Insights into Parkinson's balance problems

In PD, disorganized sensorimotor signals cause muscles in the limbs to contract, such that both a muscle promoting a motion and its antagonist muscle are Read more

Cajoling brain cells to dance

“Flicker” treatment is a striking non-pharmaceutical approach aimed at slowing or reversing Alzheimer’s disease. It represents a reversal of EEG: not only recording brain waves, but reaching into the brain and cajoling cells to dance. One neuroscientist commentator called the process "almost too fantastic to believe." With flashing lights and buzzing sounds, researchers think they can get immune cells in the brain to gobble up more amyloid plaques, the characteristic clumps of protein seen in Read more

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Brain organoid model shows molecular signs of Alzheimer’s before birth

In a model of human fetal brain development, Emory researchers can see perturbations of epigenetic markers in cells derived from people with familial early-onset Alzheimer’s disease, which takes decades to appear. This suggests that in people who inherit mutations linked to early-onset Alzheimer’s, it would be possible to detect molecular changes in their brains before birth.

The results were published in the journal Cell Reports.

“The beauty of using organoids is that they allow us to trace back what could happen at the molecular level in early developmental stages,” says lead author Bing Yao, PhD, assistant professor of human genetics at Emory University School of Medicine. “A lot of epigenetic studies on Alzheimer’s use postmortem brains, which only represent the end point of the disease, in terms of molecular signatures.”

Photos of brain organoid cultures courtesy of Zhexing Wen

The brain organoid model allows scientists to probe human fetal brain development without poking into any babies; they have also been used to study schizophrenia, fragile X syndrome and susceptibility to Zika virus.

Co-author Zhexing Wen helped develop the model, in which human pluripotent stem cells recapitulate early stages of brain development, corresponding to 17-20 weeks after conception. The stem cell lines were obtained from both healthy donors and from people with mutations in PSEN1 or APP genes, which lead to early-onset Alzheimer’s.

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“Trojan horse” antibiotic underperforms; does heteroresistance explain?

A stealthy form of antibiotic resistance may be limiting the effectiveness of a new weapon against bacterial infections, research from Emory’s Antibiotic Resistance Center suggests.

The antibiotic cefiderocol (Fetroja) was developed by the Japanese company Shionogi, and was FDA-approved for the treatment of complicated urinary tract infections in 2019 and for hospital-acquired bacterial pneumonia in 2020.

In a recent international clinical trial testing cefiderocol in patients with serious infections resistant to carbapenems (CREDIBLE-CR), outcomes weren’t significantly better for cefiderocol, compared to patients who received the best available therapy otherwise. In addition, mortality was actually higher for patients treated with cefiderocol.

Resistance to carbapenems, a common class of antibiotics, is a major problem and precisely what cefiderocol was meant to circumvent. These results have had infectious disease experts asking why cefiderocol didn’t perform better, and wondering what place it should take in physicians’ tool boxes.

Cefiderocol has been touted as a “Trojan horse” antibiotic

Emory scientists think that cefiderocol’s effectiveness may have been undermined by heteroresistance, in which a small subpopulation of bacteria is already resistant to a given antibiotic before it is applied. Heteroresistance is often missed by standard tests.

Researchers led by David Weiss, director of Emory’s Antibiotic Resistance Center, surveyed bacterial samples from the Georgia Emerging Infections program, reporting their findings in Lancet Infectious Diseases.

Postdoc Jacob Choby and senior research specialist Tugba Ozturk were the primary surveyors.

They discovered that heteroresistance to cefiderocol was widespread in samples from Georgia, ranging from 9 to 59 percent, depending on the type of bacteria. Weiss acknowledges that he and his colleagues are making indirect inferences about the bacterial infections from the CREDIBLE-CR trial; they would like to test such strains directly in the future.

Still, the prevalence of cefiderocol heteroresistance is similar between bacteria isolated from different countries. Also, the prevalence among various kinds of bacteria in Georgia roughly matches up with mortality rates in the CREDIBLE-CR trial – particularly among the kinds that were the most troublesome (Acinetobacter).

