Friday, August 5, 2022
Researchers hope discovery leads to potential treatments for mitochondrial diseases
Researchers from the National Institutes of Health have developed a three-dimensional structure that allows them to see how and where disease mutations on the twinkle protein can lead to mitochondrial diseases. The protein is involved in helping cells use energy our bodies convert from food. Prior to the development of this 3D structure, researchers only had models and were unable to determine how these mutations contribute to disease. Mitochondrial diseases are a group of inherited conditions that affect 1 in 5,000 people and have very few treatments.
“For the first time, we can map the mutations that are causing a number of these devastating diseases,” said lead author Amanda A. Riccio, Ph.D., and researcher in the National Institute of Environmental Health Sciences (NIEHS) Mitochondrial DNA Replication Group, which is part of NIH. “Clinicians can now see where these mutations lie and can use this information to help pinpoint causes and help families make choices, including decisions about having more children.”
The new findings will be particularly relevant for developing targeted treatments for patients who suffer from mitochondrial diseases such as progressive external ophthalmoplegia, a condition that can lead to loss of muscle functions involved in eye and eyelid movement; Perrault syndrome, a rare genetic disorder that can cause hearing loss; infantile-onset spinocerebellar ataxia, a hereditary neurological disorder; and hepatocerebral mitochondrial DNA (mtDNA) depletion syndrome, a hereditary disease that can lead to liver failure and neurological complications during infancy.
This image depicts the 3D structure that NIEHS researchers created of the twinkle
protein. The researchers used cryo-electron microscopy and other techniques to show
how disease mutations on the protein can lead to mitochondrial diseases.
Thursday, August 4, 2022
Larger trials enrolling infants and children are underway in Mali and Kenya
One injection of a candidate monoclonal antibody (mAb) known as L9LS was found to be safe and highly protective in U.S. adults exposed to the malaria parasite, according to results from a National Institutes of Health Phase 1 clinical trial published in The New England Journal of Medicine. Additional clinical trials evaluating if L9LS can prevent malaria over six to 12 months against seasonal and perennial transmission are underway in infants and children in Mali and Kenya, where malaria is endemic. The trial was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH.
“These early clinical trial results demonstrating that a monoclonal antibody administered subcutaneously can protect people from malaria are highly encouraging,” said NIAID Director Anthony S. Fauci, M.D. “A one-time intervention that protects against malaria for six months to a year could significantly reduce morbidity and mortality among children in malaria-endemic regions and offer an effective preventive tool for health care workers, military personnel and travelers to these areas.”
Malaria is a mosquito-borne disease caused by Plasmodium parasites. The World Health Organization estimates that in 2020, about 240 million people had malaria and about 627,000 of them died. A disproportionate burden of malarial disease is seen in Sub-Saharan Africa, where children under age 5 account for approximately 80% of all malaria deaths. A vaccine to prevent malaria is now available; however, its variable efficacy underscores the need for new interventions that offer high-level protection against disease.
This image shows the lifecycle of the malaria parasite in a person.
Thursday, July 28, 2022
Discovery sets the stage for development of new therapies to treat vitelliform macular dystrophy
Using a new imaging technique, researchers from the National Eye Institute have determined that retinal lesions from vitelliform macular dystrophy (VMD) vary by gene mutation. Addressing these differences may be key in designing effective treatments for this and other rare diseases. NEI is part of the National Institutes of Health.
"The NEI's long-term investment in imaging technology is changing our understanding of eye diseases," said NEI Director Michael F. Chiang, M.D. "This study is just one example of how improved imaging can reveal subtle details about pathology in a rare eye disease that can inform the development of therapeutics.”
VMD is an inherited genetic disease that causes progressive vision loss through degeneration of the light-sensing retina. Genes implicated in VMD include BEST1, PRPH2, IMPG1, and IMPG2. Depending on the gene and mutation, age of onset and severity vary widely. All forms of the disease have in common a lesion in the central retina (macula) that looks like an egg yolk and is a build-up of toxic fatty material called lipofuscin. VMD affects about 1 in 5,500 Americans and there is currently no treatment for this condition.
Johnny Tam, Ph.D., head of the NEI Clinical and Translational Imaging Unit, used multimodal imaging to evaluate the retinas of patients with VMD at the NIH Clinical Center. Tam’s multimodal imaging uses adaptive optics — a technique that employs deformable mirrors to improve resolution — to view live cells in the retina, including the light-sensing photoreceptors, retinal pigment epithelial (RPE) cells, and blood vessels in unprecedented detail.
Retina with egg-yolk-like lesion in a person with vitelliform macular dystrophy.
