Research advances from the National Institutes of Health (NIH) Intramural Research Program (IRP) often make headlines. Read the news releases that describe our most recent findings:
Whether you’re shedding pounds with the help of effective new medicines, slimming down after weight loss surgery or cutting calories and adding exercise, there will come a day when the numbers on the scale stop going down, and you hit the dreaded weight loss plateau.
In a recent study, Kevin Hall, a researcher at the National Institutes of Health who specializes in measuring metabolism and weight change, looked at when weight loss typically stops depending on the method people were using todrop pounds. He broke down the plateau into mathematical models using data from high-quality clinical trials of different ways to lose weight to understand why people stop losing when they do. The study published Monday in the journal Obesity.
Microbiome-triggered Th17 cells switch from protective to destructive; may be potential treatment targets
An unhealthy population of microbes in the mouth triggers specialized immune cells that inflame and destroy tissues, leading to the type of bone loss associated with a severe form of gum disease, according to a new study in mice and humans. The research, led by scientists from the National Institute of Dental and Craniofacial Research (NIDCR) at the National Institutes of Health and the University of Pennsylvania School of Dental Medicine, Philadelphia, could have implications for new treatment approaches for the condition. The findings appear online Oct. 17, 2018, in Science Translational Medicine.
Periodontal disease is a common disorder that affects nearly half of American adults over age 30, and 70 percent of adults 65 and older. In those affected, bacteria trigger inflammation of the tissues that surround the teeth, which can lead to loss of bone and teeth in an advanced stage of the disease called periodontitis.
“We’ve known for years that microbes stimulate inflammation. Removing bacteria by tooth-brushing and dental care controls inflammation, but not permanently, suggesting there are other factors at play,” said study senior author Niki Moutsopoulos, D.D.S., Ph.D., a clinical investigator at NIDCR. “Our results suggest that immune cells known as T helper 17 cells are drivers of this process, providing the link between oral bacteria and inflammation.”
A new study suggests that periodontal disease is driven by Th17 immune cells, which are triggered by an unhealthy bacterial community.
A novel vaccine designed to protect people from both Lassa fever and rabies showed promise in preclinical testing, according to new research published in Nature Communications. The investigational vaccine, called LASSARAB, was developed and tested by scientists at Thomas Jefferson University in Philadelphia; the University of Minho in Braga, Portugal; the University of California, San Diego; and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
The inactivated recombinant vaccine candidate uses a weakened rabies virus vector, or carrier. The research team inserted genetic material from Lassa virus into the rabies virus vector so the vaccine expresses surface proteins from both the Lassa virus and the rabies virus. These surface proteins prompt an immune response against both Lassa and rabies viruses. The recombinant vaccine was then inactivated to “kill” the live rabies virus used to make the carrier.
This transmission electron microscopic (TEM) image depicts Lassa virus virions adjacent to some cell debris.
A new study from National Institutes of Health scientists and their Thai colleagues shows that a “good” bacterium commonly found in probiotic digestive supplements helps eliminate Staphylococcus aureus, a type of bacteria that can cause serious antibiotic-resistant infections. The researchers, led by scientists at NIH’s National Institute of Allergy and Infectious Diseases (NIAID), unexpectedly found that Bacillus bacteria prevented S. aureus bacteria from growing in the gut and nose of healthy individuals. Then, using a mouse study model, they identified exactly how that happens. Researchers from Mahidol University and Rajamangala University of Technology in Thailand collaborated on the project.
“Probiotics frequently are recommended as dietary supplements to improve digestive health,” said NIAID Director Anthony S. Fauci, M.D. “This is one of the first studies to describe precisely how they may work to provide health benefits. The possibility that oral Bacillus might be an effective alternative to antibiotic treatment for some conditions is scientifically intriguing and definitely worthy of further exploration.”
Woman selling vegetable snacks in a Thai market – a possible source of probiotic Bacillus spores.
