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.
NIH-supported study in mice could inform treatments of trauma- and stress-related psychiatric conditions
Scientists have identified an area within the brain’s frontal cortex that may coordinate an animal’s response to potentially traumatic situations. Understanding where and how neural circuits involving the frontal cortex regulate such functions, and how such circuits could malfunction, may provide insight about their role in trauma-related and stress-related psychiatric disorders in people. The study, led by scientists at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), a part of the National Institutes of Health, was published in Nature.
“Experiencing traumatic events is often at the root of trauma-related and stress-related psychiatric conditions, including alcohol use disorder (AUD),” said the study’s senior author, Andrew Holmes, Ph.D., senior investigator in NIAAA’s Laboratory of Behavioral and Genomic Neuroscience. “Additionally, witnessing others experience traumatic events can also contribute to these disorders.”
In animal models of stress and trauma, learning about potential sources of threat by observing how others deal with danger can be an effective way to avoid harm. Understanding the differences in how the brain processes direct experience of a threat compared to observing another’s response to a threat may shed light on factors that predispose humans to trauma- and stress-related psychiatric disorders.
Diagram of mouse prefrontal cortex showing neural projections to the midbrain (purple) and the amygdala (green), pathways involved in learning about threat.
National Institutes of Health Director Monica M. Bertagnolli, M.D., has named Sean Mooney, Ph.D., as director of NIH’s Center for Information Technology (CIT). Dr. Mooney is expected to join NIH in mid-March.
“Dr. Mooney has spent his career developing effective and collaborative computing systems to support biomedical research. His background in bioinformatics and expertise in the implementation and governance of a multi-faceted research IT department make him particularly suited to lead NIH CIT,” said Dr. Bertagnolli. “I look forward to welcoming Dr. Mooney to the NIH leadership team and extend my gratitude to Ivor D’Souza who is serving as acting director of CIT following the retirement of former director Andrea Norris in September 2022.”
As CIT director, Dr. Mooney will oversee an approximately $400 million portfolio that includes a world-renowned supercomputer that allows researchers to conduct large-scale data analyses; a state-of-the-art network that enables research across NIH and around the world; cloud-based services that give researchers a cost-effective way to access datasets and advanced computational tools and services; and the latest collaboration tools to promote flexibility and productivity. CIT collaborates with the NIH intramural community in computational bioscience, engineering, informatics and statistics to help make biomedical discoveries that protect and improve our nation’s health. Additionally, CIT provides IT infrastructure and IT services to support all of NIH.
NIH collaboration has implications for neural-immune system responses and aging
In a recent study of the brain’s waste drainage system, researchers from Washington University in St. Louis, collaborating with investigators at the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institute of Health (NIH), discovered a direct connection between the brain and its tough protective covering, the dura mater. These links may allow waste fluid to leave the brain while also exposing the brain to immune cells and other signals coming from the dura. This challenges the conventional wisdom which has suggested that the brain is cut off from its surroundings by a series of protective barriers, keeping it safe from dangerous chemicals and toxins lurking in the environment.
“Waste fluid moves from the brain into the body much like how sewage leaves our homes,” said NINDS’s Daniel S. Reich, M.D., Ph.D. “In this study, we asked the question of what happens once the ‘drain pipes’ leave the ‘house’ — in this case, the brain — and connect up with the city sewer system within the body.” Reich’s group worked jointly with the lab of Jonathan Kipnis, Ph.D., a professor at Washington University in St. Louis.
Reich’s lab used high-resolution magnetic resonance imaging (MRI) to observe the connection between the brain and body’s lymphatic systems in humans. Meanwhile Kipnis’s group was independently using live-cell and other microscopic brain imaging techniques to study these systems in mice.
Fluid containing light-emitting molecules was seen to slip through the arachnoid barrier where blood vessels passed through.
Proteins could serve as biomarkers that improve diagnosis and guide the development of novel therapies
Researchers at the National Institutes of Health detected abnormal proteins in the spinal fluid of people with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which could help improve diagnosis of these diseases. The findings were published in Science Translational Medicine.
