many can feel empathy with the situation Banerjee describes. It was her first public presentation eight years ago, facing “a room full of scientists, who for whatever reason, did not look very happy that day.”

“What if I fail in front of the crowd? What if everybody thinks I’m an idiot?”

That feeling of scrutiny might have an evolutionary relationship to the fear of being eaten by a predator, she speculates.

Through participating in Toastmasters International, she has made public speaking more of a habit. She contrasts the two parts of the brain: the amygdala, tuner of emotional responses, with the basal ganglia, director of habits.

“I still get stage fright,” she says. “In fact, I have it right now, thinking how all you predators might try to eat me up! But my brain pays less attention to it.”

Banerjee is a postdoctoral scientist in cell biologist Gary Bassell’s lab, studying myotonic dystrophy. In 2017, she was funded by the Myotonic Dystrophy Foundation to create a mouse model of the neurological/sleep symptoms of myotonic dystrophy.

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Beyond birthmarks and beta blockers, to cancer prevention

Ahead of this week’s Morningside Center conference on repurposing drugs, we wanted to highlight a recent paper in NPJ Precision Oncology by dermatologist Jack Arbiser. It may represent a new chapter in the story of the beta-blocker propranolol.

Infantile hemangioma (stock photo)

Several years ago, doctors in France accidentally discovered that propranolol is effective against hemangiomas: bright red birthmarks made of extra blood vessels, which appear in infancy. Hemangiomas often don’t need treatment and regress naturally, but some can lead to complications because they compromise other organs. Infants receiving propranolol require close monitoring to ensure that they do not suffer from side effects related to propranolol’s beta blocker activity, such as slower heart rate or low blood sugar.

Arbiser’s lab showed that only one of two mirror-image forms of propranolol is active against endothelial or hemangioma cells, but it is the inactive one, as far as being a beta-blocker. Many researchers were already looking at repurposing propranolol based on its anti-cancer properties. The insight could be a way to avoid beta-blocker side effects, even beyond hemangiomas to malignant tumors. Check out the Office of Technology Transfer’s feature on this topic. Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Drying up the HIV reservoir

Immunologists refer to the cells that harbor HIV, even while someone is getting effective antiretroviral drugs, as the “reservoir.” That term inspires a lot of waterway metaphors! Unfortunately, drying up the HIV reservoir is not as straightforward as building a dam across a stream.  But it is the goal, if we are talking about the still-elusive possibility of a HIV cure.

Maud Mavigner, Ann Chahroudi and colleagues at Yerkes recently published a paper in Journal of Virology on targeting the Wnt/beta-catenin pathway as a tactic. They were studying SIV-infected macaques, in the context of ongoing antiretroviral therapy.

The HIV reservoir is more difficult to visualize than a human-made aquatic reservoir

Wnt is one of those funky developmental signaling pathways that gets re-used over and over again, whether it’s in the early embryo,the brain or the intestine. Beta-catenin is a central protein in that pathway.

In this case, Wnt/beta-catenin regulates the balance between self-renewal and differentiation of memory T cells – important components of the HIV reservoir. Mavigner’s team used PRI-724, a molecule that blocks interaction between beta-catenin and another protein it needs to turn on genes. PRI-724 has also been investigated in the context of cancer clinical trials. Read more

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Overcoming cardiac pacemaker “source-sink mismatch”

Instead of complication-prone electronic cardiac pacemakers, biomedical engineers at Georgia Tech and Emory envision the creation of “biological pacemakers.” Hee Cheol Cho and colleagues have been taking advantage of his work on a gene called TBX18 that can reprogram heart muscle cells into specialized pacemaker cells.

Graduate student Sandra Grijalva in lab

Every heartbeat originates from a small group of cells in the heart called the sinoatrial node. How these cells drive contractions in the relatively massive, and electrically sturdy, rest of the heart is a problem cardiology researchers call the “source-sink mismatch.” Until Cho’s innovations, it was only possible to isolate a handful of pacemaker cells from animal hearts, and the isolated cells could not be cultured.

Cho and colleagues recently published a paper in Advanced Science describing TBX18-induced pacemaker cell spheroids, a platform for studying source-sink mismatch in culture

Graduate student Sandra Grijalva is the first author of the paper. We first spotted Grijalva’s work when it was presented at the American Heart Association meeting in 2017. Read more

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Hope Clinic part of push to optimize HIV vaccine components

Ten years ago, the results of the RV144 trial– conducted in Thailand with the help of the US Army — re-energized the HIV vaccine field, which had been down in the dumps. It was the first vaccine clinical trial to ever demonstrate any efficacy in preventing HIV. The Hope Clinic of Emory Vaccine Center has been involved in efforts to build on the RV144 trial’s promising results. These early-stage studies have been optimizing the best vaccine components and techniques for larger vaccine efficacy trials, some of which are now underway.

