Diabetic foot ulcerations — open sores or wounds that refuse to heal – affect more than 15 percent of people with diabetes and result in thousands of lower extremity amputations per year in the United States.
To gain a better understanding of diabetic foot ulcers’ biology, a team of researchers at Emory and Beth Israel Deaconess Medical Center in Boston compared cells taken from patients with ulcers that healed to those taken from patients whose ulcers failed to heal, as well as to cells taken from intact forearm skin in patients with and without diabetes.
The team identified a subpopulation of fibroblasts enriched in the foot ulcers that healed, pointing to potential interventions. The results were published in Nature Communications on January 10.
“In this study, we present a comprehensive single cell map of the diabetic foot ulcer microenvironment,” says Manoj Bhasin, PhD, associate professor of pediatrics and biomedical informatics at Emory University School of Medicine, who is co-corresponding author of the study. “To our knowledge, we are the first to identify a unique subpopulation of fibroblasts that are significantly enriched in diabetic foot ulcers that are destined to heal.”
Various cell types, including endothelial cells, fibroblasts, keratinocytes and immune cells, were known to play an important role in wound healing processes. Yet diabetic foot ulcerations’ failure to heal and high associated mortality remain poorly understood.
“Our data suggests that specific fibroblast subtypes are key players in healing these ulcers and targeting these cells could be one therapeutic option,” says co-corresponding author Aristidis Veves, DSc, MD, director of the Rongxiang Xu, MD, Center for Regenerative Therapeutics and research director of the Joslin-Beth Israel Deaconess Foot Center. “While further testing is needed, our data set will be a valuable resource for diabetes, dermatology and wound healing research and can serve as the baseline for designing experiments for the assessment of therapeutic interventions.”
A third dose of an mRNA COVID-19 vaccine is necessary to give someone robust neutralizing antibody activity against the Omicron variant, according to data from Emory researchers posted on the preprint server Biorxiv.
The findings support public health efforts to promote booster vaccination as a measure to fight Omicron, which is currently overwhelming hospitals around the world. They also explain why more breakthrough infections are occurring with the Omicron variant in people who have been vaccinated twice, and are in line with what other investigators have observed.
Compared with the 2020 Wuhan strain, the Omicron variant of SARS-CoV2 has more than 30 mutations in the viral spike protein, which is the primary target of neutralizing antibodies generated by vaccination.
“Our findings highlight the need for a third dose to maintain an effective antibody response for neutralizing the Omicron variant,” says lead author Mehul Suthar, a virologist based at Emory Vaccine Center and Yerkes National Primate Research Center.
Vaccinated individuals who develop breakthrough Omicron infections are likely to experience less severe symptoms, and it is possible for Omicron to infect people even after receiving a booster, Suthar notes. Still, a majority of patients now coming into hospitals continue to be those who are unvaccinated.
In the preprint, Emory researchers tested blood samples from people who participated in Pfizer/BioNTech or Moderna vaccine studies in the laboratory for their ability to smother SARS-CoV-2 variants in culture. The preprint does not include clinical outcomes from infection, and also does not cover other aspects of vaccine-induced antiviral immunity, such as T cells.
In people who were vaccinated twice with mRNA vaccines, either Pfizer/BioNTech or Moderna, none showed measurable neutralizing antibody activity against Omicron six months after vaccination. But 90 percent displayed some neutralizing activity against Omicron a few weeks after a third dose.
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 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.
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.
One of the tricky issues in studying in long COVID is: how widely do researchers cast their net? Initial reports acknowledged that people who were hospitalized and in intensive care may take a while to get back on their feet. But the number of people who had SARS-CoV-2 infections and were NOT hospitalized, yet experienced lingering symptoms, may be greater.
A recent report from the United Kingdom, published in PLOS Medicine, studied more than 270,000 people using electronic health records. This research found that more than a third of patients had one or more features of long COVID three to six months after COVID-19 diagnosis.
That would be consistent with recently published findings from Emory, which surveyed 290 people from a telemedicine program: Emory Healthcare’s Virtual Outpatient Management Clinic. Almost 40 percent reported persistent symptoms. However, none of the individual symptoms, such as fatigue, mental fog or difficulty breathing, were reported at a rate of more than about 20 percent.
With this survey, Emory investigators were trying to capture the larger number of people out there who were recovering from COVID-19, without selecting for people who are especially miserable (to put it bluntly). Initial symptom severity predicted the likelihood of long-term symptoms, but there were outliers from this trend. This was a cross-sectional but not longitudinal study. One intriguing finding was that people with hypertension were less likely to experience persistent COVID symptoms, which may have to do with ACE inhibitors, common anti-hypertension drugs.
The second item reports data on autoantibodies from a long COVID cohort at Emory, from immunologists Ignacio Sanz and Eun-Hyung Lee. Autoantibodies are a feature of autoimmune diseases, such as lupus and rheumatoid arthritis, and their presence in long COVID may explain persistent symptoms such as fatigue, skin rash and joint pain.
