Thursday, April 2, 2020
NIH study provides insight into one mechanism underlying the higher prevalence of males in some cases of autism
A new study in Neuron offers clues to why autism spectrum disorder (ASD) is more common in boys than in girls. National Institutes of Health scientists found that a single amino acid change in the NLGN4 gene, which has been linked to autism symptoms, may drive this difference in some cases. The study was conducted at NIH’s National Institute of Neurological Disorders and Stroke (NINDS).
Researchers led by Katherine Roche, Ph.D., a neuroscientist at NINDS, compared two NLGN4 genes, (one on the X chromosome and one on the Y chromosome), which are important for establishing and maintaining synapses, the communication points between neurons.
Every cell in our body contains two sex chromosomes. Females have two X chromosomes; males have one X and one Y chromosome. Until now, it was assumed that the NLGN4X and NLGN4Y genes, which encode proteins that are 97% identical, functioned equally well in neurons.
New findings suggest that a single mutation may contribute to increased prevalence of autism in boys than in girls.
Tuesday, March 31, 2020
Findings provide insight that may inform search for treatments
Researchers at the National Institutes of Health have discovered a second gene that causes melorheostosis, a rare group of conditions involving an often painful and disfiguring overgrowth of bone tissue. The gene, SMAD3, is part of a pathway that regulates cell development and growth. The researchers are now working to develop an animal model with a mutant version of SMAD3 to test potential treatments for the condition. The study appears in the Journal of Experimental Medicine.
Melorheostosis affects about 1 in 1 million people. Its causes have long been unknown. DNA tests of blood and skin could not identify a mutation. The key to finding the gene was to biopsy the affected bone directly and compare it to unaffected bone. Earlier, the researchers used this method to discover the gene for “dripping candle wax bone disease,” a form of melorheostosis in which excess bone growth appears to drip from the bone surface like hot wax. In that study, mutations in the gene MAP2K1 accounted for eight cases of the disease among 15 patients.
In the current study, researchers scanned the exome — the part of the genome that codes for proteins — and found mutations in the affected bone. These mutations occurred during the patient’s lifetime rather than being inherited from parents and are not present in all the cells of the body.
The researchers found SMAD3 mutations in four of the patients who did not have mutations in MAP2K1. SMAD3 is involved in a pathway crucial for skeletal development both before and after birth. The SMAD3 mutations increase the maturation of bone-forming cells and are involved in a cellular pathway distinct from the MAPK2K1 pathway.
Friday, March 27, 2020
Findings may have implications for understanding epilepsy, autism spectrum disorders
Researchers at the National Institutes of Health have discovered in mice what they believe is the first known genetic mutation to improve cognitive flexibility — the ability to adapt to changing situations. The gene, KCND2, codes for a protein that regulates potassium channels, which control electrical signals that travel along neurons. The electrical signals stimulate chemical messengers that jump from neuron to neuron. The researchers were led by Dax Hoffman, Ph.D., chief of the Section on Neurophysiology at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). It appears in Nature Communications.
The KCND2 protein, when modified by an enzyme, slows the generation of electrical impulses in neurons. The researchers found that altering a single base pair in the KCND2 gene enhanced the ability of the protein to dampen nerve impulses. Mice with this mutation performed better than mice without the mutation in a cognitive task. The task involved finding and swimming to a slightly submerged platform that had been moved to a new location. Mice with the mutation found the relocated platform much faster than their counterparts without the mutation.
The researchers plan to investigate whether the mutation will affect neural networks in the animals’ brains. They added that studying the gene and its protein may ultimately lead to insights on the nature of cognitive flexibility in people. It also may help improve understanding of epilepsy, schizophrenia, Fragile X syndrome, and autism spectrum disorder, which all have been associated with other mutations in KCND2.
Tuesday, March 24, 2020
In a new study, higher daily step counts were associated with lower mortality risk from all causes. The research team, which included investigators from the National Cancer Institute (NCI) and the National Institute on Aging (NIA), both parts of the National Institutes of Health, as well as from the Centers for Disease Control and Prevention, also found that the number of steps a person takes each day, but not the intensity of stepping, had a strong association with mortality.
The findings were published March 24, 2020, in the Journal of the American Medical Association.
“While we knew physical activity is good for you, we didn’t know how many steps per day you need to take to lower your mortality risk or whether stepping at a higher intensity makes a difference,” said Pedro Saint-Maurice, Ph.D., of NCI’s Division of Cancer Epidemiology and Genetics, first author of the study. “We wanted to investigate this question to provide new insights that could help people better understand the health implications of the step counts they get from fitness trackers and phone apps.”
