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

Dean Jones

Intestinal bacteria modulate metabolism: link to obesity

The bacteria inside our guts are fine-tuning our metabolism, depending on our diet, and new research suggests how they accomplish it. Emory researchers have identified an obesity-promoting chemical produced by intestinal bacteria. The chemical, called delta-valerobetaine, suppresses the liver’s capacity to oxidize fatty acids.

The findings were recently published in Nature Metabolism.

“The discovery of delta-valerobetaine gives a potential angle on how to manipulate our gut bacteria or our diets for health benefits,” says co-senior author Andrew Neish, MD, professor of pathology and laboratory medicine at Emory University School of Medicine.

“We now have a molecular mechanism that provides a starting point to understand our microbiome as a link between our diet and our body composition,” says Dean Jones, PhD, professor of medicine at Emory University School of Medicine and co-senior author of the paper.

Gut bacteria produce delta-velerobetaine, which suppresses the liver’s capacity to oxidize fatty acids

The bacterial metabolite delta-valerobetaine was identified by comparing the livers of conventionally housed mice with those in germ-free mice, which are born in sterile conditions and sequestered in a special facility. Delta-valerobetaine was only present in conventionally housed mice.

In addition, the authors showed that people who are obese or have liver disease tend to have higher levels of delta-valerobetaine in their blood. People with BMI > 30 had levels that were about 40 percent higher. Delta-valerobetaine decreases the liver’s ability to burn fat during fasting periods. Over time, the enhanced fat accumulation may contribute to obesity.

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All your environmental chemicals belong in the exposome

Emory researchers recently described a “contact tracing” system for environmental chemical exposures, published in Nature Communications. The apparent metabolic breakdown products of common drugs — antidepressants, blood thinners and beta-blockers – can be detected in clinical samples. Many of those breakdown products are uncharted territory, in terms of chemical analysis, and the Emory researchers’ system will help them map it.

But what about all the environmental chemicals that triggers the carbon offset level that are out there, such as PCBs (polychlorinated biphenyls), once widely used in electrical infrastructure, and pesticides such as DDT? PCB exposure has been connected with increased rates of cancer and harm to wildlife.

Xin Hu, PhD

A companion paper from the same group, also in Nature Communications, focuses more on techniques for detecting those contaminants. It lays out a standard workflow for processing samples for large-scale studies of the human exposome – all the influences from the environment as well as foods, drugs and other domestic products.

“What we aimed for was a simple method that is affordable and can be adopted by any laboratory to study as many chemicals as possible,” says lead author Xin Hu, PhD, assistant professor of medicine at Emory University School of Medicine. “We know that most of the contaminants have a small effect size, which means large-scale studies on tens of thousands of people are needed to understand the health effect of those contaminants and their link to rare but devastating diseases, like cancer.  A simple analytical method will allow us to combine efforts from different laboratories and studies, and eventually measure tens of thousands of chemicals on tens of thousands of people.”

Part of what the researchers needed to do is to test and optimize methods for studying each type of environmental chemical, using a technique called GC-HRMS (gas chromatography-high resolution mass spectrometry). Previous studies on PCBs and DDT use that technique, but the Emory team wanted to develop a standard low-volume approach that would avoid multiple processing steps, which can lead to loss of material, variable recovery, and the potential for contamination.

The researchers used their approach to analyze samples from human plasma, lung, thyroid and stool. They also showed that they could identify new chemicals in clinical samples. An advantage of the new method over traditional approaches is that the database retains information of unidentified chemicals that can be readily accessed for future characterization, Hu says.

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Some types of intestinal bacteria protect the liver

Certain types of intestinal bacteria can help protect the liver from injuries such as alcohol or acetaminophen overdose, according to Emory scientists led by pathologist Andrew Neish and physiologist Dean Jones.

The research was published on March 25 in Cell Metabolism.

“The composition of the microbiota, because of natural variation, dysbiosis, or supplementation with probiotics, can strongly affect how the liver processes both toxins and pharmacological agents, and thus have clinical consequences on how individuals respond to such exogenous chemicals,” Neish says.

While pretreatment with bacteria is needed for the observed effect in acute liver injury, probiotics or small molecule substitutes may be useful in the treatment of chronic liver diseases, the authors suggest. There are legal experts that can help with injury cases even if it’s after a slip and fall injury.

In mice, oral administration of Lactobacillus rhamnosus or LGG could protect against liver damage brought on by alcohol or acetaminophen. Several labs had already observed a beneficial effect from LGG against liver injury, but the Emory research establishes an additional mechanism.