The proteins in question are built from 'cryptic' exons — abnormal portions of RNA, the cell’s instructions for how to build proteins. Cryptic exons occur when TDP-43, a protein that regulates how RNA is processed, stops functioning normally. TDP-43 dysfunction is linked to ALS, FTD, Alzheimer’s disease, and Limbic Associated TDP-43 Encephalopathy (LATE).
The study showed that these mis-spliced sections of RNA can sometimes generate new proteins from the cryptic sequence. The findings advance our understanding of how cryptic exons may be involved in the dementia disease process and could help identify diseases involving TDP-43 dysfunction before symptoms appear. Currently, TDP-43 aggregates in the brain can only be detected at autopsy.
Protein containing a cryptic peptide (red) that results from a lack of functional TDP-43, as in ALS and FTD.
An analysis conducted by the National Institutes of Health’s National Center for Complementary and Integrative Health (NCCIH) reveals a substantial increase in the overall use of complementary health approaches by American adults from 2002 to 2022. The study, published in the Journal of the American Medical Association, highlights a surge in the adoption of complementary health approaches for pain management over the same period.
Researchers utilized data from the 2002, 2012, and 2022 National Health Interview Survey (NHIS) to evaluate changes in the use of seven complementary health approaches, including yoga, meditation, massage therapy, chiropractic care, acupuncture, naturopathy, and guided imagery/progressive muscle relaxation.
Researchers at the National Institutes of Health observed rapid and distinct immune system changes in a small study of people who switched to a vegan or a ketogenic (also called keto) diet. Scientists closely monitored various biological responses of people sequentially eating vegan and keto diets for two weeks, in random order. They found that the vegan diet prompted responses linked to innate immunity — the body’s non-specific first line of defense against pathogens — while the keto diet prompted responses associated with adaptive immunity — pathogen-specific immunity built through exposures in daily life and vaccination. Metabolic changes and shifts in the participants’ microbiomes — communities of bacteria living in the gut — were also observed. More research is needed to determine if these changes are beneficial or detrimental and what effect they could have on nutritional interventions for diseases such as cancer or inflammatory conditions.
Scientific understanding of how different diets impact the human immune system and microbiome is limited. Therapeutic nutritional interventions — which involve changing the diet to improve health — are not well understood, and few studies have directly compared the effects of more than one diet. The keto diet is a low-carbohydrate diet that is generally high in fat. The vegan diet eliminates animal products and tends to be high in fiber and low in fat.
The study was conducted by researchers from the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the Metabolic Clinical Research Unit in the NIH Clinical Center. The 20 participants were diverse with respect to ethnicity, race, gender, body mass index (BMI), and age. Each person ate as much as desired of one diet (vegan or keto) for two weeks, followed by as much as desired of the other diet for two weeks. People on the vegan diet, which contained about 10% fat and 75% carbohydrates, chose to consume fewer calories than those on the keto diet, which contained about 76% fat and 10% carbohydrates. Throughout the study period, blood, urine, and stool were collected for analysis. The effects of the diets were examined using a “multi-omics” approach that analyzed multiple data sets to assess the body’s biochemical, cellular, metabolic, and immune responses, as well as changes to the microbiome. Participants remained on site for the entire month-long study, allowing for careful control of the dietary interventions.
Scientists have unexpectedly discovered that the weakened form of the bacteria Coxiella burnetii (C. burnetii) not typically known to cause disease, naturally acquired an ability to do so. C. burnetii causes Q Fever in humans and its weakened forms are those used for scientific purposes. Subsequently, the scientists identified the genetic mutation responsible for the increased ability to cause disease (virulence) and created a form of the bacteria without the genetic flaw that could safely be used for research. The study, by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health and collaborators at Washington State University and Northern Arizona University, is published in Nature Communications.
C. burnetti naturally infects livestock, including goats, sheep and cattle. The bacterium causes Q Fever, a rare human disease with fewer than 1,000 cases annually reported in the United States. Individuals at highest risk for C. burnetii infection include farmers, veterinarians and animal researchers as infection is caused by breathing dust contaminated by infected animal products, such as feces, urine, milk, and birth products. Q Fever is characterized by mild-to-severe flu-like symptoms and can be treated with antibiotics. Those who develop severe disease may experience infection of the lungs (pneumonia) or liver (hepatitis). A small percentage of people (fewer than 5 out of 100) who are infected develop a more serious infection called chronic Q fever, which develops months or years following the initial infection. This condition requires months of antibiotic treatment and can result in death.