Monday, July 18, 2022
Loss of the protein pigment epithelium-derived factor (PEDF), which protects retinal support cells, may drive age-related changes in the retina, according to a new study in mice from the National Eye Institute (NEI). The retina is the light-sensitive tissue at the back of the eye, and aging-associated diseases of the retina, like age-related macular degeneration (AMD), can lead to blindness. This new finding could lead to therapies to prevent AMD and other aging conditions of the retina. The study was published in the International Journal of Molecular Sciences. NEI is part of the National Institutes of Health.
“People have called PEDF the ‘youth’ protein, because it is abundant in young retinas, but it declines during aging,” said Patricia Becerra, Ph.D., chief of NEI’s Section of Protein Structure and Function and senior author of the study. “This study showed for the first time that just removing PEDF leads to a host of gene changes that mimic aging in the retina.”
The retina is composed of layers of cells that function together to detect and process light signals, which the brain uses to generate vision. The retina’s light-sensing photoreceptors sit above the retinal pigment epithelium (RPE), a layer of support cells. The RPE nourishes photoreceptors and recycles pieces of the photoreceptor cells called 'outer segments,' which get used up and their tips shed each time photoreceptors detect light. If the RPE cannot provide recycled components of older outer segment tips back to photoreceptors, these cells lose their ability to make new segments, and eventually become unable to sense light. And without nutrients supplied by the RPE, photoreceptors die. In people with AMD or certain types of retinal dystrophies, senescence (aging) or death of RPE cells in the retina leads to vision loss.
RPE from mice without Serpin1 accumulate more lipids than wild-type mice. Super-resolution confocal microscopy of RPE tissue from wild-type (upper) and Serpin1-null (lower) mice. Detailed images on the right are magnified regions of the RPE tissue imaged on the left (dotted square area). RPE cell boundaries are stained in red, and accumulated lipids are stained in green.
Thursday, July 14, 2022
Researchers from the National Cancer Institute, part of the National Institutes of Health, and their collaborators have discovered that people of European and African ancestries who were hospitalized for COVID-19 are more likely to carry a particular combination of genetic variants in a gene known as OAS1 than patients with mild disease who were not hospitalized. People with this combination of genetic variants also remain positive for SARS-CoV-2 infection longer. However, interferon treatment may reduce the severity of COVID-19 in people with these genetic factors. Interferons are a type of protein that can help the body’s immune system fight infection and other diseases, such as cancer.
The study appears July 14 in Nature Genetics.
These findings build on previous studies that have suggested that genetic factors, such as genetic variants affecting OAS antiviral proteins that facilitate the detection and breakdown of the SARS-CoV-2 virus, may influence the risk of SARS-CoV-2 infection.
The NCI researchers and their collaborators found that treatment of cells with an interferon decreased the viral load of SARS-CoV-2. The researchers also analyzed data from a clinical trial in which patients with COVID-19 who were not hospitalized were treated with the recombinant interferon pegIFN-λ1 and found that treatment improved viral clearance in all patients; those with the OAS1 risk variants benefitted the most. The results suggest that interferon treatment may improve COVID-19 outcomes and specifically in patients with certain OAS1 genetic variants who have impaired ability to clear infection.
Monday, July 11, 2022
NIH study of pregnant women confirms link with chemicals that could put pregnancy at risk
Pregnant women who were exposed to multiple phthalates during pregnancy had an increased risk of preterm birth, according to new research by the National Institutes of Health. Phthalates are chemicals used in personal care products, such as cosmetics, as well as in solvents, detergents, and food packaging.
After analyzing data from more than 6,000 pregnant women in the United States, researchers found that women with higher concentrations of several phthalate metabolites in their urine were more likely to deliver their babies preterm, which is delivering three or more weeks before a mother’s due date.
“Having a preterm birth can be dangerous for both baby and mom, so it is important to identify risk factors that could prevent it,” said Kelly Ferguson, Ph.D., an epidemiologist at the National Institute of Environmental Health Sciences (NIEHS), part of NIH, and the senior author on the study published in the journal JAMA Pediatrics.
The image shows how a pregnant person may be exposed to phthalates
by eating packaged foods and beverages or through personal care product use.
Thursday, July 7, 2022
Newly identified brain circuits may point to more effective pain therapies
An international team of scientists has identified the neural mechanisms through which sound blunts pain in mice. The findings, which could inform development of safer methods to treat pain, were published in Science. The study was led by researchers at the National Institute of Dental and Craniofacial Research (NIDCR); the University of Science and Technology of China, Hefei; and Anhui Medical University, Hefei, China. NIDCR is part of the National Institutes of Health.
