Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more

Heart

Nogueira’s trailblazing work on stroke recognized

Neurologist Raul Nogueira’s clinical research on thrombectomy, a life-saving intervention after ischemic stroke, is getting recognition – in non-traditional ways.

A group of Korean neurologists and radiologists recently analyzed the most mentioned neurointervention papers by “altmetrics.” Altmetrics measure the impact a research paper has by looking at online discussion – in international news media, blogs, Wikipedia and social media platforms, as well as attention from post-publication peer-review and patient advocacy groups.

Raul Noguiera, MD

As it turned out, one of Nogueira’s papers was the most mentioned and he was also an author on 12 of the 101 top articles. Nogueira was the first author of a 2018 paper in the New England Journal of Medicine, reporting on results from the DAWN trial. The study was a landmark, extending the time window for thrombectomy to 24 hours. Those treated with thrombectomy in addition to standard care regained significantly more functional independence after 90 days than those who received standard treatment only.

Another recent example that fits within altmetrics: The DAWN study was cited by the American Heart Association as a top research finding in stroke for 2018.

Nogueira is a professor of neurology, neurosurgery and radiology at Emory University School of Medicine and director of endovascular services at Grady Memorial Hospital’s Marcus Stroke & Neuroscience Center. Thrombectomy is the removal of a clot from a blood vessel in the brain – in this case, through a mechanical stent-retriever device.

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Mapping shear stress in coronary arteries can help predict heart attacks

A heart attack is like an earthquake. When a patient is having a heart attack, it’s easy for cardiologists to look at a coronary artery and identify the blockages that are causing trouble. However, predicting exactly where and when a seismic fault will rupture in the future is a scientific challenge – in both geology and cardiology.

In a recent paper in Journal of the American College of Cardiology, Habib Samady, MD, and colleagues at Emory and Georgia Tech show that the goal is achievable, in principle. Calculating and mapping how hard the blood’s flow is tugging on the coronary artery wall – known as “wall shear stress” – could allow cardiologists to predict heart attacks, the results show.

Map of wall shear stress (WSS) in a coronary artery from someone who had a heart attack

“We’ve made a lot of progress on defining and identifying ‘vulnerable plaque’,” says Samady, director of interventional cardiology/cardiac catheterization at Emory University Hospital. “The techniques we’re using are now fast enough that they could help guide clinical decision-making.”

Here’s where the analogy to geography comes in. By vulnerable plaque, Samady means a spot in a coronary artery that is likely to burst and cause a clot nearby, obstructing blood flow. The researchers’ approach, based on fluid dynamics, involves seeing a coronary artery like a meandering river, in which sediment (atherosclerotic plaque) builds up in some places and erodes in others. Samady says it has become possible to condense complicated fluid dynamics calculations, so that what once took months now might take a half hour.

Previous research from Emory showed that high levels of wall shear stress correlate with changes in the physical/imaging characteristics of the plaque over time. It gave hints where bad things might happen, in patients with relatively mild heart disease. In contrast, the current results show that where bad things actually did happen, the shear stress was significantly higher.

“This is the most clinically relevant work we have done,” says Parham Eshtehardi, MD, a cardiovascular research fellow, looking back on the team’s previous research, published in Circulation in 2011.  Read more

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MSCs: what’s in a name?

At a recent symposium of cellular therapies held by the Department of Pediatrics, we noticed something. Scientists do not have consistent language to talk about a type of cells called “mesenchymal stem cells” or “mesenchymal stromal cells.” Within the same symposium, some researchers used the first term, and others used the second.

Guest speaker Joanne Kurtzberg from Duke discussed the potential use of MSCs to treat autism spectrum disorder, cerebral palsy, and hypoxic-ischemic encephalopathy. Exciting stuff, although the outcomes of the clinical studies underway are still uncertain. In these studies, the mesenchymal stromal cells (the language Kurtzberg used) are derived from umbilical cord blood, not adult tissues.

Nomenclature matters, because a recent editorial in Nature calls for the term “stem cell” not to be used for mesenchymal (whatever) cells. They are often isolated from bone marrow or fat. MSCs are thought have the potential to become cells such as fibroblasts, cartilage, bone and fat. But most of their therapeutic effects appear to come from the growth factors and RNA-containing exosomes they secrete, rather than their ability to directly replace cells in damaged tissues.

The Nature editorial argues that “wildly varying reports have helped MSCs to acquire a near-magical, all-things-to-all-people quality in the media and in the public mind,” and calls for better characterization of the cells and more rigor in clinical studies.

At Emory, gastroenterologist Subra Kugathasan talked about his experience with MSCs in inflammatory bowel diseases. Hematologist Edwin Horwitz discussed his past work with MSCs on osteogenesis imperfecta. And Georgia Tech-based biomedical engineer Krishnendu Roy pointed out the need to reduce costs and scale up, especially if MSCs start to be used at a higher volume.

Several of the speakers were supported by the Marcus Foundation, which has a long-established interest in autism, stroke, cerebral palsy and other neurological conditions.