NIH-funded research raises possibility of designer treatments for common form of pain
Ever wonder why things that normally feel gentle, like putting on soft shirts, are painful after a sunburn? In a study of four patients with a rare genetic disorder, IRP researchers found that PIEZO2, a gene previously shown to control our sense of our bodies in space and gentle touch, may also be responsible for tactile allodynia: the skin’s reaction to injury that makes normally gentle touches feel painful. This and a second NIH-funded study, both published in Science Translational Medicine, used mice to show how the gene may play an essential role in the nervous system’s reaction to injury and inflammation, making PIEZO2 a target for developing precise treatments for relieving the pain caused by cuts, burns, and other skin injuries.
“For years scientists have been trying to solve the mystery of how gentle touch becomes painful. These results suggest PIEZO2 is the gene for tactile allodynia. We hope that these results will help researchers develop better treatments for managing this form of pain,” said Alexander T. Chesler, Ph.D., a Stadtman Investigator at the National Center for Complementary and Integrative Health (NCCIH) and a senior author of one of the studies.
An IRP study found that the PIEZO2 gene may control the skin’s reaction to injuries, like sunburns, that make gentle touches feel painful.
The severity of birth defects caused by Zika virus infection may be influenced by natural variations in a pregnant woman’s genes for a key enzyme, according to a study by researchers at the National Institutes of Health, Uniformed Services University of the Health Sciences, Federal University of Rio de Janeiro, and Professor Joaquim Amorim Neto Research Institute in Campina Grande, Brazil. The enzyme, adenylate cyclase, is required to make cyclic adenosine monophosphate (cAMP), which plays a role in placental development and other cellular processes, including the immune response to infection. The findings appear in the Journal of Internal Medicine.
The study enrolled 52 women who had given birth after testing positive for Zika virus infection. Of these women, 28 gave birth to children with reduced head size and other Zika-related birth defects; infants born to the remaining 24 women did not appear to have any Zika-related effects. After sequencing genes from the women, the researchers found that mothers of severely affected infants were more likely to have variations in two genes essential for making adenylate cyclase, ADCY3 and ADCY7.
The variation in ADCY3 has previously been associated with higher levels of adenylate cyclase, leading to higher levels of cAMP. The researchers believe higher cAMP levels could stimulate reproduction of the virus. Similarly, a variation in ADCY7 has been linked to lower levels of cAMP, which could protect against the virus’ effects. The authors note that, because of the relatively small number of women studied, additional research is needed to confirm these results. However, future research on drugs that influence cAMP production might yield potential therapies that protect against Zika exposure during pregnancy.
Findings in rat cell cultures could lead to new method for tracking communications throughout the brain
Neurons absorb and release water when they relay messages throughout the brain, according to a study by researchers at the National Institutes of Health and other institutions. Tracking this water movement with imaging technology may one day provide valuable information on normal brain activity, as well as how injury or disease affect brain function. The study appears in Magnetic Resonance in Medicine.
Current functional magnetic resonance imaging (fMRI) technologies measure neuronal activity indirectly by tracking changes in blood flow and blood oxygen levels. Neurons communicate with each other by a process known as firing. In this process, they emit a slight electrical charge as an enzyme moves positively charged molecules — potassium and sodium ions — through the cell membrane. In the current study, when researchers stimulated cell cultures of rat neurons to fire, they found that the exchanges of potassium and sodium ions was accompanied by an increase in the number of water molecules moving into and out of the cell.
The researchers noted that their method works only in cultures of neurons and additional studies are necessary to advance the technology so that it can be used to monitor neuronal firing in living organisms.
Increasing time between meals made male mice healthier overall and live longer compared to mice who ate more frequently, according to a new study published in the Sept. 6, 2018 issue of Cell Metabolism. Scientists from the National Institute on Aging (NIA) at the National Institutes of Health, the University of Wisconsin-Madison, and the Pennington Biomedical Research Center, Baton Rouge, Louisiana, reported that health and longevity improved with increased fasting time, regardless of what the mice ate or how many calories they consumed.
“This study showed that mice who ate one meal per day, and thus had the longest fasting period, seemed to have a longer lifespan and better outcomes for common age-related liver disease and metabolic disorders,” said NIA Director Richard J. Hodes, M.D. “These intriguing results in an animal model show that the interplay of total caloric intake and the length of feeding and fasting periods deserves a closer look.”
