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

Take heart, Goldilocks — and get more sleep

Sleeping too little or too much increases the risk of cardiovascular events and death in those with coronary artery disease, according to a new paper from Emory Clinical Cardiovascular Research Institute.

Others have observed a similar U-shaped risk curve in the general population, with respect to sleep duration. The new study, published in American Journal of Cardiology, extends the finding to people who were being evaluated for coronary artery disease.

Arshed Quyyumi, MD and colleagues analyzed data from a registry of 2846 patients undergoing cardiac catheterization at Emory. The “sweet spot” appeared to be those who report sleeping between 6.5 and 7.5 hours per night.

39 percent of patients with coronary artery disease reported that they slept fewer than 6.5 hours per night, and 35 percent slept longer than 7.5 hours. For the next few years, both groups had higher risks of all-cause mortality: elevated risk of 45 percent and 41 percent, respectively. Patients were followed for an average of 2.8 years.

The extreme ends of sleep duration both had even higher risk: people who reported less than 4.5 hours per day had almost double mortality risk (96 percent), and those more than 8.5 hours had 84 percent higher mortality risk.

Patients with short sleep durations also had higher cardiovascular mortality (48 percent), but adjusting for cardiovascular risk factors attenuated the association between long sleep duration and CV risk.

A detailed assessment of someone’s sleep can require PSG (polysomnography). In this study,  researchers were able to get information by simply asking about sleep duration.

The participants in the Emory study were simply asked: “How many hours of sleep do you usually get each night (or when you usually sleep)?” This question may not always be answered accurately, since time in bed isn’t necessarily time asleep. Still, the broad strokes show that the sleep-CV health relationship is robust.

“What is most stunning to me are that these data were collected from cardiac patients about to undergo an invasive procedure, who still reported an aspect of their sleep that was meaningful and predictive of future survival,” says Donald Bliwise, PhD, a specialist in sleep and aging research who is a co-author on the Emory study. “Often, epidemiologic studies collect data far away from a clinic setting, where anxiety is less and estimations may be sharper. We have here in this clinical study beautiful evidence that estimates made ‘from the gurney’ may be just as meaningful as those collected in the field.”

Quyyumi says if patients with heart disease are sleeping poorly, it’s important to recognize that they are at higher risk and counsel them regarding getting more sleep, as well as factors that can disrupt sleep, such as caffeine, alcohol and looking at screens late in the day.

More specific treatments may depend what is interfering with high-quality sleep in a given patient. Several conditions can lead to difficulty sleeping, such as sleep apnea, restless leg syndrome, as well as depression, all of which have been linked with heart disease. Physiologically, several mechanisms are probably exerting their effects, such as weakening circadian rhythms and sleep fragmentation with aging, and obesity/metabolic syndrome driving inflammation. Read more

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Repurposing a transplant drug for bone growth

The transplant immunosuppressant drug FK506, also known as tacrolimus or Prograf, can stimulate bone formation in both cell culture and animal models. This info comes from orthopedics researcher Nick Willett, PhD and colleagues, published in International Journal of Molecular Sciences (open access).

Nick Willett, PhD

The results suggest that FK506 might be repurposed as a “stand-alone” replacement for recombinant BMP-2 (bone morphogenic protein 2). That product has been a huge commercial success for Medtronic, in the context of spinal fusion surgeries, although controversial because of cost and side effects.

BMP-2 is more potent gram for gram, but FK506 still may offer some opportunities in local delivery. From Sangadala et al (2019)

One of Willett’s co-authors is orthopedics chair Scott Boden, MD, whose lab previously developed a system to search for drugs that could enhance BMP-2. Previously, other researchers had observed that FK506 can enhance the action of BMP-2 – this makes sense because FK506’s target protein is a regulator of the BMP pathway. Willett’s team used FK506 on its own, delivered in a collagen sponge.

“That is the big finding here, that it has the potential to be used on its own without any BMP-2,” he says.

The sponge is a possible mechanism for getting the drug to tissues without having too many systemic effects. Willett’s lab is now working on refining delivery, dosing and toxicity, he says.

Willett, based at the Atlanta VA Medical Center, is in the Department of Orthopedics and the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. He and Sree Sangadala, PhD (first author of the IJMS paper) currently have a grant from National Center for Advancing Translational Sciences on this project.

 

 

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Beyond the amyloid hypothesis: proteins that indicate cognitive stability

If you’re wondering where Alzheimer’s research might be headed after the latest large-scale failure of a clinical trial based on the “amyloid hypothesis,” check this out.

Plaques. Tangles. Clumps. These are all pathological signs of neurodegenerative diseases that scientists can see under the microscope. But they don’t explain most of the broader trends of cognitive resilience or decline in aging individuals. What’s missing?

A recent proteomics analysis in Nature Communications from Emory researchers identifies key proteins connected with cognitive trajectory – meaning the rate at which someone starts to decline and develop mild cognitive impairment or dementia.

