Two Emory graduate students, Anzar Abbas and Katie Strong, will be spending the summer testing their communication skills as part of the AAAS Mass Media fellowship program. The program is supposed to promote science communication by giving young scientists a taste of what life is like at media organizations around the country. Both of Emory's fellows have already gained some experience in this realm.
Abbas, a Neuroscience student who recently joined brain imaging number cruncher Shella Keilholz's lab, will be at Howard Hughes Medical Institute. He is part of the group that recently revived the Science Writers at Emory publication In Scripto.
Strong, a Chemistry student working with Dennis Liotta on selective NMDA receptor drugs, will be at the Sacramento Bee. She has been quite prolific at the American Journal of Bioethics Neuroscience and its Neuroethics Blog.
(Thanks to Ian Campbell, a previous AAAS Mass Media fellow from Emory, for notifying me on this!)
Genetic variation and exposure to pesticides both appear to affect risk for Parkinson's disease. A new study has found a connection between these two risk factors, in a way that highlights a role for immune responses in progression of the disease.
The results are published in the inaugural issue of NPJ Parkinson's Disease.
The findings implicate a type of pesticide called pyrethroids, which are found in the majority of commercial household insecticides, and are being used more in agriculture as other insecticides are being phased out. Although pyrethroids are neurotoxic for insects, exposure to them is generally considered safe for humans by federal authorities.
The study is the first making the connection between pyrethroid exposure and genetic risk for Parkinson's, and thus needs follow-up investigation, says co-senior author Malu Tansey, PhD, associate professor of physiology at Emory University School of Medicine.
The genetic variation the team probed, which has been previously tied to Parkinson's in larger genome-wide association studies, was in a non-coding region of a MHC II (major histocompatibility complex class II) gene, part of a group of genes that regulate the immune system.
"We did not expect to find a specific association with pyrethroids," Tansey says. "It was known that acute exposure to pyrethroids could lead to immune dysfunction, and that the molecules they act on can be found in immune cells; now we need to know more about how longer-term exposure affects the immune system in a way that increases risk for Parkinson's."
"There is already ample evidence that brain inflammation or an overactive immune system can drive the progression of Parkinson's. What we think may be happening here is that environmental exposures may be altering some people's immune responses, in a way that promotes chronic inflammation in the brain."
For this study, Emory investigators led by Tansey and Jeremy Boss, PhD, chair of microbiology and immunology, teamed up with Stewart Factor, DO, head of Emory's Comprehensive Parkinson's Disease Center, and public health researchers from UCLA led by Beate Ritz, MD, PhD. The first author of the paper is MD/PhD student George T. Kannarkat.
The UCLA researchers used a California state geographical database covering 30 years of pesticide use in agriculture. They defined exposure based on proximity (someone's work and home addresses), but did not measure levels of pesticides in the body. Pyrethroids are thought to decay relatively quickly, especially in sunlight, with half-lives in soil of days to weeks.
In a group of 962 people from California's Central Valley, a common MHC II variant combined with above-average exposure to pyrethroid pesticides to increase the risk of Parkinson's disease. The riskiest form of the gene (where an individual is carrying two risk alleles) was found in 21 percent of Parkinson's patients and 16 percent of controls.
In this group, genes or pyrethroid exposure by themselves did not significantly increase Parkinson's risk, but together, they did. People with more-than-average exposure to pyrethroids and carrying the riskiest form of the MHC II gene had 2.48 times more risk for Parkinson's than less-exposed people with the least risky gene form. Exposure to other types of pesticides such as organophosphates or paraquat did not heighten risk in the same way.
Larger genetic studies (some including Factor and his patients) have previously identified variations in MHC II genes as having connections to Parkinson's. Puzzlingly, the same genetic variants affect Parkinson's risk differently in Caucasian/European and Chinese populations. MHC II genes are highly variable between individual humans; that's why they play a big role in organ transplant matching.
Other experiments showed that the genetic variant connected to Parkinson's is connected with immune cell function. In a group of 81 Parkinson's patients and control participants from Emory of European ancestry the immune cells from people who had the higher-risk MHC II gene variant studied in California displayed more MHC molecules on their surfaces, the researchers found.
MHC molecules are central to the process of "antigen presentation," a driver for T cells to become activated and have the rest of the immune system get involved. Heightened expression of MHC II was present in resting cells from both Parkinson's patients and healthy controls; but greater responsiveness to immune challenges were observed in Parkinson's patients with the higher risk genotype.
The authors conclude: "Our data suggest that cellular biomarkers (like MHC II activation) may prove more useful than soluble molecules in plasma and cerebrospinal fluid to identify individuals at risk for disease or for patient recruitment into neuroprotective trials testing immunomodulatory drugs."
Drug discovery veteran Dennis Liotta and his team continue to look for ways to fight against HIV. Working with pharmaceutical industry colleagues, he and graduate student Anthony Prosser have discovered compounds that are active against three different targets: immune cells’ entry gates for the virus (CCR5 and CXCR4), and the replication enzyme reverse transcriptase. That’s like one arrow hitting three bulls eyes. An advantage for these compounds: it could be less likely for viral resistance to develop.
For more, please go to the American Chemical Society — there will be a press conference from the ACS meeting in Denver on Monday, and live YouTube.