The scientists randomly divided 292 male mice into two diet groups. One group received a naturally sourced diet that was lower in purified sugars and fat, and higher in protein and fiber than the other diet. The mice in each diet group were then divided into three sub-groups based on how often they had access to food. The first group of mice had access to food around the clock. A second group of mice was fed 30 percent less calories per day than the first group. The third group was meal fed, getting a single meal that added up to the exact number of calories as the round-the-clock group. Both the meal-fed and calorie-restricted mice learned to eat quickly when food was available, resulting in longer daily fasting periods for both groups.
Asthma patients, with a specific genetic profile, exhibit more intense symptoms following exposure to traffic pollution, according to researchers at the National Institutes of Health and collaborators. The study appeared online in Scientific Reports.
The research team, made up of scientists from the National Institute of Environmental Health Sciences (NIEHS), part of NIH, and Rice University, Houston, also found that asthma patients that lack this genetic profile do not have the same sensitivity to traffic pollution and do not experience worse asthma symptoms. The work brings scientists closer to being able to use precision medicine, an emerging field that intends to prevent and treat disease based on factors specific to an individual.
Co-lead author Shepherd Schurman, M.D., associate medical director of the NIEHS Clinical Research Unit, stated the results are based on genetic variation, the subtle differences in DNA that make each person unique. He further added that to understand the concept, one should think of human genes, which are made up of DNA base pairs A, C, G, and T, as written instructions for making proteins.
The research suggests when individuals with specific variations in certain genes are exposed to traffic pollution, they display more intense asthma symptoms than people that lack those same gene variations.
IRP study identifies potential new target for malaria drug development
Researchers from the National Institutes of Health and other institutions have deciphered the role of a key protein that the malaria parasite Plasmodium falciparum uses to obtain nutrients while infecting red blood cells. Their study appears in Nature Microbiology.
According to the World Health Organization, in 2016 there were an estimated 216 million malaria cases and 445,000 malaria deaths. P. falciparum is responsible for most malaria-related deaths globally.
The parasite remodels the red blood cell it infects to obtain nutrients. During this process, the parasite secretes hundreds of proteins that need to be transported from the vacuole, the compartment in which the parasite resides, to the interior of the cell. A group of proteins, called the Plasmodium translocon of exported proteins (PTEX), has been shown to be essential for transporting materials to and from the vacuole. Previous studies have uncovered the function of one of the proteins in the PTEX group to reshape proteins for transport, but the function of other proteins in the group have not been well understood.
In the current study, researchers analyzing blood cell cultures from healthy people determined that the PTEX protein EXP2 forms a channel in the vacuole membrane, which allows for passage of proteins and cellular nutrients to supply the parasite. The researchers hope that their discovery will lead to the development of new drugs to prevent formation of the channel and block the transport of nutrients and proteins to the parasite.
Researchers at NIH have determined that the protein EXP2 forms a channel in the vacuole membrane, which allows for passage of proteins and cellular nutrients to supply the parasite.
In a new study, researchers developed a gene expression predictor that can indicate whether melanoma in a specific patient is likely to respond to treatment with immune checkpoint inhibitors, a novel type of immunotherapy. The predictor was developed by Noam Auslander, Ph.D., with other researchers in the Center for Cancer Research (CCR) at the National Cancer Institute (NCI), part of the National Institutes of Health, and colleagues at Harvard University, Cambridge, Massachusetts; the University of Pennsylvania, Philadelphia; and the University of Maryland, College Park. The study was published Aug. 20, 2018 in Nature Medicine.
“There is a critical need to be able to predict how cancer patients will respond to this type of immunotherapy,” said Eytan Ruppin, M.D., Ph.D., of NCI’s newly established Cancer Data Science Laboratory, who led the study. “Being able to predict who is highly likely to respond and who isn’t will enable us to more accurately and precisely guide patients’ treatment.”
Treatment with checkpoint inhibitors is effective for some patients with late-stage melanoma and certain other types of cancer. However, not all patients with melanoma respond to this treatment, and it can have considerable side effects. But developing a predictor of response has been challenging, partly because of the limited number of patients who have received this relatively new form of treatment.
