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.

Posted on February 6, 2019 by Quinn Eastman in Heart, Neuro Leave a comment

How intestinal bacteria affect bone formation

Helpful intestinal bacteria may stimulate bone formation via butyrate, according to a recent paper in Immunity. Butyrate increases bone formation through its regulation of T cells, Emory researchers report.

The finding adds to evidence for beneficial effects of butyrate and other SCFA (short chain fatty acid) metabolites, which are produced by bacterial fermentation of fiber in the intestines.

Roberto Pacifici and colleagues had observed that probiotic supplements protected female mice from the loss of bone density occurring after ovary removal, a simulation of the hormonal changes of menopause. Probiotic bacteria could also stimulate bone formation in mice with intact ovaries, the researchers found.

The new Immunity paper shows how this effect is produced. The probiotic bacteria do not make butyrate themselves, but they encourage the growth of other Clostridum bacteria that do produce butyrate. Read more

Posted on December 17, 2018 by Quinn Eastman in Immunology Leave a comment

Vulnerability to stress – Tet by Tet

Geneticist Peng Jin and colleagues have a paper in Cell Reports this week that is part of a mini-boom in studying the Tet enzymes and their role in the brain. The short way to explain what Tet enzymes do is that they remove DNA methylation by oxidizing it out.

Methylation, a modification of DNA that generally shuts genes off, has been well-studied for decades. The more recent discovery of how cells remove methylation with the Tet enzymes opened up a question of what roles the transition markers have. It’s part of the field of epigenetics: the meaning of these modifications “above” the DNA sequence.

This is my favorite analogy to explain the transition states, such as 5-hydroxymethylcytosine. They’re not really a new letter of the genetic alphabet – they’ve been there all along. We just didn’t see them before.

Imagine that you are an archeologist, studying an ancient civilization. The civilization’s alphabet contains a limited number of characters. However, an initial pass at recently unearthed texts was low-resolution, missing little doodads like the cedilla in French: Ç.

Are words with those marks pronounced differently? Do they have a different meaning?

The new Cell Reports paper shows that it matters what pen writes the little doodads. In mice, removing one Tet enzyme, Tet1, has the opposite effect from removing Tet2, when it comes to response to chronic stress. One perturbation (loss of Tet1) makes the mice more resistant to stress, while the other (loss of Tet2) has them more vulnerable. The researchers also picked up an interaction between Tet1 and HIF1-alpha, critical for regulation of cells’ response to hypoxia. Read more

Posted on December 11, 2018 by Quinn Eastman in Neuro Leave a comment

Circadian rhythms go both ways: in and from retina

In case you missed it, the 2017 Nobel Prize in Medicine marked the arrival of the flourishing circadian rhythm field. Emory Eye Center’s Mike Iuvone teamed up with Gianluca Tosini at Morehouse School of Medicine to probe how a genetic disruption of circadian rhythms affects the retina in mice.

Removal of the Bmal1 gene – an essential part of the body’s internal clock — from the retina in mice was known to disrupt the electrical response to light in the eye. The “master clock” in the body is set by the suprachiasmatic nucleus, part of the hypothalamus, which receives signals from the retina. Peripheral tissues, such as the liver and muscles, have their own clocks. The retina is not so peripheral to circadian rhythm, but its cellular clocks are important too.

What the new paper in PNAS shows is that removal of Bmal1 from the retina accelerates the deterioration of vision that comes with aging, but it also shows developmental effects – see below.

You might think: “OK, the mice have disrupted circadian rhythms for their whole lives, so that’s why their retinas are messed up.” But the Emory/Morehouse experimenters removed the Bmal1 gene from the retina only.

P. Michael Iuvone, PhD, director of vision research at Emory Eye Center

The authors write: “BMAL1 appears to play important roles in both cone development and cone viability during aging… Cones are known to be among the cells with highest metabolism within the body and therefore, alteration of metabolic processes within these cells is likely to affect their health status and viability.”

