Wednesday, July 11, 2018
Findings could inform the development of new antimalarial drugs
The vacuole, a compartment inside human red blood cells in which malaria parasites reproduce and develop, takes on a distinct spherical shape just minutes before its membrane ruptures, leading to the release of parasites into the blood stream, according to researchers at the National Institutes of Health and other institutions. Their study appears in Cellular Microbiology.
The researchers, working with red blood cells from healthy donors, were able to chemically block the sequence of events leading to this rounding of the vacuole. They note that targeting this sequence could inform new treatment strategies against Plasmodium falciparum, the species of malaria parasite that causes the most deaths worldwide and, in several areas, has become drug-resistant.
To track the rounding sequence under a microscope, researchers dyed the membrane of the vacuole with a substance that gives off green light. About 10 minutes before the membrane ruptured, the vacuole morphed from a lumpy, uneven shape to a sphere. Previous studies have shown that malaria parasites use calcium to trigger the biochemical reactions needed for their release from the cell. When the researchers treated the cells with a compound that blocks calcium’s effect, the vacuoles couldn’t transition to the spherical form, trapping the parasites inside the cell.
Wednesday, July 11, 2018
Details could advance vaccine development for several human diseases
Virus-like particles (VLPs) are protein-based structures that mimic viruses and bind to antibodies. Because VLPs are not infectious, they show considerable promise as vaccine platforms for many viral diseases, including influenza. Realizing that fine details about influenza VLPs were scant, a team of researchers who specialize in visualizing molecular structures developed a 3D model based on the 1918 H1 pandemic influenza virus. They say their research, which appears online in Scientific Reports, could benefit VLP vaccine projects, targeting a range of viruses from HIV to Ebola and SARS coronavirus. The research was conducted by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
Other researchers had produced VLPs for 1918 H1 influenza that successfully protected animals from different influenza viruses. The NIAID group prepared hundreds of such VLP samples and analyzed their structure with a technique called cryo-electron microscopy, which quick-freezes samples with glass-like clarity. They then sliced through those VLP 3D structures—like slicing through a loaf of bread—to analyze their internal structure, using computers to document the size and placement of key molecules. After averaging all their data, the group then created a 3D 1918 influenza VLP model.
On the left is a 1918 H1 influenza virus-like particle (VLP) as seen by cryo-electron microscopy. On the right is the same VLP rendered in 3D with structural components computationally segmented and colored; hemagglutinin and membrane are light blue and internal components (molecular cargo) are red.
Tuesday, July 10, 2018
IRP study uses software and cameras to monitor teen driving behaviors
Teenage drivers are eight times more likely to be involved in a collision or near miss during the first three months after getting a driver’s license, compared to the previous three months on a learner’s permit, suggests a study led by the National Institutes of Health. Teens are also four times more likely to engage in risky behaviors, such as rapid acceleration, sudden braking and hard turns, during this period. In contrast, teens on a learner’s permit drove more safely, with their crash/near crash and risky driving rates similar to those of adults. The study appears in the Journal of Adolescent Health.
“Given the abrupt increase in driving risks when teenagers start to drive independently, our findings suggest that they may benefit from a more gradual decrease in adult supervision during the first few months of driving alone,” said Bruce Simons-Morton, Ed.D., M.P.H., senior investigator at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and one of the authors of the study.
Friday, July 6, 2018
IRP scientists see therapeutic potential against bacteria, viruses
National Institutes of Health researchers have identified a naturally occurring lipid—a waxy, fatty acid—used by a disease-causing bacterium to impair the host immune response and increase the chance of infection. Inadvertently, they also may have found a potent inflammation therapy against bacterial and viral diseases.
Lipids are known to help Francisella tularensis bacteria, the cause of tularemia, to suppress host inflammation when infecting mouse and human cells. In a new study published in the Journal of Innate Immunity, researchers from NIH’s National Institute of Allergy and Infectious Diseases found a form of the lipid phosphatidylethanoloamine, or PE, present in the bacterium. The composition of PE found in F. tularensis differs from PE found in other bacteria. In cell-culture experiments, the researchers discovered that the natural and a synthetic form of PE reduced inflammation caused by both tularemia bacteria and dengue fever virus.
Thursday, June 28, 2018
NIH and Iowa researchers shed light on molecular mechanisms of inherited form of human deafness
A small-molecule drug is the first to preserve hearing in a mouse model of an inherited form of progressive human deafness, report investigators at the University of Iowa, Iowa City, and the National Institutes of Health’s National Institute on Deafness and Other Communication Disorders (NIDCD). The study, which appears online in Cell, sheds light on the molecular mechanism that underlies a form of deafness (DFNA27), and suggests a new treatment strategy.
“We were able to partially restore hearing, especially at lower frequencies, and save some sensory hair cells,” said Thomas B. Friedman, Ph.D., chief of the Laboratory of Human Molecular Genetics at the NIDCD, and a coauthor of the study. “If additional studies show that small-molecule-based drugs are effective in treating DFNA27 deafness in people, it’s possible that using similar approaches might work for other inherited forms of progressive hearing loss.”