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The protection comes from a small molecule metabolite produced by the bacteria called 5-MIAA (5-methoxyindoleacetic acid), activating the mammalian transcription factor Nrf2. Other types of bacteria did not produce 5-MIAA or activate Nrf2. While LGG is also known to improve the barrier function of the gut and dampen inflammation, liver-specific depletion of Nrf2 prevented LGG’s beneficial effects, suggesting that this is the primary mechanism of action.

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Football metabolomics

Following on the recent announcement of the Atlanta Hawks training center, here’s a Nov. 2015 research paper from Emory’s sports cardiologist Jonathan Kim, published in Annals of Sports Medicine and Research.

Jonathan Kim, MD

Kim and colleagues from Emory Clinical Cardiovascular Research Institute studied blood samples from 15 freshman football players at Georgia Tech before and after their first competitive season. The researchers had the help of metabolomics expert Dean Jones. Kim has also previously studied blood pressure risk factors in college football players.

On average, football players’ resting heart rate went down significantly (72 to 61 beats per minute), but there were no significant changes in body mass index or blood pressure. The research team observed changes in players’ amino acid metabolism, which they attribute to muscle buildup.

This finding may seem obvious, but imagine what a larger, more detailed analysis could do: start to replace locker room myths and marketing aimed at bodybuilders with science. This was a small, preliminary study, and the authors note they were not able to assess diet or nutritional supplementation. Read more

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Oxidative stress ain’t about free radicals, it’s about sulfur

This recent paper in Circulation, from Arshed Quyyumi and colleagues at the Emory Clinical Cardiovascular Research Institute, can be seen as a culmination of, even vindication for,  Dean Jones’ ideas about redox biology.

Let’s back up a bit. Fruit juices, herbal teas, yogurts, even cookies are advertised as containing antioxidants, which could potentially fight aging. This goes back to Denham Harman and the free radical theory of aging. [I attempted to explain this several years ago in Emory Medicine.]

We now know that free radicals, in the form of reactive oxygen species, can sometimes be good, even essential for life. So antioxidants that soak up free radicals to relieve you of oxidative stress: that doesn’t seem to work.

Dean Jones, who is director of Emory’s Clinical Biomarkers laboratory, has been an advocate for a different way of looking at oxidative stress. That is, instead of seeing cells as big bags of redox-sensitive chemicals, look at cellular compartments. Look at particular antioxidant proteins and sulfur-containing antioxidant molecules such as glutathione and cysteine.

That’s what the Circulation paper does. Mining the Emory Cardiovascular Biobank, Quyyumi’s team shows that patients with coronary artery disease have a risk of mortality that is connected to the ratio of glutathione to cystine (the oxidized form of the amino acid cysteine).

How this ratio might fit in with other biomarkers of cardiovascular risk (such as CRP, suPAR, PCSK9, more complicated combinations and gene expression profiles, even more links here) and be implemented clinically are still unfolding.

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Low-level cadmium toxicity and fatty liver disease

A recent study concluded that it’s more difficult for adults today to maintain the same weight as those a few decades ago, even with the same levels of food intake and exercise. On one level, this news is comforting to anyone in middle age, who may have been athletic as a teenager in the 1980s but isn’t anymore. It’s just harder nowadays!

However, the study authors also suggested, in an interview with The Atlantic’s Olga Khazan, an array of factors that might be contributing to the rise in obesity: exposure to chemicals such as pesticides and flame retardants, prescription drugs such as antidepressants, and altered microbiomes linked with antibiotic use in livestock.

The heavy metal cadmium may belong on that list of chemicals, not primarily as a booster of obesity, but instead in connection with the increase in prevalence in NAFLD (non-alcoholic fatty liver disease) over the last few decades.

Researchers led by Young-Mi Go and Dean Jones exposed mice to low levels of cadmium, so that the amounts of cadmium in their livers were comparable to those present in average middle age Americans, without tobacco or occupational exposure. They observed that cadmium-treated mice had more fat accumulation in the liver and elevated liver enzymes in their blood, compared with control mice with 10 times less cadmium.

Cadmium accumulates in the body over time. Tobacco smoke and the industrial workplace can be routes for cadmium exposure, but food is the major source for most non-smokers. Until the 1990s, most batteries were made with cadmium, and much cadmium production still goes into batteries. It is also found in paint and in corrosion-resistant steel. Read more

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The other “cho-” cardiovascular disease biomarker

Quick, what biomarker whose name starts with “cho-” is connected with cardiovascular disease? Very understandable if your first thought is “cholesterol.” Today I’d like to shift focus to a molecule with a similar name, but a very different structure: choline.