“We’ve shown that heteroresistance can cause treatment failure in animal models, but these data suggest that it may be contributing to treatment failure in hospitals right now,” Weiss says.

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Revealing brain temperature via MR imaging and biophysical modeling

Magnetic resonance (MR) imaging technology and biophysical modeling being developed at Emory and Georgia Tech could provide more accurate predictions of brain temperature, which is difficult for doctors to directly assess. The temperature of the brain is critical information after someone has experienced a stroke or cardiac arrest, and even more important during treatment. 

The results of a pilot study were published today in the journal Communications Physics.

The project grew out of a collaboration between Candace Fleischer, PhD, an assistant professor of radiology and imaging sciences at Emory, and Andrei Fedorov, PhD, a world expert on thermodynamics and biophysical modeling and a professor of mechanical engineering at Georgia Tech. The first author of the paper is Georgia Tech/Emory biomedical engineering graduate student Dongsuk Sung.

The researchers developed a biophysical model based on heat transfer, using data acquired by imaging individuals’ brain tissue and blood vessel structure. As predicted and in agreement with MR whole brain measurements, brain temperature is slightly higher than core body temperature – about 1 degree C; there are “hot” spots in the brain domains with high rate of metabolism; and the regions of the brain that are closer to the scalp are also slightly cooler than the midbrain.

“We find that every subject’s brain temperature and spatial temperature patterns are different, setting the stage for a personalized approach to managing brain temperature,” says Fleischer, who is also a faculty member in the Wallace H. Coulter Department of Biomedical Engineering and Georgia Tech at Emory.

Metabolic heat, cerebral blood flow, and model-predicted brain temperature maps for three healthy volunteers. From Sung et al (2021), via Creative Commons 4.0

Researchers then compared the predictions of their model with measurements based on the magnetic resonance properties of water, which change with temperature, and the temperature-insensitive brain metabolite N-acetylaspartate. The Communications Physics paper shows temperature modeling and MR-based measurements for three healthy volunteers.

Fleischer recently received a three-year, $400,000 Trailblazer grant from the National Institute of Biomedical Imaging and Bioengineering to monitor brain temperature while patients are undergoing therapeutic hypothermia after cardiac arrest. More information about that here.

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Killing viruses, pointy ears or not

After success finding flu virus-killing peptides in frog slime, immunologist Joshy Jacob and his colleagues at Emory Vaccine Center turned their attention from influenza to Zika. Their follow-up paper on an antiviral peptide that destroys Zika virus was published earlier this year in Scientific Reports.

The findings illustrate how frogs’ skin secretions are a rich source of potential antiviral weapons, even though Zika itself is not thought to infect frogs. Jacob reports his team is currently investigating peptides with activity against SARS-CoV-2. Lab Land is expecting to hear more about that soon.

But before SARS-CoV-2, you may recall Zika as a virus of public health concern. Carried by mosquitoes, its insidious infection can lead to neurological birth defects and disabilities in infants and Guillain-Barre syndrome in adults. Neither antiviral drugs or vaccines are available against Zika, leaving the field wide open for Jacob’s amphibian approach.

Jacob and his crew decided to call their antiviral Zika-destroying peptide Yodha, which means “warrior” in Sanskrit. Just in case you might have some other associations for that word, which sounds like the name of a few recent Bollywood movies, as well as a diminutive Jedi trainer from the Star Wars universe.

The Yodha peptide emerged from a screen of many frog peptides, and it was the only one of several Zika-killing peptides that was not toxic to human red blood cells. The peptide comes from the skin of Indosylvirana aurantiaca which lives in the western Ghats of India and is commonly known as the “golden frog.” (The website India Biodiversity, linked above, has photos of the frogs.)

Using electron microscopy, Jacob’s lab could show that the Yodha peptide blasts Zika virus particles apart with a few minutes of exposure. It was active against Zika and all four varieties of the related dengue virus.

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New antibiotic tactic vs gonorrhea

A new antibiotic compound can clear infection of multi-drug resistant gonorrhea in mice with a single oral dose, according to a new study led by researchers at Penn State and Emory.