Thursday, March 19, 2020
A study by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, offers new insight into genetic alterations associated with osteosarcoma, the most common cancerous bone tumor of children and adolescents. The researchers found that more people with osteosarcoma carry harmful, or likely harmful, variants in known cancer-susceptibility genes than people without osteosarcoma. This finding has implications for genetic testing of children with osteosarcoma, as well as their families.
The study was published March 19, 2020, in JAMA Oncology.
“With this study, we wanted to find out how many people with osteosarcoma may have been at high risk for it because of their genetics,” said Lisa Mirabello, Ph.D., of NCI’s Division of Cancer Epidemiology and Genetics (DCEG), who led the research. “We not only learned that at least a quarter of the people in the study with osteosarcoma had a variant in a gene known to predispose someone to cancer, we also uncovered variants that had never before been associated with this cancer.”
In the study, the researchers looked for harmful (or likely harmful) variants in 238 known cancer-susceptibility genes in DNA samples from 1,244 people with osteosarcoma and compared the frequency of such variants with that in people in a cancer-free control group. They identified a harmful or likely harmful variant in a known cancer-susceptibility gene in 28% of the people with osteosarcoma. By contrast, only 12% of people in the cancer-free control group had such a variant.
An x-ray of a femur (thigh bone) from a patient with osteosarcoma.
Wednesday, March 18, 2020
Findings from a phase 2 clinical trial show that the drug selumetinib improves outcomes for children with the genetic disorder neurofibromatosis type 1 (NF1). In the trial, selumetinib shrank the inoperable tumors that develop with NF1 called plexiform neurofibromas, and children experienced reduced pain, improved function, and better overall quality of life after receiving the treatment.
The trial was led by intramural researchers in the Center for Cancer Research (CCR) at the National Cancer Institute (NCI), part of the National Institutes of Health. Results of the trial were published March 18, 2020, in the New England Journal of Medicine.
“Until now, no effective medical therapies have existed for children with NF1 and plexiform neurofibromas, and it’s been a long journey to find a drug that can help them,” said Brigitte Widemann, M.D., lead author of the study, and chief of CCR’s Pediatric Oncology Branch, which developed and coordinated the trial. “While this is not yet a cure, this treatment is shrinking tumors and it’s making children feel better and have a better quality of life.”
Eva Dombi, M.D., Trish Whitcomb, R.N., Brigitte Widemann, M.D., Andrea Gross, M.D., and Andrea Baldwin, C.R.N.P., of the Pediatric Oncology Branch at NCI.
Tuesday, March 17, 2020
The virus that causes coronavirus disease 2019 (COVID-19) is stable for several hours to days in aerosols and on surfaces, according to a new study from National Institutes of Health, CDC, UCLA and Princeton University scientists in The New England Journal of Medicine. The scientists found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detectable in aerosols for up to three hours, up to four hours on copper, up to 24 hours on cardboard and up to two to three days on plastic and stainless steel. The results provide key information about the stability of SARS-CoV-2, which causes COVID-19 disease, and suggests that people may acquire the virus through the air and after touching contaminated objects. The study information was widely shared during the past two weeks after the researchers placed the contents on a preprint server to quickly share their data with colleagues.
The NIH scientists, from the National Institute of Allergy and Infectious Diseases’ Montana facility at Rocky Mountain Laboratories, compared how the environment affects SARS-CoV-2 and SARS-CoV-1, which causes SARS. SARS-CoV-1, like its successor now circulating across the globe, emerged from China and infected more than 8,000 people in 2002 and 2003. SARS-CoV-1 was eradicated by intensive contact tracing and case isolation measures and no cases have been detected since 2004. SARS-CoV-1 is the human coronavirus most closely related to SARS-CoV-2. In the stability study the two viruses behaved similarly, which unfortunately fails to explain why COVID-19 has become a much larger outbreak.
The NIH study attempted to mimic virus being deposited from an infected person onto everyday surfaces in a household or hospital setting, such as through coughing or touching objects. The scientists then investigated how long the virus remained infectious on these surfaces.
This scanning electron microscope image shows SARS-CoV-2 (yellow) — also known as 2019-nCoV, the virus that causes COVID-19 — isolated from a patient in the U.S., emerging from the surface of cells (blue/pink) cultured in the lab.
Friday, March 13, 2020
Finding may lead to novel therapeutic target for blinding disease
A protein that normally deposits mineralized calcium in tooth enamel may also be responsible for calcium deposits in the back of the eye in people with dry age-related macular degeneration (AMD), according to a study from researchers at the National Eye Institute (NEI). This protein, amelotin, may turn out to be a therapeutic target for the blinding disease. The findings were published in the journal Translational Research. NEI is part of the National Institutes of Health.