This paper fits in with the multi-year push for “unbiased” Alzheimer’s/aging research at Emory. The lead and senior authors are Aliza and Thomas Wingo, with proteomics from biochemist Nick Seyfried and company.

The proteins the Emory team spotlights are not the usual suspects that scientists have been grinding on for years in the Alzheimer’s field, such as beta-amyloid and tau. They’re proteins connected with cellular energy factories (mitochondria) or with synapses, the connections between brain cells.

“Our most notable finding is that proteins involving mitochondrial activities or synaptic functions had increased abundance among individuals with cognitive stability regardless of the burden of β-amyloid plaques or neurofibrillary tangles,” the authors write. “Taken together, our findings and others highlight that mitochondrial activities would be a fruitful research target for early prevention of cognitive decline and enhancement of cognitive stability.” Read more

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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 biologist in Emory’s Department of Human Genetics. “She started asking about vomiting and other specific symptoms.”

Her son had tested positive by newborn screening for a rare disorder called galactosemia. Galactosemia is an inherited disease that results from inability to metabolize galactose, a component of human milk and cow-milk-based formula. If a baby with “classic” galactosemia continues to drink milk, the baby may quickly develop symptoms such as jaundice, vomiting and diarrhea, progressing to liver disease and other serious complications that can lead to infant death. If a newborn has classic galactosemia, it is critical for the baby to stop drinking milk and switch to a low-galactose formula, such as soy-based formula, as soon as possible.

Caspary and Katz, a cell biologist, learned several days later that their son did not have classic galactosemia but instead had inherited Duarte galactosemia, a milder, more common form of the metabolic disorder, affecting more than 1 in 5,000 children in the United States. But there was still a looming question.

“We needed to figure out what to feed the baby!” Katz exclaimed, recalling their confusion years later.

The looming question was: what to feed the baby?

Their pediatrician didn’t know what to recommend. Galactosemia, in whatever form, is rare enough in the US that most pediatricians don’t develop experience with it. There was no uniform standard of care, and state-level guidelines for children with Duarte galactosemia varied widely, from no dietary restrictions to banning all milk products for the first year. Some of the limited research available at the time suggested that affected children might experience developmental problems as they grew up. Read more

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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 the network of proteins found in human cells, both from individuals affected by 22q11 deletion syndrome and their healthy relatives.

The results are published in Journal of Neuroscience. Note: this is a sprawling paper, involving both proteomics (courtesy of Nick Seyfried, whose Emory epithet is “wizard”) and mutant Drosophila fruit flies. There are four co-first authors: Avanti Gokhale, Cortnie Hartwig, Amanda Freeman and Julia Bassell.

Victor Faundez, PhD

Mitochondrial proteins are important for keeping cells fueled up and in metabolic balance, but how does altering them affect the brain in a way that leads to schizophrenia? That’s the overall question: how do changes in the miniature power plants within the cell affect synapses, the junctions between cells?

The scientists were focusing on one particular mitochondrial protein, SLC25A1, whose corresponding gene is in the 22q11 deletion. Faundez says that SCL25A1 has been largely ignored by other scientists studying 22q11.

“We think SLC25A1 exerts a powerful influence on the neurodevelopmental phenotypes in 22q11,” he says. “Our main focus forward is going to be the function that mitochondria play in synapse biology.” Read more

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Fetal alcohol cardiac toxicity – in a dish

Alcohol exposure is known to perturb fetal heart development; half of all children with fetal alcohol syndrome have congenital heart defects, such as arrhythmias or structural abnormalities. Chunhui Xu and colleagues recently published a paper in Toxicological Scienceson how human cardiac muscle cells, derived from iPS (induced pluripotent stem cells), can be used as a model for studying the effects of alcohol.

Alcohol-induced cardiac toxicity is usually studied in animal models, but human cells are different, and a cell-culture based approach could make it easier to study the effects of alcohol and possible interventions more easily.

Red shows toxic effects of alcohol on iPS-derived cardiomyocytes

Xu and her colleagues observed that high levels of alcohol damaged cardiac muscle cells and put them under oxidative stress. But even at relatively low concentrations of alcohol, the researchers also saw perturbations in cells’ electrical activity and the ability to contract, which reasonably matches the effects of alcohol on human heart development. The lowest level tested was 17 millimolar – the legal limit for driving in most states (0.08% blood alcohol content). Read more

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Fighting cancer with combinatorial imagination

In his undergraduate days, Winship Cancer Institute dermatologist and cancer researcher Jack Arbiser was an organic chemist. That may be why he recognized an organic synthesis reagent based on the metal palladium as a potential anti-cancer drug.

We’re talking about Tris-DBA-palladium. Arbiser and colleagues showed in a 2008 Clinical Cancer Research paper that this deep purple stuff (see photo) is active against melanoma, and since then, against other types of cancer such as pancreatic cancer, multiple myeloma, and CLL leukemia.

Tris-DBA-PD has a deep purple color. The palladium atoms can be seen in the diagram as two blue balls at the center. From Wikipedia.