Like other antibiotics, this one targets the ribosome, the factories that generate proteins in bacterial (and human) cells. But it does so at a site that is different from other antibiotics. This one interferes with the process of trans-translation, which bacteria use to rescue their ribosomes out of rough spots.

The results were published in Nature Communications. This was a collaboration involving several groups: biochemist Christine Dunham’s at Emory and Ken Keiler’s at Penn State, along with others at Florida State, the Uniformed Services University and the Massachusetts-based pharmaceutical company Microbiotix.

Zachary Aron, director of chemistry at Microbiotix, is the first author of the paper, and the compound is called MBX-4132. It is also active against other Gram-positive bacteria, including tuberculosis and Staph aureus, and the company says it will continue to optimize it.

At Emory, Dunham’s lab used cryo-electron microscopy to produce high-resolution images of the compound as it binds to the bacterial ribosome — see below.

Christine Dunham’s lab specializes in ribosomal structural studies

“A derivative of MBX-4132 binds to a location on the ribosome that is different from all known antibiotic binding sites,” Dunham says. “The new drug also displaces a region of a ribosomal protein that we think could be important during the normal process of trans-translation. Because trans-translation only occurs in bacteria and not in humans, we hope that the likelihood of the compound affecting protein synthesis in humans is greatly reduced, a hypothesis strongly supported by the safety and selectivity studies performed by Microbiotix.”

Multi-drug resistant gonorrhea is listed by the CDC as one of the five most urgent threats, among antibiotic resistant bacteria. Half of all gonorrhea infections are resistant to at least one antibiotic.

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First (and massive) whole-genome study of IBD in African Americans

In African Americans, the genetic risk landscape for inflammatory bowel disease (IBD) is very different from that of people with European ancestry, according to results of the first whole-genome study of IBD in African Americans. The authors say that future clinical research on IBD needs to take ancestry into account.

Findings of the multi-center study, which analyzed the whole genomes of more than 1,700 affected individuals with Crohn’s disease and ulcerative colitis and more than 1,600 controls, were published on February 17 in the American Journal of Human Genetics.

As part of their analysis, the researchers developed an algorithm that corrects for ancestry when calculating an IBD polygenic risk score. Polygenic risk scores are tools for calculating gene-based risk for a disease, which are used for IBD as well as other complex conditions such as coronary artery disease.

“Even though the disease destination looks the same, the populations look very different, in terms of what specific genes contribute to risk for IBD,” says lead author Subra Kugathasan, MD. “It shows that you can’t develop a polygenic risk score based on one population and apply it to another.”

Kugathasan is scientific director of the pediatric IBD program and director of the Children’s Center for Transplantation and Immune-mediated Disorders at Children’s Healthcare of Atlanta, as well as Marcus professor of pediatrics and human genetics at Emory University School of Medicine.

The first author of the paper is geneticist Hari Somineni, PhD, who earned his doctorate working with Kugathasan at Emory, and is now working at Goldfinch Bio in Massachusetts.

The primary sites to recruit study participants were Emory, Cedars-Sinai and Rutgers, along with Johns Hopkins and Washington University at Saint Louis. Along with Kugathasan, the co-senior authors and co-organizers of the study were Steven Brant, MD from Rutgers and Dermot McGovern, MD, PhD from Cedars-Sinai.

“One of our goals in treating IBD is to move toward a more personalized approach,” says McGovern, the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics at Cedars-Sinai. “Deciphering the genetic architecture is an important part of this effort. Studies such as this one are vital to ensure that diverse populations, including African-Americans, benefit from the tremendous advances promised by genomic medicine.”

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Strengthening SARS-CoV-2 genomic surveillance: support from CDC, private foundations

As part of an effort to strengthen genomic surveillance for emerging strains of SARS-CoV-2, the Centers for Disease Control and Prevention (CDC) has awarded a contract to Emory University researchers to characterize viral variants circulating in Georgia.