In mice with a mutation that induces hearing loss, treatment with HDAC inhibitors partially
restored the organization and structure of hair cells (pictured above).
Wednesday, June 27, 2018
Young women with high body fat have a decreased chance of developing breast cancer before menopause, according to scientists at the National Institutes of Health and their collaborators. The finding, published online in the journal JAMA Oncology, may help researchers better understand the role obesity plays in breast cancer risk.
"It is well known that women who gain weight, particularly after menopause, carry an increased risk of postmenopausal breast cancer," said Dale Sandler, Ph.D., co-senior author and head of the Epidemiology Branch at the National Institute of Environmental Health Sciences (NIEHS), part of NIH. "Our finding that breast cancer risk is not increased in obese premenopausal women, and in fact decreases, points to the possibility that different biologic mechanisms are responsible for causing breast cancer in younger women."
Thursday, June 7, 2018
Women in early pregnancy who have high levels of a certain thyroid hormone may be at greater risk for gestational diabetes, compared to women who have normal levels of the hormone, according to researchers at the National Institutes of Health. Their study appears in the Journal of Clinical Endocrinology and Metabolism.
The researchers found that pregnant women with the highest levels of the thyroid hormone triiodothyronine (T3), were more than four times more likely to develop gestational diabetes, compared to women with lower levels of the hormone. T3 is produced from the related hormone thyroxine (T4). The researchers also found that a high T3/T4 ratio — which indicates a high conversion rate from T4 to T3 — was strongly associated with a higher risk for gestational diabetes.
Monday, June 4, 2018
IRP study results represent major advance for structure-based HIV vaccine design
An experimental vaccine regimen based on the structure of a vulnerable site on HIV elicited antibodies in mice, guinea pigs and monkeys that neutralize dozens of HIV strains from around the world. The findings were reported today in the journal Nature Medicine by researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and their colleagues.
Peter D. Kwong, Ph.D., and John R. Mascola, M.D., led the study. Dr. Kwong is chief of the Structural Biology Section at the NIAID Vaccine Research Center, and Dr. Mascola is the center director.
“NIH scientists have used their detailed knowledge of the structure of HIV to find an unusual site of vulnerability on the virus and design a novel and potentially powerful vaccine,” said NIAID Director Anthony S. Fauci, M.D. “This elegant study is a potentially important step forward in the ongoing quest to develop a safe and effective HIV vaccine.”
This protein structure diagram illustrates the location of the fusion peptide epitope (red) on the HIV spike (green), which projects out of the viral membrane (grey). The diagram also shows how a broadly neutralizing antibody (yellow) binds to the fusion peptide.
Monday, June 4, 2018
A novel approach to immunotherapy developed by researchers at the National Cancer Institute (NCI) has led to the complete regression of breast cancer in a patient who was unresponsive to all other treatments. This patient received the treatment in a clinical trial led by Steven A. Rosenberg, M.D., Ph.D., chief of the Surgery Branch at NCI’s Center for Cancer Research (CCR), and the findings were published June 4, 2018 in Nature Medicine. NCI is part of the National Institutes of Health.
“We’ve developed a high-throughput method to identify mutations present in a cancer that are recognized by the immune system,” Dr. Rosenberg said. “This research is experimental right now. But because this new approach to immunotherapy is dependent on mutations, not on cancer type, it is in a sense a blueprint we can use for the treatment of many types of cancer.”
The new immunotherapy approach is a modified form of adoptive cell transfer (ACT). ACT has been effective in treating melanoma, which has high levels of somatic, or acquired, mutations. However, it has been less effective with some common epithelial cancers, or cancers that start in the lining of organs, that have lower levels of mutations, such as stomach, esophageal, ovarian, and breast cancers.
Left: MRI scans of a woman with breast cancer before TIL therapy show a lesion invading the chest wall (top) and metastatic lesions in the liver (bottom). Right: Scans 14 months after treatment show all lesions have disappeared.
Thursday, May 31, 2018
IRP study finds Information integration trumps emotional, sensory, motor functions
Some human brains are nearly twice the size of others — but how might that matter? Researchers at the National Institute of Mental Health (NIMH) and their NIH grant-funded colleagues have discovered that these differences in size are related to the brain’s shape and the way it is organized. The bigger the brain, the more its additional area is accounted for by growth in thinking areas of the cortex, or outer mantle – at the expense of relatively slower growth in lower order emotional, sensory, and motor areas.
This mirrors the pattern of brain changes seen in evolution and individual development – with higher-order areas showing greatest expansion. The researchers also found evidence linking the high-expanding regions to higher connectivity between neurons and higher energy consumption.
“Just as different parts are required to scale-up a garden shed to the size of a mansion, it seems that big primate brains have to be built to different proportions,” explained Armin Raznahan, M.D., Ph.D., of the NIMH Intramural Research Program (IRP). “An extra investment has to be made in the part that integrates information – but that’s not to say that it’s better to have a bigger brain. Our findings speak more to the different organizational needs of larger vs. smaller brains.”
Larger human brains show relatively more growth in integrative cortex areas (red) than smaller human brains – at a cost of relatively less growth in lower sensory, motor and emotion processing areas.