Genomics plus human intelligence

Emory geneticists Hong Li and Michael Gambello recently identified the first pediatric case of a rare inherited metabolic disorder: glucagon receptor deficiency. Their findings, published in Molecular Genetics and Metabolic Reports, show the power of gene sequencing to solve puzzles – when combined with human intelligence. Although the diagnosis did not resolve all the issues faced by the patient, it allowed doctors to advise the family about diet and possible pancreatic tumor risk.

The family of a now 9-year-old girl came to Li when the girl was 4 years old. Based on newborn screening, the girl had been diagnosed with a known disorder called arginase deficiency. Arginase breaks down the amino acid arginine; if it is deficient, arginine and toxic ammonia tend to accumulate. At birth, the girl had high arginine levels – hence the initial diagnosis.

The girl had a history of low body weight, anorexia and intermittent vomiting, which led doctors to place a feeding tube through the abdominal wall into her stomach. For several years, she was given a special low-protein liquid diet and supplements, aimed at heading off nutritional imbalance and tissue breakdown. However, she did not have intellectual disability or neurological symptoms, which are often seen with arginase deficiency.

In fact, her blood amino acids, including arginine, were fully normalized, and a genetic test for arginase deficiency was normal as well. These results were perplexing. By reviewing all the clinical, biochemical and molecular data, Li concluded the girl did not have arginase deficiency, and began looking for an alternative diagnosis. Read more

Posted on November 15, 2018 by Quinn Eastman in Uncategorized Leave a comment

‘Master key’ microRNA has links to both ASD and schizophrenia

Recent studies of complex brain disorders such as schizophrenia and autism spectrum disorder (ASD) have identified a few “master keys,” risk genes that sit at the center of a network of genes important for brain function. Researchers at Emory and the Chinese Academy of Sciences have created mice partially lacking one of those master keys, called MIR-137, and have used them to identify an angle on potential treatments for ASD.

The results were published this week in Nature Neuroscience.

Mice partially lacking MIR-137 display learning and memory deficits, repetitive behaviors and impaired sociability. MIR-137 encodes a microRNA, which regulates hundreds of other genes, many of which are also connected to schizophrenia and autism spectrum disorder.

By treating mutant mice with papaverine, a vasodilator discovered in the 19th century, scientists could improve the performance of the mice on maze navigation and social behavior tests. Papaverine is an inhibitor of the enzyme Pde10a (phosphodiesterase 10a), which is elevated in mutant mice.

Papaverine is a component of opium, but it has a structure (and effects) that are different from opiates.

Other Pde10a inhibitors have been tested in schizophrenia clinical trials, but the new results suggest this group of compounds could have potential for some individuals with ASD, says senior author Peng Jin, PhD, professor of human genetics at Emory University School of Medicine.

Having just the right level of MIR-137 function is important. Previous studies of people with genetic deletions show that a loss of MIR-137 is connected with intellectual disability and autism spectrum disorder. The reverse situation, in which a genetic variation increases MIR-137 levels, appears to contribute to schizophrenia.

“It’s interesting to think about in the context of precision medicine,” Jin says. “Individuals with a partial loss of MIR137 – either genomic deletions or reduced expression — could potentially be candidates for treatment with Pde10a inhibitors.”

To create the mutant mice, Jin’s lab teamed up with Dahua Chen, PhD and Zhao-Qian Teng, PhD scientists at the State Key Laboratories of Stem Cell and Reproductive Biology and Membrane Biology, part of the Institute of Zoology, Chinese Academy of Sciences in Beijing. Jin says that generating mice with a heritable disruption of MIR-137 was technically challenging, taking several years. Read more

Posted on November 9, 2018 by Quinn Eastman in Neuro Leave a comment

Shape-shifting RNA regulates viral sensor

Congratulations to Emory biochemists Brenda Calderon and Graeme Conn. Their recent Journal of Biological Chemistry paper on a shape-shfting RNA was selected as an Editor’s Pick and cited as a “joy to read… Technically, the work is first class, and the writing is clear.”

Calderon, a former BCDB graduate student and now postdoc, was profiled by JBC in August.