The two-year contract is part of the SPHERES (SARS-CoV-2 Sequencing for Public Health Emergency Response, Epidemiology and Surveillance) initiative, with roughly $620,000 in total costs. The principal investigator is Anne Piantadosi, MD, PhD, assistant professor of pathology and laboratory medicine, with co-investigator Mehul Suthar, PhD, assistant professor of pediatrics (infectious diseases).

Both Piantadosi and Suthar are affiliated with Emory University School of Medicine and Emory Vaccine Center. Additional Emory partners include assistant professor of medicine Ahmed Babiker, MBBS, assistant professor of medicine Jesse Waggoner, MD and assistant professor of biology Katia Koelle, PhD.

“We are analyzing SARS-CoV-2 genomes from patients in Georgia to understand the timing and source of virus introduction into our community,” Piantadosi says. “We want to know whether there have been population-level changes in the rates of viral spread, and whether there are associations between viral genotype, viral phenotype in vitro, and clinical phenotype or clinical outcome.”

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Combo approach vs drug-resistant fungus

Before 2020 and the COVID-19 pandemic, concern among infectious disease specialists was rising about Candida auris, an emerging fungal pathogen that is often drug-resistant and difficult to eradicate from hospitals.

CDC image of Candida auris

Many people know Candida can cause mouth or vaginal infections and diaper rashes. According to the CDC, Candida also can cause invasive infections in the bloodstream, particularly in hospital or nursing home patients with weakened immune systems. About 30 percent of patients with an invasive Candida infection die – and C. auris is just one particularly hardy variety.

Emory Antibiotic Resistance Center director David Weiss and colleagues have identified a combination of existing antifungal drugs (micafungin and amphotericin B) with enhanced activity against C. auris when used together. The results – in vitro only, so far — were published in a letter to The Lancet Microbe. Postdoctoral fellow Siddharth Jaggavarapu was the first author. Weiss reports his team continues to investigate combination approaches against C. auris.

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Engineered “stealth bomber” virus could be new weapon against metastatic cancer

Many cancer researchers can claim to have devised “smart bombs.” What has been missing is the stealth bomber – a delivery system that can slip through the body’s radar defenses. 

Oncolytic viruses, or viruses that preferentially kill cancer cells, have been discussed and tested for decades. An oncolytic virus against melanoma was approved by the FDA in 2015. But against metastatic cancers, they’ve always faced an overwhelming barrier: the human immune system, which quickly captures viruses injected into the blood and sends them to the liver, the body’s garbage disposal.

Researchers at Emory and Case Western Reserve have now circumvented that barrier. They’ve re-engineered human adenovirus, so that the virus is not easily caught by parts of the innate immune system.

The re-engineering makes it possible to inject the virus into the blood, without arousing a massive inflammatory reaction.

A cryo-electron microscopy structure of the virus and its ability to eliminate disseminated tumors in mice were reported on November 25 in Science Translational Medicine.

“The innate immune system is quite efficient at sending viruses to the liver when they are delivered intravenously,” says lead author Dmitry Shayakhmetov, PhD. “For this reason, most oncolytic viruses are delivered directly into the tumor, without affecting metastases. In contrast, we think it will be possible to deliver our modified virus systemically at doses high enough to suppress tumor growth — without triggering life-threatening systemic toxicities.”

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Don’t go slippery on me, tRNA

RNA can both carry genetic information and catalyze chemical reactions, but it’s too wobbly to accurately read the genetic code by itself. Enzymatic modifications of transfer RNAs – the adaptors that implement the genetic code by connecting messenger RNA to protein – are important to stiffen and constrain their interactions.

Biochemist Christine Dunham’s lab has a recent paper in eLife showing a modification on a proline tRNA prevents the tRNA and mRNA from slipping out of frame. The basics of these interactions were laid out in the 1980s, but the Dunham lab’s structures provide a comprehensive picture with mechanistic insights.

The mRNA code for proline is CCC – all the nucleotides are the same — so it is susceptible to frameshifting.

The paper includes videos that virtually unwrap the RNA interactions. The X-ray crystal structures indicate that tRNA methylation – a relatively small bump — at position 37 influences interactions between the tRNA and the ribosome.

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