“Using a simple cell culture model of retinal pigment epithelial cells, we were able to show that amelotin gets turned on by a certain kind of stress and causes formation of a particular kind of calcium deposit also seen in bones and teeth. When we looked in human donor eyes with dry AMD, we saw the same thing,” said Graeme Wistow, Ph.D., chief of the NEI Section on Molecular Structure and Functional Genomics, and senior author of the study.
There are two forms of AMD — wet and dry. While there are treatments that can slow the progression of wet AMD, there are currently no treatments for dry AMD, also called geographic atrophy. In dry AMD, deposits of cholesterol, lipids, proteins, and minerals accumulate at the back of the eye. Some of these deposits are called soft drusen and have a specific composition, different from deposits found in wet AMD. Drusen form under the retinal pigment epithelium (RPE), a layer of cells that transports nutrients from the blood vessels below to support the light-sensing photoreceptors of the retina above them. As the drusen develop, the RPE and eventually the photoreceptors die, leading to blindness. The photoreceptors cannot grow back, so the blindness is permanent.
Top: HAP spherules (pink) and amelotin protein (green) in soft drusen from eye with dry AMD. Bottom: OCT image of eye with dry AMD, showing soft drusen beneath the retinal pigment epithelium.
Wednesday, March 11, 2020
Disabling key enzymes overcomes previous limitations to blocking angiogenesis, may inform cancer treatment strategies
Scientists at the National Institutes of Health and other institutions have devised a new strategy to stop tumors from developing the new blood vessels they need to grow. Once thought to be extremely promising for the treatment of cancer, blocking molecules that stimulate new blood vessel growth (angiogenesis) has proven ineffective because tumor cells respond by producing more stimulatory molecules. The new strategy involves disabling key enzymes that replenish the molecule that cells need for the reactions that sustain new vessel growth. The research team was led by Brant M. Weinstein, Ph.D., chief of the Section on Vertebrate Organogenesis at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The study appears in Nature Communications.
Among the angiogenesis factors that stimulate new vessel growth is vascular endothelial growth factor (VEGF), which binds to a receptor on cell surfaces. This binding sets off a sequence of chemical reactions inside the cells lining the inside of blood vessels, culminating in new vessel growth. Previous attempts have sought to prevent this binding by targeting VEGF with antibodies or drugs, or by blocking the receptor so VEGF can’t bind to it. However, tumors respond by producing more VEGF, overwhelming such efforts.
After binding occurs, an enzyme that converts the compound phosphatidylinositol-(4,5)-bisphosphate (PIP2) into inositol triphosphate, which is needed for the reactions that fuel new blood vessel growth, and diacylglycerol (DAG). Through a series of enzyme-assisted steps, DAG is converted back into PIP2, allowing it to be recycled, as needed.
The researchers showed that they could stop angiogenesis by blocking any of the enzymes in this PIP2 recycling series. They first halted angiogenesis in human cell cultures and zebrafish embryos by disabling the genes for one or more of the enzymes. They then targeted tumors in mice with drugs that block the recycling enzymes. Compared to normal mice, the treated mice had less tumor and tumor blood vessel growth. Moreover, adding more VEGF depleted any remaining PIP2, further reducing blood vessel growth.
Monday, March 9, 2020
New strategy could be applied to other infectious diseases
A new approach to direct the body to make a specific antibody against HIV led to sustained production of that antibody for more than a year among participants in a National Institutes of Health clinical trial. This drug-delivery technology uses a harmless virus to deliver an antibody gene into human cells, enabling the body to generate the antibody over an extended time. With further development, such a strategy could be applied to prevent and treat a wide variety of infectious diseases, according to the study investigators.
Researchers from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) reported the findings on March 9 in an oral presentation at the 2020 Conference on Retroviruses and Opportunistic Infections (CROI).
Antibodies are immune system proteins that help prevent or clear infections. Traditional vaccines induce the immune system to generate protective antibodies. Another approach to preventing infections is to deliver monoclonal antibodies — preparations of a specific antibody designed to bind to a single target — directly into people. Monoclonal antibodies also are used therapeutically, with many already approved for treating cancer, autoimmune diseases and other conditions and others being evaluated for treatment of infectious diseases, such as Ebola virus disease.
Administering proteins to people requires periodic injections or infusions to retain protective or therapeutic levels, which can be challenging, particularly in resource-limited settings. Delivery of antibody genes using a virus as a carrier, or vector, offers a potential alternative.
The new drug-delivery technology uses a harmless virus to deliver an antibody gene into human cells.