Insane in the membrane - inflamed in the brain

Green and red fluorescent cells allow the visualization of brain inflammation in status Read more

Flow mediated dilation

Demonstration of flow-mediated dilation, a test of endothelial function. Impaired endothelial function is an early stage in the process of Read more

Nutty stimulant revealed as anticancer tool

Areca nuts are chewed for their stimulant effects in many Asian countries. Analogous to nicotine, arecoline was identified in a chemical screen as an enzyme inhibitor that thwarts the Warburg effect in cancer Read more

Insane in the membrane – inflamed in the brain

Inflammation in the brain is a feature of several neurological diseases, ranging from Parkinson’s and Alzheimer’s to epilepsy. Nick Varvel, a postdoc with Ray Dingledine’s lab at Emory, was recently presenting his research and showed some photos illustrating the phenomenon of brain inflammation in status epilepticus (prolonged life-threatening seizures).

The presentation was at a Center for Neurodegenerative Disease seminar; his research was also published in PNAS and at the 2016 Society for Neuroscience meeting.green-red-brain

Varvel was working with mice in which two different types of cells are marked by fluorescent proteins. Both of the cell types come originally from the blood and can be considered immune cells. However, one kind – marked with green — is in the brain all the time, and the red kind enters the brain only when there is an inflammatory breach of the blood brain barrier.

Both markers, CX3CR1 (green) and CCR2 (red), are chemokine receptors. Green fluorescent protein is selectively produced in microglia, which settle in the brain before birth and are thought to have important housekeeping/maintenance functions.

Monocytes, a distinct type of cell that is not usually in the brain in large numbers, are lit up red. Monocytes rush into the brain in status epilepticus, and in traumatic brain injury, hemorrhagic stroke and West Nile virus encephalitis, to name some other conditions where brain inflammation is also seen.

In the PNAS paper, Varvel and his colleagues include a cautionary note about using these mice for studying situations of more prolonged brain inflammation, such as neurodegenerative diseases: the monocytes may turn down production of the red protein over time, so it’s hard to tell if they’re still in the brain after several days.

Targeting CCR2 – good or bad? Depends on the disease model

The researchers make the case that “inhibiting brain invasion of CCR2+ monocytes could represent a viable method for alleviating several deleterious consequences of status epilepticus.” Read more

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Flow mediated dilation

On Friday, researchers from Emory Clinical Cardiovascular Research Institute demonstrated a test for how much blood vessels adjust to changes in blood flow. This test is known as “flow-mediated dilation” or FMD. A blood pressure measurement cuff is tightened on the arm for five minutes, restricting blood flow.

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ECCRI investigator Salman Sher, MD demonstrates flow-mediated dilation

When the cuff is released, blood flow increases, but how much the arm’s main artery expands depends on the endothelium – the lining of the artery — and its ability to respond to nitric oxide, which is induced by the increased flow. Researchers monitor the artery’s expansion by ultrasound.

ECCRI co-director Arshed Quyyumi and his colleagues at Emory have extensive experience using the FMD test. Impaired endothelial function is an early stage in the process of atherosclerosis.

The FMD test is relatively non-invasive, in that no catheter probe is necessary. However, practitioners need practice and careful study design to ensure accuracy, ECCRI investigator Salman Sher explained. Posture, time of day and whether the patient has eaten can all affect the results.

Lab Land asked Sher (seated in the photo) whether the effect was similar to the common experience of sleeping on an arm and having it turn numb, followed by “pins and needles” when the pressure is relieved. This feeling actually comes from nerve compression. Read more

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Nutty stimulant revealed as anticancer tool

Arecoline — the stimulant component of areca nuts — has anticancer properties, researchers at Winship Cancer Institute of Emory University have discovered. The findings were published Thursday, November 17 in Molecular Cell.

areca-nut-and-arecoline

Areca nut and chemical structure of arecoline. From Wikimedia.

Areca nuts are chewed for their stimulant effects in many Asian countries, and evidence links the practice to the development of oral and esophageal cancer. Analogous to nicotine, arecoline was identified as an inhibitor of the enzyme ACAT1, which contributes to the metabolism-distorting Warburg effect in cancer cells.

Observers of health news have complained that coffee, as a widely cited example, is implicated in causing cancer one week and absolved the next. Arecoline is not another instance of the same trend, stresses senior author Jing Chen, PhD, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute.