Several research groups have shown that autoantibodies can result from the intense inflammation of COVID-19 (examples outside Emory here, here), which breaks down the guardrails that normally constrain immune cells from attacking the body itself. But a key question is: how long does that deranged state last? And do autoantibodies correlate with persistent symptoms? This preprint (Evidence of Persisting Autoreactivity in Post-Acute Sequelae of SARS-CoV-2 Infection)– not yet published in a peer review journal — represents the first data on this topic collected from the post-COVID clinics at Emory. More to come on this topic.
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 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.
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.
Now Emory, Harvard and Case Western Reserve scientists have identified a gene activity signature that may explain why the vaccine regimen in the RV144 study was protective in some individuals, while other HIV vaccine studies were not successful.
The researchers think that this signature, observed in immune cells in the blood after vaccination, could be used to design future vaccines that will have a better chance of providing protection against HIV infection.
“We may not need to take ‘shots in the dark’, when testing vaccine platforms or adjuvants for efficacy,” says senior author Rafick-Pierre Sekaly, PhD. “Instead, we can now identify adjuvants and/or vaccine regimens which more potently induce the activation of this signature.”
The results, published this week in Nature Immunology, also contain hints on a contributing factor explaining why a recent HIV vaccine study conducted in South Africa (HVTN702) did not show a protective effect. HVTN702 was designed as a follow-up to RV144, but multiple parameters were different between the Thai and South African vaccine studies, such as the demographics of the participants, the adjuvant used, and the levels and varieties of HIV circulating.
“Our findings highlight one potential mechanism which may have contributed to the muted efficacy of HVTN702,” says Sekaly, professor of pathology and laboratory medicine at Emory University School of Medicine and a Georgia Research Alliance Eminent Scholar.
This mechanism involves the choice of adjuvant, a vaccine additive that enhances immune responses. While RV144 used the adjuvant alum (aluminum hydroxide), HVTN702 used the oil-based adjuvant MF59, also found in some influenza vaccines, to stimulate higher antibody production.
“There are multiple ways that a vaccine can promote protection and some of these do not involve antibodies,” Sekaly says. “Since MF59 failed to potently induce the gene signature we found to be associated with protection, this signature could guide us to mechanisms distinct from antibodies which could trigger protection from HIV-1.”
Scientists at the Max Planck Institute for Biophysical Chemistry in Germany have generated a structure showing how the antiviral drug molnupiravir drug works.
Molnupiravir was originally discovered by Emory’s non-profit drug development company DRIVE, and is now being developed by Merck. The drug, previously known as EIDD-2801, can be provided as a pill in an outpatient setting – potentially a step up in ease of distribution and convenience.
Molnupiravir is currently in clinical trials for non-hospitalized people with COVID-19 and at least one risk factor; results are expected later in the fall of 2021. Merck also recently began a prevention study for adults who live with a currently infected person. Previous small-scale studies conducted by Merck’s partner Ridgeback Biotherapeutics showed that the drug is safe and can reduce viral levels to undetectable in non-hospitalized people within five days.
The structure shows how the active form of molnupiravir interacts with the enzyme that makes new copies of the SARS-CoV-2 genome (RNA-dependent RNA polymerase). Incorporation of the active form of the drug into the RNA genome leads to mutations – so many that the virus can’t generate enough accurate copies of itself. Molnupiravir is likely to work in a similar way when deployed against other viruses such as influenza.
Bypassing stem cells, Emory scientists can now create engineered heart tissue by directly reprogramming connective tissue cells in mice. The findings could provide new avenues for a quest many cardiologists have pursued: repairing the damaged heart like patching a roof.
“This is the first study demonstrating direct tissue reprogramming from single adult cells from the body,” says senior author Young-sup Yoon, MD, PhD, professor of medicine at Emory University School of Medicine.
The research could potentially provide therapeutic options for millions of people with heart failure or other conditions. If heart muscle is damaged by a heart attack, the damaged or dead cells do not regenerate. Other scientists have shown they can create human heart tissue from induced pluripotent stem cells (example), but the Emory team showed that it is possible to avoid stem cells and the technologies required to create them, such as viruses.
“Direct reprogramming into tissues that contain multiple cell types has not previously been reported, and it could open new pathways in the regenerative medicine field,” Yoon says. “It could serve as a platform for cell-based therapy by avoiding the problems of current stem cell-based approaches, and for disease modeling and drug development.”
Yoon is also part of the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. First author Jaeyeaon Cho, PhD was a post-doctoral fellow at Emory and is currently a research assistant professor at Yonsei University College of Medicine in South Korea. Emory faculty members Rebecca Levit, MD and Hee Cheol Cho, PhD are co-authors on the paper.
Applying a combination of growth factors, regulatory microRNA and vitamins, the Emory researchers could create tissue that contains cardiac muscle, along with blood vessels containing endothelial cells and smooth muscle cells, and fibroblasts. In culture, the four cell types weave themselves together, bypassing any need to build heart tissue from separate components.
