Mother's milk is OK, even for the in-between babies

“Stop feeding him milk right away – just to be safe” was not what a new mother wanted to hear. The call came several days after Tamara Caspary gave birth to fraternal twins, a boy and a girl. She and husband David Katz were in the period of wonder and panic, both recovering and figuring out how to care for them. “A nurse called to ask how my son was doing,” says Caspary, a developmental Read more

Focus on mitochondria in schizophrenia research

Despite advances in genomics in recent years, schizophrenia remains one of the most complex challenges of both genetics and neuroscience. The chromosomal abnormality 22q11 deletion syndrome, also known as DiGeorge syndrome, offers a way in, since it is one of the strongest genetic risk factors for schizophrenia. Out of dozens of genes within the 22q11 deletion, several encode proteins found in mitochondria. A team of Emory scientists, led by cell biologist Victor Faundez, recently analyzed Read more

Fetal alcohol cardiac toxicity - in a dish

Alcohol-induced cardiac toxicity is usually studied in animal models; a cell-culture based approach could make it easier to study possible interventions more Read more

Laughter may be best medicine for brain surgery

Neuroscientists at Emory University School of Medicine have discovered a focal pathway in the brain that when electrically stimulated causes immediate laughter, followed by a sense of calm and happiness, even during awake brain surgery. The effects of stimulation were observed in an epilepsy patient undergoing diagnostic monitoring for seizure diagnosis. These effects were then harnessed to help her complete a separate awake brain surgery two days later.

The behavioral effects of direct electrical stimulation of the cingulum bundle, a white matter tract in the brain, were confirmed in two other epilepsy patients undergoing diagnostic monitoring. The findings are scheduled for publication in the Journal of Clinical Investigation.

Emory neurosurgeons see the technique as a “potentially transformative” way to calm some patients during awake brain surgery, even those who are not especially anxious. For optimal protection of critical brain functions during surgery, patients may need to be awake and not sedated, so that doctors can talk with them, assess their language skills, and detect impairments that may arise from resection. Read more

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Probing hyperexcitability in fragile X syndrome

Researchers at Emory University School of Medicine have gained insight into a feature of fragile X syndrome, which is also seen in other neurological and neurodevelopmental disorders.

In a mouse model of fragile X syndrome, homeostatic mechanisms that would normally help brain cells adjust to developmental changes don’t work properly. This helps explain why cortical hyperexcitability, which is linked to sensory sensitivity and seizure susceptibility, gradually appears during brain development.

Studying a model of fragile X syndrome, Emory researchers were looking at neurons displaying single spiking and multi-spiking behavior. 

These physiological insights could help guide clinical research and efforts at early intervention, the scientists say. The results were published Feb. 5 by Cell Reports (open access).

Fragile X syndrome is the most common inherited form of intellectual disability and a leading single-gene cause of autism. Individuals with fragile X syndrome often display sensory sensitivity and some — about 15 percent— have seizures.

Scientists’ explanation for these phenomena is cortical hyperexcitability, meaning that the response of the cortex (the outer part of the brain) to sensory input is more than typical. Cortical hyperexcitability has also been observed in the broader category of autism spectrum disorder, as well as migraine or after a stroke.

At Emory, graduate student Pernille Bülow forged a collaboration between Peter Wenner, PhD and Gary Bassell, PhD. Wenner, interested in homeostatic plasticity, and Bassell, an expert in fragile X neurobiology, wanted to investigate why a mechanism called homeostatic intrinsic plasticity does not compensate for the changes in the brain brought about in fragile X syndrome. More here.

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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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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

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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

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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.”

More from the official news release:

…Bmal1 removal significantly affects visual information processing and reduces the thickness of inner retinal layers. The absence of Bmal1 also affected visual acuity and contrast sensitivity. Another important finding was a significant age-related decrease in the number of cone photoreceptors (outer segments and nuclei) in mice lacking Bmal1, which suggests that these cells are directly affected by Bmal1 removal.

“When we genetically disrupted the circadian clocks in the retinas of mice, we found accelerated age-related cone photoreceptor death, similar to that in age-related macular degeneration in humans,” Iuvone says. “This loss of photoreceptor cones affects retinal responses to bright light.

“We also noted developmental effects in young mice,” Iuvone continues, “including abnormalities in rod bipolar cells that affected dim light responses. These findings have potential implications for pregnant shift workers and other women with sleep and circadian disorders, whose offspring might develop visual problems due to their mother’s circadian disruption.”

 

 

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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

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‘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

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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

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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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