A risk calculator for cardiovascular disease, developed as a companion for the 2013 American College of Cardiology/American Heart Association cholesterol guidelines, may account for racial differences in sub-clinical vascular function better than the Framingham Risk Score, Emory cardiology researchers say.
African Americans, especially men, tend to have a higher prevalence of cardiovascular disease, but this differences are not reflected in the Framingham Risk score. Arterial stiffness is a sign of heart disease risk that tends to appear more prominently among African Americans than whites. Cardiovascular research fellow Jia Shen, MD, MPH, and Emory colleagues analyzed data on arterial stiffness and structure from 1235 people – 777 whites and 458 African-Americans — enrolled in two large studies (Center for Health Discovery and Well Being and META-Health). Read more
MicroRNAs have emerged as important master regulators in cells, since each one can shut down several target genes. Riding on top of the master regulators is Drosha, the RNA-cutting enzyme that initiates microRNA processing in the nucleus. Drosha and its relative Dicer have been attracting attention in cancer biology, because they are thought to be behind a phenomenon where cancerous cells can “infect” their healthy neighbors via tiny membrane-clothed packets called exosomes.
At Emory, pharmacologist Zixu Mao and colleagues recently published in Molecular Cell their findings that Drosha is regulated by stress (experimentally: heat or peroxide) through p38 MAP kinase.
Our recent news item on Emory pathologist Keqiang Ye’s obesity-related research (Molecule from trees helps female mice only resist weight gain) understates how many disease models the proto-drug he and his colleagues have discovered, 7,8-dihydroxyflavone, can be beneficial in. We do mention that Ye’s partners in Australia and Shanghai are applying to begin phase I clinical trials with a close relative of 7,8-dihydroxyflavone in neurodegenerative diseases.
The increasing clinical use of next generation sequencing, especially whole exome and whole genome, continues to be a hot topic. The ability to contribute to diagnosis, clinical utility, incidental findings and whether insurance will cover next-gen sequencing are all changing.
A Nature Medicine article lays out a lot of the emerging business issues on next-gen sequencing. On the topic of incidental findings, Buzzfeed science editor Virginia Hughes last week reported stories of women who receive a cancer diagnosis as a result of having a prenatal genetic test.
“These cases, though extremely rare, are raising ethical questions about the unregulated – and rapidly evolving – genetic-testing industry,” Buzzfeed says.
At a recent Department of Pediatrics seminar, Emory geneticist Michael Gambello described examples of how whole exome sequencing, performed to diagnose intellectual disability or developmental problems in a child, can uncover cancer or neurodegenerative disease risk mutations in a parent. The question becomes, whether to notify the parent for something that may or may not be actionable. This is why Emory Genetics Laboratory’s whole exome sequencing service has an extensive “opt-in/opt-out” consent process.
Emory Genetics Laboratory executive director Madhuri Hegde, working with the Association of Molecular Pathology, has been a leader in pushing genetic testing laboratories to adopt best practices. Read more
Everything is connected, especially in the brain. A protein called BAI1 involved in limiting the growth of brain tumors is also critical for spatial learning and memory, researchers have discovered.
Mice missing BAI1 have trouble learning and remembering where they have been. Because of the loss of BAI1, their neurons have changes in how they respond to electrical stimulation, and subtle alterations in parts of the cell needed for information processing.
Erwin Van Meir, PhD, and his colleagues at Winship Cancer Institute of Emory University have been studying BAI1 (brain-specific angiogenesis inhibitor 1) for several years. Part of the BAI1 protein can stop the growth of new blood vessels, which growing cancers need. Normally highly active in the brain, the BAI1 gene is lost or silenced in brain tumors, suggesting that it acts as a tumor suppressor.
The researchers were surprised to find that the brains of mice lacking the BAI1 gene looked normal anatomically. They didn’t develop tumors any faster than normal, and they didn’t have any alterations in their blood vessels, which the researchers had anticipated based on BAI1’s role in regulating blood vessel growth. What they did have was problems with spatial memory.
In the 1990s, neuroscientists identified a class of drugs that showed promise in the area of stroke. NMDA receptor antagonists could limit damage to the brain in animal models of stroke. But one problem complicated testing the drugs in a clinical setting: the side effects included disorientation and hallucinations.
Now researchers have found a potential path around this obstacle. The results were published in Neuron.
“We have found neuroprotective compounds that can limit damage to the brain during ischemia associated with stroke and other brain injuries, but have minimal side effects,” says senior author Stephen Traynelis, PhD, professor of pharmacology at Emory University School of Medicine.
“These compounds are most active when the pH is lowered by biochemical processes associated with injury of the surrounding tissue. This is a proof of concept study that shows this mechanism of action could potentially be exploited clinically in several conditions, such as stroke, traumatic brain injury and subarachnoid hemorrhage.” Read more
A recent publication from Bill Kaiser’s and Ed Mocarski’s labs in Cell Host & Microbe touches on a concept that needs explaining: oncolytic viruses.
Viruses have been subverting the machinery of healthy cells for millions of years, and many viruses tend to infect particular tissues or cell types. So they are a natural starting point for researchers to engineer oncolytic viruses, which preferentially infect and kill cancer cells.