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Mini-monsters of cardiac regeneration

After a heart attack, cardiac muscle cells die because they are deprived of blood and oxygen. In an adult human, those cells represent a dead end. They can’t change their minds about what kind of cell they’ve become.

In newborn babies, as well as in adult fish, the heart can regenerate after injury. Why can’t the human heart be more fishy? At Emory, researcher Jinhu Wang is seeking answers, which could guide the development of regenerative therapies.

“If we want to understand cardiac regeneration in mammals, we can look at it from the viewpoint of the fish,” he says.

A lot of research in regenerative medicine focuses on the potential of stem cells, which have not committed to become one type of tissue, such as brain, skin or muscle. Wang stresses that the ability of zebrafish hearts to regenerate does not originate from stem cells. It comes from the regular tissues. The cells are induced to go back in time and multiply, although their capacity to regenerate may vary with the age of the animal, he says.

Jinhu Wang, PhD manages an impressive set of fish tanks

Zebrafish hearts are simpler than mammals’: theirs have just two chambers, while ours have four. Nobel Prize winner Christiane Nusslein-Vollhard has promoted the use of zebrafish as a genetic model in developmental biology. Its embryos are transparent, making it easy to spot abnormalities.

Wang’s fish room in the basement of Emory’s Rollins Research Center contains more than 1000 fish tanks, with different sizes of cage for various ages and an elaborate water recycling system. The adult fish eat brine shrimp that are stored in vats in one corner of the lab. Read more

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Racial disparities in a CV biomarker

Because circulating progenitor cells repair blood vessels, they are a measure of regenerative capacity in the cardiovascular system. Cardiologist Arshed Quyyumi, MD and his colleagues at Emory Clinical Cardiovascular Research Institute have intensively studied this cell type as a marker of vulnerability or resilience.

A recent paper from Quyyumi’s team in Circulation Research examines circulating progenitor cells (CPCs) through the lens of racial disparity. The authors find that African-Americans tend to have lower levels of this regenerative biomarker:

In a large well-characterized biracial cohort, we demonstrate that black participants had significantly lower CPC counts compared with whites, even after adjustment for differences in demographic factors and CVD risk factors. These results were validated in an independent cohort. Thus, on average, after adjustment for sex and other CVD risk factors, blacks have CPC levels that are ≈15% to 30% lower compared with whites, even in subjects free of risk factors. CPC levels decline with age, reaching on average half the levels at age 80 compared with age 20. We found that blacks have CPC counts equivalent to those in whites who are 14 years older. CPC levels are higher after AMI as a result of mobilization because of injury. We show for first time that blacks have 30% to 35% lower CPC mobilization in the setting of AMI.

This is a tricky area to study. How many socioeconomic and environmental factors go into the racial disparities of cardiovascular disease risk? Diet. Exercise. Geography, education, access to healthcare. Air pollution. Psychological stress and inflammation associated with discrimination. It is possible to view CPCs as summing up many of these influences, analogous to the way hemoglobin A1C measurements integrate someone’s blood sugar levels over time as a marker of diabetes. Read more

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Stem cells driven into selective suicide

The term “stem cell” is increasingly stretchy. Orthopedic specialists have been using it when referring to bone marrow concentrate or platelet rich plasma, which are marketed as treatments for joint pain. At Lab Land, we have an interest in pluripotent stem cells, which can differentiate into many types of tissues.

For many applications, the stem cells are actually impurities that need to be removed, because pluripotent stem cells are capable of becoming teratomas, a type of tumor. For quality control, researchers want to figure out how to ensure that the stem-cell-derived cardiac muscle or neural progenitor or pancreas cells (or whatever) are as pure as possible.

Cardiologist and stem cell expert Chunhui Xu has been continuing a line of investigation on this topic. In a recent paper in ACS Chemical Biology, her team showed that “suicide-inducing molecules” can eliminate undifferentiated stem cells from a mixture of cells. This stem-cell-derived mixture was mostly cardiac muscle cells or their progenitors, which Xu’s team wants to use for therapeutic purposes.

Other labs have used metabolic selection – depriving cells of glucose and giving them only lactate –as a selective method for eliminating stem cells from cardiac muscle cultures. This paper shows that the “selective suicide” method works for early-stage differentiation cultures, containing cardiac progenitors, while the metabolic method works only for late-stage cultures contains beating cardiomyocytes.

Read more

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Blue plate special: express delivery to the heart

The anti-arrhythmia drug amiodarone is often prescribed for control of atrial fibrillation, but can have toxic effects upon the lungs, eyes, thyroid and liver. Emory and Georgia Tech scientists have developed a method for delivering amiodarone directly to the heart in an extended release gel to reduce off-target effects.

The results were published in Circulation: Arrhythmia and Electrophysiology.

The senior author is Rebecca Levit, MD, assistant professor of medicine (cardiology) at Emory University School of Medicine and adjunct in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. Graduate student Jose Garcia – part of co-author Andres Garcia’s lab at Georgia Tech — and Peter Campbell, MD are the first authors.

An amiodarone-containing gel was applied to the outside of the heart by a minimally invasive procedure. After a one-time delivery, the gel could reduce the duration of atrial fibrillation and the likelihood of its development for a month in a pig model. The researchers were also able to show that amiodarone did not have toxic effects on the pigs’ lungs.