“This is just a proof of principle, showing that ACAT1 is a good anticancer target,” Chen says. “We view arecoline as a lead to other compounds that could be more potent and selective.”

Chen says that arecoline could be compared to arsenic, a form of which is used as a treatment for acute promyelocytic leukemia, but is also linked to several types of cancer. Plus, arecoline’s cancer-promoting effects may be limited if it is not delivered or absorbed orally, he says. When arecoline first arose in a chemical screen, Chen says: “It sounded like a carcinogen to me. But it all depends on the dose and how it is taken into the body.” Read more

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Oxytocin receptor levels predict comforting behavior in prairie voles

Different levels of a receptor for a hormone involved in social bonding may explain individual variation in offering comfort during stressful situations. Like humans, animals console each other in times of distress: monkeys hug and kiss, and prairie voles groom each other.

James Burkett, PhD

James Burkett, PhD

Emory postdoc James Burkett described his research on voles at a press conference on “The Neuroscience of Emotion and Social Behavior” at the Society for Neuroscience meeting in San Diego on Sunday. Here are Video (Burkett’s part is roughly from 4:50 to 9:00) and the scientific abstract.

Burkett’s presentation, on oxytocin-dependent comforting behavior in prairie voles, outlined an extension of his graduate work with Larry Young at Yerkes National Primate Research Center, which was published in Science in January 2016 and impressed oxytocin skeptic Ed Yong. Burkett, now in Gary Miller’s laboratory at Rollins School of Public Health, also masterminded a Reddit “Ask me anything” in February.

The rest of the Society for Neuroscience press release:

Previous research indicates oxytocin—a hormone that promotes social and maternal bonding—acts in the anterior cingulate cortex (ACC) of the prairie vole brain to encourage consoling behavior. In humans, the ACC activates when people see others in pain. Some degree of personal distress motivates comforting behaviors, but too much actually makes animals (including humans, chimpanzees, and rats) less likely to offer comfort.

Read more

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Nerve gas, angel dust and genetic epilepsy

Last week, Lab Land noticed similarities between two independent lines of research from the Escayg and Traynelis/Yuan labs at Emory. Both were published recently and deal with rare forms of genetic epilepsy, in which molecular understanding of the cause leads to individualized treatment, albeit with limited benefit.

Both conditions are linked to an excess of neuronal excitation, and both can be addressed using medications that have also been tested for Alzheimer’s. A critical difference is that memantine is FDA-approved for Alzheimer’s, but huperzine A is not.

What condition? Dravet syndrome/GEFS+ Epilepsy-aphasia syndrome
What gene is mutated? SCN1A – sodium ion channel GRIN2A – NMDA receptor subunit
What is the beneficial drug? Huperzine A Memantine
How does the drug work? Acetylcholinesterase inhibitor NMDA receptor antagonist
Other drugs that use the same mechanism Alzheimer’s medications such as donepezil

Irreversible + stronger: insecticides, nerve gas

Ketamine, phencyclidine (aka PCP)
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Antiviral success makes some immune cells stickier

As they succeed in clearing a viral infection from the body, some virus-hunting T cells begin to stick better to their target cells, researchers from Emory Vaccine Center and Georgia Tech have discovered.

The increased affinity helps the T cells kill their target cells more efficiently, but it depends both on the immune cells’ anatomic location and the phase of the infection.

The results were published this week in the journal Immunity.

Arash Grakoui, PhD

Arash Grakoui, PhD

After the peak of the infection, cells within the red pulp of the spleen or in the blood displayed a higher affinity for their targets than those within the white pulp. However, the white pulp T cells were more likely to become long-lasting memory T cells, critical for vaccines.

“These results provide a better understanding of how memory precursor populations are established and may have important implications for the development of efficacious vaccines,” the scientists write.

In the mouse model the researchers were using, the differences in affinity were only detectable a few days after the non-lethal LCMV viral infection peaks. How the differences were detected illustrates the role of serendipity in science, says senior author Arash Grakoui, PhD.

Typically, the scientists would have taken samples only at the peak (day 7 of the infection) and weeks later, when memory T cells had developed, Grakoui says. In January 2014, the weather intervened during one of these experiments. Snow disrupted transportation in the Atlanta area and prevented postdoctoral fellow Young-Jin Seo, PhD from taking samples from the infected mice until day 11, which is when the differences in affinity were apparent.