A dry fracture of a Vero cell exposing the contents of a vacuole where Coxiella burnetii are busy growing.
NIH researchers found widespread differences in the brains of children with anxiety disorders that improved after treatment
Researchers at the National Institutes of Health have found overactivation in many brain regions, including the frontal and parietal lobes and the amygdala, in unmedicated children with anxiety disorders. They also showed that treatment with cognitive behavioral therapy (CBT) led to improvements in clinical symptoms and brain functioning. The findings illuminate the brain mechanisms underlying the acute effects of CBT to treat one of the most common mental disorders. The study, published in the American Journal of Psychiatry, was led by researchers at NIH’s National Institute of Mental Health (NIMH).
“The findings can help our understanding of how and for which children CBT works, a critical first step in personalizing anxiety care and improving clinical outcomes,” said senior author Melissa Brotman, Ph.D., Chief of the Neuroscience and Novel Therapeutics Unit in the NIMH Intramural Research Program.
Sixty-nine unmedicated children diagnosed with an anxiety disorder underwent 12 weeks of CBT following an established protocol. CBT, which involves changing dysfunctional thoughts and behaviors through gradual exposure to anxiety-provoking stimuli, is the current gold standard for treating anxiety disorders in children.
Three different HIV antibodies each independently protected monkeys from acquiring simian-HIV (SHIV) in a placebo-controlled proof-of-concept study intended to inform development of a preventive HIV vaccine for people. The antibodies — a human broadly neutralizing antibody and two antibodies isolated from previously vaccinated monkeys — target the fusion peptide, a site on an HIV surface protein that helps the virus fuse with and enter cells. The study, published in Science Translational Medicine, was led by the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
Antibodies that target the fusion peptide can neutralize diverse strains of HIV in vitro, that is, in a test tube or culture dish outside of a living organism. The NIAID VRC isolated a fusion peptide-directed human antibody, called VRC34.01, from a person living with HIV who donated blood samples for research. They also isolated two antibodies from rhesus macaques — a species of monkey with immune systems like humans’ — who previously had received a vaccine regimen designed to generate fusion peptide-directed antibodies. Demonstrating that these antibodies protect animals would validate the fusion peptide as a target for human vaccine design. SHIV challenge—administering an infective dose of SHIV — to rhesus macaques is a widely used animal model for assessing the performance of HIV antibodies and vaccines.
In this study, rhesus macaques in each of four groups received a single intravenous infusion of one type of antibody — a 2.5 or 10 mg/kg of bodyweight dose of VRC34.01, or one of the two vaccine-elicited rhesus macaque antibodies — and other monkeys received a placebo infusion. To determine the protective effect of the antibodies, each monkey was challenged five days after infusion with a strain of SHIV known to be sensitive to fusion peptide-directed antibodies.
Transmission electron micrograph of HIV-1 virus particles (red) budding and replicating from a segment of a chronically infected H9 cell (blue).
An atlas revealing the activity of individual placental cells during childbirth offers insight on what happens at the maternal-fetal interface during term labor, according to a study supported by the National Institutes of Health (NIH). The atlas provides a single-cell analysis of the human placenta and its surrounding membranes and is the first to use this method to understand the communication that occurs between maternal and fetal cells during the process of labor. Studying these processes aids understanding of typical labor and delivery at term, as well as preterm labor and delivery, which occurs before 37 weeks of pregnancy and is a leading cause of infant death and long-term disability. The work, led by researchers at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), is published in the latest issue of Science Translational Medicine.
The study team created the placental atlas by using single-cell RNA sequencing (also called single-cell transcriptomics), which examines the activity and signaling patterns of individual cells. The atlas, which is based on samples from 42 term pregnancies, describes changes in gene expression patterns among the different cell types in the placenta and its surrounding membranes, which include both maternal and fetal-derived cells.
The researchers found that cells most affected by labor were in the chorioamniotic membranes, which surround the fetus and rupture as part of the labor and delivery process. They also found that fetal stromal and maternal decidual cells were particularly active in generating inflammatory signaling. These findings are consistent with previous research showing that inflammation (unrelated to infection) is important for sustaining labor.