Nadine Rouphael, interim director of the Hope Clinic, was first author on a recent paper in Journal of Clinical Investigation, reporting a multi-center study from the HIV Vaccine Trials Network. HVTN is headquartered at the Fred Hutchinson Cancer Research Center in Seattle and supported by the National Institute of Allergy and Infectious Diseases.

“Our study shows that there are tools available to us now to improve on the immunogenicity seen in RV144, which may lead to better efficacy in future field trials,” Rouphael says. (See statement on the HVTN 105 study here.) Read more

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Invasive cancer cells marked by distinctive mutations

What does it take to be a leader – of cancer cells?

Adam Marcus and colleagues at Winship Cancer Institute are back, with an analysis of mutations that drive metastatic behavior among groups of lung cancer cells. The findings were published this week on the cover of Journal of Cell Science, and suggest pharmacological strategies to intervene against or prevent metastasis.

Marcus and former graduate student Jessica Konen previously developed a technique for selectively labeling “leader” or “follower” lung cancer cells in culture, using lasers that turn a fluorescent protein from green to red. The leaders are more adventurous and invasive, but the followers support the leaders and help them survive. Check out our prize-winning video and their 2017 Nature Communications paper.

The magenta cells have leader-specific mutated Arp3 protein, while the green cells are unmodified followers.

The new research harnesses their technique to track the mutations that are specific to leader or follower cells. It was a collaboration with the lab of Paula Vertino, formerly at Winship and now at University of Rochester. Cancer Biology graduate students Elizabeth Zoeller and Brian Pedro led the work, with sophisticated genomics from Ben Barwick.

One of the leader-specific mutations was in Arp3, part of a protein complex that promotes the protrusion of cellular blobs, facilitating migration. The researchers took the mutated Arp3 protein from leader cells and forced its production in follower cells. In the cover image, the magenta cells on the outside are the ones with the mutated Arp3 protein, while the green cells are unmodified. Read more

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Biochemists grab slippery target: LRH-1

To fight fat, scientists had to figure out how to pin down a greasy, slippery target. Researchers at Emory University and Baylor College of Medicine have identified compounds that potently activate LRH-1, a liver protein that regulates the metabolism of fat and sugar. These compounds have potential for treating diabetes, fatty liver disease and inflammatory bowel disease.

Their findings were recently published online in Journal of Medicinal Chemistry.

LRH-1 is thought to sense metabolic state by binding a still-undetermined group of greasy molecules: lipids or phospholipids. It is a nuclear receptor, a type of protein that turns on genes in response to hormones or vitamins. The challenge scientists faced was in designing drugs that fit into the same slot occupied by the lipids.

“Phospholipids are typically big, greasy molecules that are hard to deliver as drugs, since they are quickly taken apart by the digestive system,” says Eric Ortlund, PhD, associate professor of biochemistry at Emory University School of Medicine. “We designed some substitutes that don’t fall apart, and they’re highly effective – 100 times more potent that what’s been found already.”

Previous attempts to design drugs that target LRH-1 ran into trouble because of the grease. Two very similar molecules might bind LRH-1 in opposite orientations. Ortlund’s lab worked with Emory chemist Nathan Jui, PhD and his colleagues to synthesize a large number of compounds, designing a “hook” that kept them in place. Based on previous structural studies, the hook could stop potential drugs from rotating around unpredictably. Read more

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GRIN families join together for neuroscience

Editor’s note: This post was a collaboration with MMG graduate student Megan Hockman.

They were brought together by their children’s epilepsies, and by rapid advances in genetic sequencing. Only a few years ago, these families would have been isolated, left to deal with their children’s seizures and neurological problems on their own. Now, they’ve organized themselves and are shaping the future of research.

Agonist binding domains of NMDA receptors, where several disease-causing mutations can be found. Adapted from Swanger et al, AJHG (2016).

In mid-September, parents of children affected by variations in GRIN genes gathered at Emory Conference Center to meet with scientists to discuss current research. GRIN disorders occur because of mutations in genes encoding NMDA receptors, which play key roles in memory, learning and neuronal development. NMDA receptors are a type of receptor for glutamate, the main excitatory neurotransmitter in the brain. The receptors themselves are encoded by multiple genes and assemble into tetramers. When their function is altered by mutations in one of these genes, symptoms appear in infancy or early childhood, usually including epilepsy and developmental delay.