Seo and Grakoui collaborated with graduate student Prithiviraj Jothikumar and Cheng Zhu, PhD at Georgia Tech, using a technique Zhu’s laboratory has developed to measure the interactions between T cells and their target cells. Co-author Mehul Suthar, PhD performed gene expression analysis.

Read more

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Emory clinical research highlights for #AHA16

Clinical research presentations at 2016 American Heart Association Scientific Sessions: telomeres + circulating progenitor cells, food deserts, and troponin as risk marker for atrial fibrillation.

 

Telomere Shortening, Regenerative Capacity, and Cardiovascular Outcomes Nov. 13, 4:45 pm, Room 346-347

Aging, in general, depletes our bodies’ regenerative capacities. Arshed Quyyumi, MD and colleagues at Emory Clinical Cardiovascular Research Institute have shown how circulating progenitor cells or CPCs, which regenerate blood vessels and correlate with outcomes in cardiovascular disease, are a finite resource.

Working with Quyyumi, research fellow Muhammad Hammadah, MD is presenting data on how telomere length interacts with the levels of CPCs, in a study of mental stress ischemia in 566 patients with stable coronary artery disease. Telomeres tend to shorten with ageing and cellular stress, and their length has been a widely studied biomarker.

Hammadah concludes that low leukocyte telomere length is associated with decreased regenerative capacity, independently of age and cardiovascular risk factors. However, telomere length and CPC levels are independent and additive predictors of adverse cardiovascular outcomes (such as death, heart attack, stroke, or hospitalization for heart failure), he finds. Hammadah is a finalist for the Elizabeth Barrett-Connor Research Award for Young Investigators in Training. Read more

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Emory basic research highlights for #AHA16

Basic research presentations at 2016 American Heart Association Scientific Sessions: cell therapy for heart attack (mesenchymal stem cells) in animal models and role of CD73, gradual release drug for atrial fibrillation, how particles from stored blood affects blood vessels.

Mesenchymal Stem Cells Require CD73 Activity to Reduce Leukocyte Associated Inflammation Following Myocardial Ischemia-Reperfusion Injury

Nov.13, 1:30 pm, Science and Technology Hall- Basic Science Theater

Cell therapy, using the patient’s own cells to reduce damage to the heart after a heart attack, has been a hot topic. Mesenchymal stem cells are derived from the bone marrow and can’t replace heart muscle. But they do exert anti-inflammatory and anti-oxidative effects, Eric Shin, MD, Rebecca Levit, MD and colleagues show in a rat model of heart attack.

The researchers use the gel material alginate to encapsulate the cells, in a way previously described by Levit. They say this is the first study to demonstrate that mesenchymal stem cells reduce reactive oxygen species production in the heart. and that the molecule CD73, which degrades ATP/ADP into adenosine, is needed for the anti-inflammatory effect. CD73 is also a cancer immunotherapy target. Read more

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Deep dive into NMDA receptor variation

The study of human genetics has often focused on mutations that cause disease. When it comes to genetic variations in healthy people, scientists knew they were out there, but didn’t have a full picture of their extent. That is changing with the emergence of resources such as the Exome Aggregation Consortium or ExAC, which combines sequences for the protein-coding parts of the genome from more than 60,000 people into a database that continues to expand.

ajhg-fig-2-092016

Rare mutations in the NMDA receptor genes cause epilepsy (GRIN2A) or intellectual disability (GRIN2B). Shown in blue are agonist binding domains of the receptors, where several disease-causing mutations can be found.

At Emory, the labs of Stephen Traynelis and Hongjie Yuan have published an analysis of ExAC data, focusing on the genes encoding two NMDA receptor subunits, GRIN2A and GRIN2B. These receptors are central to signaling between brain cells, and rare mutations in the corresponding genes cause epilepsy (GRIN2A) or intellectual disability (GRIN2B). GRIN2B mutations have also been linked with autism spectrum disorder.

steveandhongjie

Steve Traynelis and Hongjie Yuan

The new paper in the American Journal of Human Genetics makes a deep dive into ExAC data to explore the link between normal variation in the healthy population and regions of the proteins that harbor disease-causing mutations.

In addition, the paper provides a detailed look at how 25 mutations that were identified in individuals with neurologic disease actually affect the receptors. For some patients, this insight could potentially guide anticonvulsant treatment with a repurposed Alzheimer’s medication. Also included are three new mutations from patients identified by whole exome sequencing, one in GRIN2A and two in GRIN2B.