Brenda Calderon, PhD

Calderon and Conn’s JBC paper examines regulation of the enzyme OAS (oligoadenylate synthetase). OAS senses double-stranded RNA: the form that viral genetic material often takes. When activated, OAS makes a messenger molecule that drives internal innate immunity enzymes to degrade the viral material (see below).

OAS is in turn regulated by a non-coding RNA, called nc886. Non-coding means this RNA molecule is not carrying instructions for building a protein. Calderon and Conn show that nc886 takes two different shapes and only one of them activates OAS.

Conn says in a press release prepared by JBC that although nc886 is present in all human cells, it’s unknown how abundance of its two forms might change in response to infection. Read more

Posted on October 29, 2018 by Quinn Eastman in Uncategorized Leave a comment

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

Posted on October 29, 2018 by Quinn Eastman in Heart Leave a comment

Cells in “little brain” have distinctive metabolic needs

Cells’ metabolic needs are not uniform across the brain, researchers have learned. “Knocking out” an enzyme that regulates mitochondria, cells’ miniature power plants, specifically blocks the development of the mouse cerebellum more than the rest of the brain.

The results were published in Science Advances.

“This finding will be tremendously helpful in understanding the molecular mechanisms underlying developmental disorders, degenerative diseases, and even cancer in the cerebellum,” says lead author Cheng-Kui Qu, MD, PhD, professor of pediatrics at Emory University School of Medicine, Winship Cancer Institute and Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta.

The cerebellum or “little brain” was long thought to be involved mainly in balance and complex motor functions. More recent research suggests it is important for decision making and emotions. In humans, the cerebellum grows more than the rest of the brain in the first year of life and its development is not complete until around 8 years of age. The most common malignant brain tumor in children, medulloblastoma, arises in the cerebellum.

Qu and his colleagues have been studying an enzyme, PTPMT1, which controls the influx of pyruvate – a source of energy derived from carbohydrates – into mitochondria. They describe pyruvate as “the master fuel” for postnatal cerebellar development.

Cells can get energy by breaking down sugar efficiently, through mitochondria, or more wastefully in a process called glycolysis. Deleting PTPMT1 provides insight into which cells are more sensitive to problems with mitochondrial metabolism. A variety of mitochondrial diseases affect different parts of the body, but the brain is especially greedy for sugar; it never really shuts off metabolically. When someone is at rest, the brain uses a quarter of the body’s blood sugar, despite taking up just 2 percent of body weight in an adult. More here.

Also, see this 2017 item from Stanford on the cerebellum (Nature paper).

Posted on October 24, 2018 by Quinn Eastman in Neuro Leave a comment

Clues to lupus’s autoimmune origins in precursor cells

In the autoimmune disease systemic lupus erythematosus or SLE, the immune system produces antibodies against parts of the body itself. How cells that produce those antibodies escape the normal “checks and balances” has been unclear, but recent research from Emory University School of Medicine provides information about a missing link.

Investigators led by Ignacio (Iñaki) Sanz, MD, studied blood samples from 90 people living with SLE, focusing on a particular type of B cells. These “DN2” B cells are relatively scarce in healthy people but substantially increased in people with SLE.

The results were published in the journal Immunity.

People with lupus can experience a variety of symptoms, such as fatigue, joint pain, skin rashes and kidney problems. Levels of the DN2 cells were higher in people with more severe disease or kidney problems. DN2 B cells are thought to be “extra-follicular,” which means they are outside the B cell follicles, regions of the lymph nodes where B cells are activated in an immune response.

“Overall, our model is that a lot of lupus auto-antibodies come from a continuous churning out of new responses,” says postdoctoral fellow Scott Jenks, PhD, co-first author of the paper. “There is good evidence that DN2 cells are part of the early B cell activation pathway happening outside B cells’ normal homes in lymph nodes.”

Previous research at Emory has shown that African American women have significantly higher rates of lupus than white women. In the current study, the researchers observed that the frequency of DN2 cells was greater in African American patients. Participants in the study were recruited by Emory, University of Rochester and Johns Hopkins. Read more

Posted on October 24, 2018 by Quinn Eastman in Immunology Leave a comment

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