As noted in the book Off-label prescribing – Justifying unapproved medicine, amiodarone is “one of the very few drugs approved by the FDA in modern times without rigorous randomized clinical trials.” Read more

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Duel of the inflammatory master regulators: insights for drug discovery

Anti-inflammatory drugs such as dexamethasone can have harmful side effects on the skin, bones and metabolism. Structural biology research from Emory University School of Medicine has implications for the long-standing quest to separate these drugs’ benefits from their side effects.

The findings were recently published in Nature Communications (open access).

Dexamethasone is a synthetic glucocorticoid hormone, used to treat conditions such as allergies, asthma, autoimmune diseases and cancer. It mimics the action of the natural hormone cortisol. Both cortisol and synthetic hormones act by binding the glucocorticoid receptor (GR) protein.

The market for synthetic glucocorticoid hormones, oral and topical, is estimated at $10 billion. Examples include dexamethasone, prednisone, and hydrocortisone. Yet these drugs might not be approved today, given the array of known side effects.

GR can bind DNA in two modes. At some sites, it pairs up or “dimerizes” – turning genes on. At others, it binds one at a time, turning genes off. For GR-targeting drugs, the side effects are thought to come from turning on genes involved in processes such as metabolism and bone growth, while the desired anti-inflammatory effects result mainly from turning inflammatory and immune system genes off.

In their new paper, Eric Ortlund, PhD, and colleagues report that GR’s ability to directly bind DNA extends more broadly than previously appreciated. The first author is Will Hudson, PhD, previously a graduate student with Ortlund and now a postdoctoral fellow in Rafi Ahmed’s lab at Emory Vaccine Center.

GR was known to interfere with another important family of DNA-binding proteins, master regulators of inflammation, which are together called NFkB. Ortlund’s team found that GR can directly bind one at a time to many of the same stretches of DNA that NFkB interacts with.

“This type of interaction, where GR is acting one at a time – we think it’s druggable,” says Ortlund, who is associate professor of biochemistry at Emory University School of Medicine. Read more

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For nanomedicine, cell sex matters

The biological differences between male and female cells may influence their uptake of nanoparticles, which have been much discussed as specific delivery vehicles for medicines.

Biomedical engineer Vahid Serpooshan, PhD

New Emory/Georgia Tech BME faculty member Vahid Serpooshan has a recent paper published in ACS Nano making this point. He and his colleagues from Brigham and Women’s Hospital and Stanford/McGill/UC Berkeley tested amniotic stem cells, derived from placental tissue. They found that female amniotic cells had significantly higher uptake of nanoparticles (quantum dots) than male cells. The effect of cell sex on nanoparticle uptake was reversed in fibroblasts. The researchers also found out that female versus male amniotic stem cells exhibited different responses to reprogramming into induced pluripotent stem cells (iPSCs).

Female human amniotic stem cells with nanoparticles .Green: quantum dots/ nanoparticles; red: cell staining; blue: nuclei.

“We believe this is a substantial discovery and a game changer in the field of nanomedicine, in taking safer and more effective and accurate steps towards successful clinical applications,” says Serpooshan, who is part of the Department of Pediatrics and the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.

Serpooshan’s interests lie in the realm of pediatric cardiology. His K99 grant indicates that he is planning to develop techniques for recruiting and activating cardiomyoblasts, via “a bioengineered cardiac patch delivery of small molecules.” Here at Emory, he joins labs with overlapping interests such as those of Mike Davis, Hee Cheol Cho and Nawazish Naqvi. Welcome!

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Elevated (but still low) troponin as a long term cardio biomarker

This weekend (March 10) at the American College of Cardiology meeting, data will emerge on whether expensive and much-discussed PCSK9 inhibitors can lower the risk of heart disease as much as they reduce LDL cholesterol.

To help doctors decide who should take cholesterol-lowering drugs that cost thousands of dollars a year, the focus of discussion could fall on risk models, such as the Framingham score and its successors, or other biomarkers besides various forms of cholesterol. What a coincidence! We have experts on those topics at Emory Clinical Cardiovascular Research Institute: ECCRI co-director Arshed Quyyumi, MD and Laurence Sperling, MD, Director of Preventive Cardiology at the Emory Clinic.

Cardiologists led by Quyyumi have a recent paper in Journal of the American Heart Association looking at troponin as a long-term cardiovascular disease biomarker. Troponin is familiar to cardiologists because it is a sign of acute damage to the heart muscle. If someone with chest pain goes to the emergency department of a hospital, a test for troponin in the blood can say whether a heart attack occurred.

However, as clinical tests for troponin have become more sensitive in the last decade, interpretation has moved past just a “yes/no” question. The levels of troponin now detectable are much smaller than those used to confirm a heart attack. Elevated troponin can be detected in all sorts of situations where the heart is under stress, including after strenuous exercise in healthy individuals. The “optimal cutoff” the Emory authors use in some of their statistical analyses is 5.2 picograms per milliliter. This graph, derived from a 2011 Circulation paper, illustrates just how low that is. Read more

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