Since it’s used in organic synthesis, you might expect Tris-DBA-palladium not to be very soluble in water. A new paper in Scientific Reports demonstrates that this issue can be addressed by hooking up the reagent to nanoparticles made of hyaluronic acid, which targets tumor cells. They are effective against melanoma in mice, the paper shows.

“We have already demonstrated that Tris DBA palladium by itself has activity against melanoma in mice,” Arbiser writes (in his VA grant summary). “However, we believe that we can make Tris DBA palladium into an even more powerful drug by adding it to nanoparticles that are guided to the tumor.”

In an email to Lab Land, Arbiser says he arrived at Tris-DBA-palladium by using his chemist’s imagination, in a “your chocolate landed in my peanut butter” kind of way.

“I got the idea for looking at this compound because it is a complex of Pd with a curcumin-like structure, and I figured it might have the characteristics of platinum and curcumin together,” he says. Read more

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Sifting through signs of inflammation to analyze causes of Crohn’s disease

When studying Crohn’s disease – an inflammatory disorder of the gastrointestinal tract, a challenge is separating out potential causes from the flood of systemic inflammation inherent in the condition. Researchers led by Subra Kugathasan, MD recently published an analysis that digs under signs of inflammation, in an effort to assess possible causes.

Graduate student Hari Somineni, in Kugathasan’s lab, teamed up with Emory and Georgia Tech geneticists for a sophisticated approach that may have found some gold nuggets in the inflammatory gravel. The results were published in the journal Gastroenterology.

In studying Crohn’s disease, Emory + Georgia Tech researchers may have found some gold nuggets in the inflammatory gravel.

The group looked at DNA methylation in blood samples from pediatric patients with Crohn’s disease, both at diagnosis and after treatment and follow-up. The information came from blood samples from 164 children with Crohn’s disease and 74 controls, as part of the RISK study, which is supported by the Crohn’s & Colitis Foundation and Kugathasan leads.

DNA methylation is a dynamic process that can influence molecular phenotypes of complex diseases by turning the gene(s) on or off. The researchers observed that disrupted methylation patterns at the time of diagnosis in pediatric Crohn’s disease patients returned to those resembling controls following treatment of inflammation

“Our study emphasized how important it is to do longitudinal profiling – to look at the patients before and after treatment, rather than just taking a cross section,” Somineni says.

Read more

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Predict the future of critical care in #STATMadness

Emory is participating in STAT Madness, a “March Madness” style bracket competition featuring biomedical research advances instead of basketball teams. Universities or research institutes nominate their champions, research papers that were published the previous year. It’s like “Battle of the Bands.” Whoever gets the loudest — or most numerous — cheers wins.

Please check out all 64 entries, follow the 2019 STAT Madness bracket and vote here:
https://www.statnews.com/feature/stat-madness/bracket/

Emory’s entry for 2019:
It’s like the “precogs” who predict crime in the movie Minority Report, but for sepsis, the deadly response to infection. Shamim Nemati and colleagues have been exploring ways to analyze vital signs in ICU patients and predict sepsis, hours before clinical staff might otherwise notice.

As landmark clinical studies have documented, every hour of delay in giving someone with sepsis antibiotics increases their risk of mortality. So detecting sepsis as early as possible could save thousands of lives. Many hospitals have developed “sniffer” systems that monitor patients for sepsis, but this algorithm tries to spot problems way before they become apparent.

As published in 2018 in Critical Care Medicine, the algorithm can predict sepsis onset—with some false alarms—four, eight, even 12 hours ahead of time. No algorithm is going to be perfect, but it was better than any other previous sepsis predictor. The technology is headed for additional testing and evaluation at several medical centers, as part of a project supported by the federal Biomedical Advanced Research and Development Authority (BARDA).

You can fill out a whole bracket or you can just vote for Emory. The contest will last several rounds. The first round began on Monday, March 4, and lasts until the end of the week. Before 10 am Eastern time Monday morning, there were already more than 5,000 brackets entered!

If Emory advances, then people will be able to continue voting for us starting on Friday. Emory’s first opponent is a regional rival, Vanderbilt University School of Medicine. We are on the upper left side of the bracket.

STAT News is a Boston-based news organization covering biomedical research, pharma and biotech. If you feel like it, please share on social media using the hashtag #statmadness.

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Sensitive to (transplant) rejection

An experimental screening method, developed by Emory and Georgia Tech scientists, aims to detect immune rejection of a transplanted organ earlier and without a biopsy needle.

The technology is based on nanoparticles that detect granzyme B enzymes produced by killer T cells. When the T cells are active, they slice up the nanoparticles, generating a fluorescent signal that is detectable in urine. The results from a mouse skin graft model were published in Nature Biomedical Engineering, from Gabe Kwong’s lab at GT and Andrew Adams’ at Emory. More extensive story here.

Co-first authors Quoc Mac and Dave Mathews

Adams is also developing technologies for imaging transplant rejection via immunoPET, with Georgia Tech’s Phil Santangelo.

 

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