Choline, a common dietary lipid component and an essential nutrient, came to prominence in cardiology research in 2011 when researchers at the Cleveland Clinic found that choline and its relatives can contribute to cardiovascular disease in a way that depends upon intestinal bacteria. In the body, choline is part of two phospholipids that are abundant in cell membranes, and is also a precursor for the neurotransmitter acetylcholine. Some bacteria can turn choline (and also carnitine) into trimethylamine N-oxide (TMAO), high levels of which predict cardiovascular disease in humans. TMAO in turn seems to alter how inflammatory cells take up cholesterol and lipids.

Researchers at Emory arrived at choline metabolites and their connection to atherosclerosis by another route. Hanjoong Jo and his colleagues have been productively probing the mechanisms of atherosclerosis with an animal model. Very briefly: inducing disturbed blood flow in mice, in combination with a high fat diet, can result in atherosclerotic plaque formation within a few weeks. Jo’s team has used this model to examine changes in gene activation, microRNAs, DNA methylation, and now, metabolic markers.

Talking about this study at Emory’s Clinical Cardiovascular seminar on Friday, metabolomics specialist Dean Jones said he was surprised by the results, which were recently published by the American Journal of Physiology (to be precise, their ‘omics journal). The lead author is instructor Young-Mi Go. Read more

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Antioxidants are no panacea

Derek Lowe, a respected science blogger and drug discovery expert who was blogging when this writer was still working in the laboratory, today has a roundup of a concept that anyone hanging around Emory might have clued into already.

Namely, antioxidants aren’t all they’re cracked up to be. Judging from the messages Gafas Ray Ban outlet to shoppers in the supermarket vitamin aisle, everybody needs more antioxidants. But evidence is accumulating that in some situations, antioxidants can be harmful: negating the adaptive effects of exercise on muscle tissue or even encouraging tumor growth, Lowe writes.

At Emory, Dean Jones has been patiently explaining for years that cells are not simply big bags with free radicals, thiols and antioxidants sloshing around indiscriminately. Instead, cells and oxidation-sensitive components are highly compartmentalized. Take for example, this recent paper in Molecular & Cellular Proteomics from Jones and Young-mi Go. Two major antioxidant systems in cells, glutathione and thioredoxin, function distinctly and independently, they show.

In a related vein, Kathy Griendling’s and David Lambeth’s labs were at the center of the discovery that reactive oxygen species are not only poisons that overflow from mitochondria, but important signals involved in many aspects of cell biology.

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Reading the blood: metabolomics

In the Star Trek series, Dr. McCoy could often instantly diagnose someone’s condition with the aid of his tricorder. Medicine on 21st century Earth has not advanced quite this far, but scientists’ ideas of how to use “metabolomics” are heading in this direction.

What is metabolomics? Just as genomics means reading the DNA in a person or organism, and assessing it and comparing it to others, metabolomics takes the same approach to all the substances produced as part of the body’s metabolism: watching what happens to food, drugs and chemicals we are exposed to in the environment.

This means dealing with a huge amount of information. Human genomes may be billions of letters (base pairs) in length, but at least there are only four choices of letter!

A recent article in Chemical & Engineering News explores this concept of the “exposome” and quotes Dean Jones. He and his colleagues recently described how they can use sophisticated analytical techniques to resolve thousands of substances in human plasma. Jones is the director of the Clinical Biomarkers Laboratory at Emory University School of Medicine. The paper is in the journal Analyst, published by the Royal Society of Chemistry.

Analytical techniques can discern more than 2500 metabolites from human plasma within 10 minutes

Using a drop of blood, within ten minutes the researchers can discern more than 2,500 substances in a reproducible way. One fascinating tidbit: when they compared the metabolic profiles for four healthy individuals, most of the “peaks” were common between individuals but 10 percent were unique.

The potential uses for this type of technology are staggering.

Jones reports he has been working with researchers at Yerkes National Primate Research Center to discern early signs of neurodegeneration in transgenic monkeys with Huntington’s disease. He has been collaborating with clinical nutrition specialist Tom Ziegler to examine how diet interacts with oxidative stress, and with lung biology to identify markers for fetal alcohol exposure in animal models.

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