“This is one of the first analyses like this, where we’re mapping the spectrum of variation in a gene onto the structure of the corresponding protein,” says Traynelis, PhD, professor of pharmacology at Emory University School of Medicine. “We’re able to see that the disease mutations cluster where variation among the healthy population disappears.”

Heat map of agonist binding domain for GRIN2A.

Heat map of agonist binding domain for GRIN2A. From Swanger et al AJHG (2016).

Postdoctoral fellow Sharon Swanger, PhD is first author of the paper, and Yuan, MD, PhD, assistant professor of pharmacology, is co-senior author.

It’s not always obvious, looking at the sequence of a given mutation, how it’s going to affect NMDA receptor function. Only introducing the altered gene into cells and studying protein function in the lab provides that information, Traynelis says.

NMDA receptors are complicated machines: mutations can affect how well they bind their ligands (glutamate and glycine), how they open and shut, or how they are processed onto the cell surface. On top of that complexity, mutations that make the receptors either stronger or weaker can both lead the brain into difficulty; within each gene, both types of mutation are associated with similar disorders. With some GRIN2A mutations, the functional changes identified in the lab were quite strong, but the effect on the brain was less dramatic (mild intellectual disability or speech disorder), suggesting that other genetic factors contribute to outcomes.

Clinical relevance

Traynelis and Yuan previously collaborated with the NIH’s Undiagnosed Disease Program to show that the Alzheimer’s medication memantine can be repurposed as an anticonvulsant, for a child with intractable epilepsy coming from a mutation in the GRIN2A gene. (Nature Communications, Annals of Clinical and Translational Neurology)

Memantine is an NMDA receptor antagonist, aimed at counteracting the overactivation of the receptor caused by the mutation. Memantine has also been used to treat children with epilepsy associated with mutations in the related GRIN2D gene. However, memantine doesn’t work on all activating mutations, and could have effects on the unmutated NMDA receptors in the brain as well. Traynelis reports that his clinical colleagues are developing guidelines for physicians on the use of memantine for children with GRIN gene mutations.

This study and related investigations were supported by funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD082373), the National Institute of Neurological Disorders and Stroke (R24NS092989), the Atlanta Clinical & Translational Science Institute (UL1TR000454), and CURE Epilepsy: Citizens United for Research in Epilepsy.

 

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Bad neighbors cause bad blood -> cancer

Certain DNA mutations in bone cells that support blood development can drive leukemia formation in nearby blood stem cells, cancer researchers have found.

Many cancer-driving mutations are “cell-autonomous,” meaning the change in a cell’s DNA makes that same cell grow more rapidly. In contrast, an indirect neighbor cell effect was observed in a mouse model of Noonan syndrome, an inherited disorder that increases the risk of developing leukemia.

bone-marrow-300

In mouse bone marrow, mesenchymal stem cells (red), which normally nurture blood stem cells, produce a signal that is attractive for monocytes. The monocytes (green) prod nearby blood stem cells to proliferate, leading to leukemia. From Dong et al Nature (2016).

The findings were published Wednesday, October 26 in Nature.

The neighbor cell effect could be frustrating efforts to treat leukemias in patients with Noonan syndrome and a related condition, juvenile myelomonocytic leukemia (JMML). That’s because bone marrow transplant may remove the cancerous cells, but not the cause of the problem, leading to disease recurrence. However, the researchers show that a class of drugs can dampen the cancer-driving neighbor effect in mice. One of the drugs, maraviroc, is already FDA-approved against HIV infection.

“Our research highlights the importance of the bone marrow microenvironment,” says 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. “We found that a disease-associated mutation, which disturbs the niches where blood stem cell development occurs, can lead to leukemia formation.”

Editorial note: This Nature News + Views, aptly titled “Bad neighbors cause bad blood,” explains JMML, and how the relapse rate after bone marrow transplant is high (about 50 percent). It also notes that a variety of genetic alterations provoke leukemia when engineered into bone marrow stromal cells in mice (like this), but Qu and his colleagues described one that is associated with a known human disease.

Noonan syndrome often involves short stature, distinctive facial features, congenital heart defects and bleeding problems. It occurs in between one in 1000 to one in 2500 people, and can be caused by mutations in several genes. The most common cause is mutations in the gene PTPN11. Children with Noonan syndrome are estimated to have a risk of developing leukemia or other cancers that is eight times higher than their peers.
Read more

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