“We need more effective methods of managing acute and chronic pain, and that starts with gaining a better understanding of the basic neural processes that regulate pain,” said NIDCR Director Rena D’Souza, D.D.S., Ph.D. “By uncovering the circuitry that mediates the pain-reducing effects of sound in mice, this study adds critical knowledge that could ultimately inform new approaches for pain therapy.”
Dating back to 1960, studies in humans have shown that music and other kinds of sound can help alleviate acute and chronic pain, including pain from dental and medical surgery, labor and delivery, and cancer. However, how the brain produces this pain reduction, or analgesia, was less clear.
“Human brain imaging studies have implicated certain areas of the brain in music-induced analgesia, but these are only associations,” said co-senior author Yuanyuan (Kevin) Liu, Ph.D., a Stadtman tenure-track investigator at NIDCR. “In animals, we can more fully explore and manipulate the circuitry to identify the neural substrates involved.”
Sound reduces pain in mice by lowering the activity of neurons in the
brain’s auditory cortex (green and magenta) that project to the thalamus.
Wednesday, July 6, 2022
Photoreceptor cells in mice drive vision and non-vision functions using distinct circuits in the eye
The eye’s light-sensing retina taps different circuits depending on whether it is generating image-forming vision or carrying out a non-vision function such as regulating pupil size or sleep/wake cycles, according to a new mouse study from the National Eye Institute (NEI) and the National Institute of Mental Health (NIMH). The findings could have implications for understanding how our eyes help regulate mood, digestion, sleep, and metabolism. NEI and NIMH are part of the National Institutes of Health.
“We know a lot about pathways involved in image-forming vision, but until now it remained unknown if and how non-image-forming visual behaviors rely on these same pathways in the eye,” said Johan Pahlberg, Ph.D., head of the Photoreceptor Physiology Group at NEI and a senior author of the study.
Vision begins when light travels into the eye and hits the retina’s light-sensing photoreceptors. The photoreceptors transfer signals through several layers of retinal neuron before those signals are sent to the brain. Light also triggers certain non-vision functions, such as controlling how much light enters the eye through the pupil (pupillary light reflex) and regulating the wake/sleep cycle (circadian rhythm). Circadian rhythm disruption has been linked to sleep problems, obesity, and other health issues.
Image-forming and non-image-forming functions use different neuronal circuits in the retina.
Tuesday, July 5, 2022
Findings could give insight into long-term neurological symptoms of COVID-19
A study from the National Institutes of Health describes the immune response triggered by COVID-19 infection that damages the brain’s blood vessels and may lead to short- and long-term neurological symptoms. In a study published in Brain, researchers from the National Institute of Neurological Disorders and Stroke (NINDS) examined brain changes in nine people who died suddenly after contracting the virus.
The scientists found evidence that antibodies — proteins produced by the immune system in response to viruses and other invaders — are involved in an attack on the cells lining the brain’s blood vessels, leading to inflammation and damage. Consistent with an earlier study from the group, SARS-CoV-2 was not detected in the patients’ brains, suggesting the virus was not infecting the brain directly.
Understanding how SARS-CoV-2 can trigger brain damage may help inform development of therapies for COVID-19 patients who have lingering neurological symptoms.
“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological process is not well understood,” said Avindra Nath, M.D., clinical director at NINDS and the senior author of the study. “We had previously shown blood vessel damage and inflammation in patients’ brains at autopsy, but we didn’t understand the cause of the damage. I think in this paper we’ve gained important insight into the cascade of events.”
SARS-CoV-2 infection can trigger the production of immune molecules that damage cells lining blood vessels in the brain, causing platelets to stick together and form clots. Blood proteins also leak from the blood vessels, leading to inflammation and the destruction of neurons.
Wednesday, June 29, 2022
A class of viruses known to cause severe diarrheal diseases — including the one famous for widespread outbreaks on cruise ships — can grow in the salivary glands of mice and spread through their saliva, scientists at the National Institutes of Health have discovered. The findings show that a new route of transmission exists for these common viruses, which afflict billions of people each year worldwide and can be deadly.
The transmission of these so-called enteric viruses through saliva suggests that coughing, talking, sneezing, sharing food and utensils, and even kissing all have the potential for spreading the viruses. The new findings still need to be confirmed in human studies.
The findings, which appear in the journal Nature, could lead to better ways to prevent, diagnose, and treat diseases caused by these viruses, potentially saving lives. The study was led by the National Heart, Lung, and Blood Institute (NHLBI), part of NIH.
A microscopic view of salivary gland acinar epithelial cells (pink) infected with rotavirus (green), a type of enteric virus, in a mouse.