The conference was the first time several patient advocacy groups oriented around GRIN-related disorders had met together, says Denise Rehner, president of the CureGRIN Foundation and mother of an affected child. For parents, this was an opportunity to connect with each other and advocacy groups, and to interact with scientists. For researchers, it was a chance to hear from those who are being impacted by their studies, and to discuss better ways to share data.

“We got a chance to explain to all the stakeholders – patient groups, foundations, companies – exactly what we do,” said Emory neuroscientist and conference organizer Stephen Traynelis, director of the Center for Functional Evaluation of Rare Variants. Traynelis and colleague Hongjie Yuan have been tracking the direct impacts of mutations on the function of the NMDA receptor. In doing so, they plan work with clinicians to compile registries, linking specific functional data to patient symptoms.

In addition to understanding underlying mechanisms and outcomes of GRIN disorders, researchers want to figure out how to treat affected children with existing drugs. Several options exist for targeting NMDA receptors, such as dextromethorphan (a cough suppressant) or memantine, approved for symptoms of Alzheimer’s. Traynelis and Yuan previously collaborated with the Undiagnosed Disease Program (now the Undiagnosed Disease Network) at the National Institutes of Health to investigate memantine as a treatment for a child with a GRIN2A mutation, showing that the drug could reduce seizure burden in one patient. Read more

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Immunologists identify T cell homing beacons for lungs

Scientists have identified a pair of molecules critical for T cells, part of the immune system, to travel to and populate the lungs. A potential application could be strengthening vaccines against respiratory pathogens such as influenza.

The findings were published online Thursday, September 26 in Journal of Experimental Medicine.

T cells in the lungs, courtesy of Alex Wein. Blue represents respiratory epithelium (EpCAM), while various T cells stain red, yellow or green.

Much research on immunity to influenza virus focuses on antibodies, infection- or vaccine-induced proteins in the blood that can smother viruses. But CD8 T cells, which survey other cells for signs of viral infection and kill infected cells, are an important arm of our defenses too. The epitopes – or bits of viral protein – they recognize generally do not change from year to year.

Researchers led by Jacob Kohlmeier, PhD, at Emory University School of Medicine wanted to learn more about what’s needed to get CD8 T cells into the lungs, since the lungs will often contain the first cells incoming virus will have a chance to infect. However, T cells don’t stick around in the lungs for extended amounts of time.

“The airways are a unique environment in the body,” says Alex Wein, a MD/PhD student who trained in Kohlmeier’s lab. “They’re high in oxygen but low in nutrients. Unlike other tissues, when T cells enter the airways, it’s a one-way trip and they have a half-life of a few weeks, so they must be continually repopulated.”

Wein, his fellow MD/PhD Sean McMaster, now at Boston Consulting Group, and Shiki Takamura at Kindai University are co-first authors of the paper. Kohlmeier is assistant professor of microbiology and immunology and part of the Emory-UGA Center of Excellence for Influenza Research and Surveillance.

The researchers showed that two molecules, called CXCR6 and CXCL16, are needed for CD8 T cells to reach the airways in mice. CXCR6 is found on T cells and CXCL16 is produced by the epithelial cells lining the airways of the lungs. Read more

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A new term in biophysics: force/time = “yank”

Biologists and biomedical engineers are proposing to define the term “yank” for changes in force over time, something that our muscles cause and nerves can sense and respond to. Their ideas were published on September 12 in Journal of Experimental Biology.

Expressed mathematically, acceleration is the derivative of speed or velocity with respect to time. The term for the time derivative of acceleration is “jerk,” and additional time derivatives after jerk are called “snap,” “crackle” and “pop.”

The corresponding term for force – in physics, force is measured in units of mass times acceleration – has never been defined, the researchers say.

Scientists that study sports often use the term “rate of force development”, a measure of explosive strength. Scientists who study gait and balance — in animals and humans — also often analyze how quickly forces on the body change. It could be useful in understanding spasticity, a common neuromuscular reflex impairment in multiple sclerosis, spinal cord injury, stroke and cerebral palsy.

“Understanding how reflexes and sensory signals from the muscles are affected by neurological disorders is how we ended up needing to define the rate change in force,” says Lena Ting, PhD, professor of rehabilitation medicine at Emory University School of Medicine and the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. Read more

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