When transplanted onto the damaged heart of a mouse after a simulated heart attack, cells from the engineered tissue can migrate into the host heart, and improve its functioning.
“In some previous studies, when a tissue patch composed of engineered cells and supportive biomaterials was transplanted to the damaged heart, there was little or no migration of cells from the patch to the host heart,” Yoon says.
The critical elements of the direct reprogramming approach are microRNAs, which are “master keys” that control several genes at once. The researchers discovered the potential of one microRNA fortuitously; a pilot study examined the effect of applying several microRNAs active in the heart to fibroblasts. Unexpectedly, one of them generated endothelial cell and smooth muscle along with cardiac muscle cells.
The Emory researchers say that their engineered tissue does not exactly mimic natural heart tissue. The cardiac muscle cells do spontaneously contract, but they display immature characteristics. But after transplantation, the engrafted cells mature and integrate into the host heart. Over 16 weeks, the engrafted cells become indistinguishable from the host cardiac muscle cells. The researchers checked whether their transplanted tissue induced cardiac arrhythmias in the mice – a danger when introducing immature cells into the damaged heart — and they did not.
Yoon says it took almost 9 years to complete the project; an important next step is to test direct reprogramming with human cells.
This work was supported by grants from the National Heart Lung and Blood Institute (R01HL150877, R61HL 154116, R01HL125391) and a American Heart Association Transformative Project Award.
Prolific drug discoverer and repurposer Jack Arbiser is at it again. Arbiser, an Emory dermatologist, has identified a new (but old) compound as a treatment for rosacea, a common skin condition involving redness and visible blood vessels on the face. Severe rosacea can lead to itching, pain, or thickening of the skin.
The compound is remarkable for two reasons: it is the same as Irganox 1010, an antioxidant plastic stabilizer used in industry for years, and it is a proteasome inhibitor.
The proteasome is the cell’s garbage disposal, and many kinds of proteins get tagged and thrown into it. Interfering with the disposal inhibits the inflammatory NFkB pathway. Oncologists may be familiar with the proteasome inhibitor bortezomib (a blockbuster drug known commercially as Velcade), used to treat multiple myeloma.
Arbiser has founded a company called Accuitis to develop the compound, called ACU-D1. Accuitis was funded by the Georgia Research Alliance. Accuitis’ web site notes that the compound “has the advantage of extensive toxicology testing in multiple animal species, as well as a safe record of human exposure for over 30 years.”
“ACU-D1 is a cream that works through a new mechanism of action that no current rosacea medications work through,” Arbiser told Dermatology Times. “Given the fact that there are no truly great treatments for rosacea, we are hoping that in the future our compound will be a first-in-class drug and become first-line therapy for rosacea.”
This was a first-in-human study with 40 participants, lasting 12 weeks. It was not powered for a pivotal evaluation of ACU-D1’s efficacy. However, the drug showed a pronounced effect on people with severe rosacea. The trial used a Canfield imaging system imaging as a way of measuring skin irritation objectively, separately from the opinions of the investigators.
The drug appears to take effect after a couple weeks, showing maximum efficacy at one month. It also shows positive effects on redness, which is rare for a skin medication, Arbiser says. Few adverse effects were reported.
Arbiser says ACU-D1 could be an alternative to antibiotics, a common systemic treatment for rosacea. (Rosacea is partly an inflammatory response to microbes in the skin.) He is interested in studying ACU-D1’s efficacy for other inflammatory skin conditions such as eczema and psoriasis.
We can’t read Emory neuroscientist Shannon Gourley’s papers on social isolation in adolescent mice, without thinking about how the COVID-19 pandemic is affecting children and teenagers. Much of the experimental work was completed before the pandemic began. Still, in the future, researchers will be studying the effects of the pandemic on children, in terms of depression and anxiety, or effects on relationships and education. They could look to neuroscience studies such as Gourley’s for insights into brain mechanisms.
In the brain, social isolation interferes with the pruning of dendritic spines, the structures that underly connections between neurons. One might think that more dendritic spines are good, but the brain is like a sculpture taking shape – the spines represent processes that are refined as humans and animals mature.
Mice with a history of social isolation have higher spine densities in regions of the brain relevant to decision-making, such as the prefrontal cortex, the Emory researchers found.
In a recently published review, Gourley and her co-authors, former graduate student Elizabeth Hinton and current MD/PhD Dan Li, say that more research is needed on whether non-social enrichment, such as frequent introduction of new toys, can compensate for or attenuate the effects of social isolation.
This research is part of an effort to view adolescent mental health problems, such as depression, obesity or substance abuse, through the prism of decision-making. The experiments distinguish between goal-oriented behaviors and habits. For humans, this might suggest choices about work/school, food, or maybe personal hygiene. But in a mouse context, this consists of having them poke their noses in places that will get them tasty food pellets, while they decode the information they have been given about what to expect.