“Alzheimer’s disease is a leading cause of death in the United States,” says Senior Staff Scientist Pamela Maher, a member of Salk’s Cellular Neurobiology Laboratory, run by Professor David Schubert. “And because age is a major risk factor, researchers are looking at ways to counter aging’s effects on the brain. Our identification of sterubin as a potent neuroprotective component of a native California plant called Yerba santa (Eriodictyon californicum) is a promising step in that direction.”

Native California tribes, which dubbed the plant “holy herb” in Spanish, have long used Yerba santa for its medicinal properties. Devotees brew its leaves to treat respiratory ailments, fever and headaches; and mash it into a poultice for wounds, sore muscles and rheumatism.

To identify natural compounds that might reverse neurological disease symptoms, Maher applied a screening technique used in drug discovery to a commercial library of 400 plant extracts with known pharmacological properties. The lab had previously used this approach to identify other chemicals (called flavonoids) from plants that have anti-inflammatory and neuroprotective properties.

Through the screen, the lab identified a molecule called sterubin as Yerba santa’s most active component. The researchers tested sterubin and other plant extracts for their impact on energy depletion in mouse nerve cells, as well as other age-associated neurotoxicity and survival pathways directly related to the reduced energy metabolism, accumulation of misfolded, aggregated proteins and inflammation seen in Alzheimer’s. Sterubin had a potent anti-inflammatory impact on brain cells known as microglia. It was also an effective iron remover — potentially beneficial because iron can contribute to nerve cell damage in aging and neurodegenerative diseases. Overall, the compound was effective against multiple inducers of cell death in the nerve cells, according to Maher.

“This is a compound that was known but ignored,” Maher says. “Not only did sterubin turn out to be much more active than the other flavonoids in Yerba santa in our assays, it appears as good as, if not better than, other flavonoids we have studied.”

Next, the lab plans to test sterubin in an animal model of Alzheimer’s, then determine its drug-like characteristics and toxicity levels in animals. With that data, Maher says, it might be possible to test the compound in humans, although it would be critical to use sterubin derived from plants grown under standardized, controlled conditions. She says the team will likely generate synthetic derivatives of sterubin.

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“Children and families affected by food allergies must constantly guard against an accidental exposure to foods that could cause life-threatening allergic reactions,” said NIAID Director Anthony S. Fauci, M.D. “Eczema is a risk factor for developing food allergies, and thus early intervention to protect the skin may be one key to preventing food allergy.”

Children with atopic dermatitis develop patches of dry, itchy, scaly skin caused by allergic inflammation. Atopic dermatitis symptoms range from minor itchiness to extreme discomfort that can disrupt a child’s sleep and can lead to recurrent infections in scratched, broken skin.

The study, led by Donald Y.M. Leung, M.D., Ph.D., of National Jewish Health in Denver, examined the top layers of the skin, known as the stratum corneum, in areas with eczema lesions and in adjacent normal-looking skin. The study enrolled 62 children aged 4 to 17 who either had atopic dermatitis and peanut allergy, atopic dermatitis and no evidence of any food allergy, or neither condition. Investigators collected skin samples by applying and removing small, sterile strips of tape to the same area of skin. With each removal, a microscopic sublayer of the first layer of skin tissue was collected and preserved for analysis. This technique allowed researchers to determine the skin’s composition of cells, proteins and fats, as well as its microbial communities, gene expression within skin cells and water loss through the skin barrier.

Researchers found that the skin rash of children with both atopic dermatitis and food allergy was indistinguishable from the skin rash of children with atopic dermatitis alone. However, they found significant differences in the structure and molecular composition of the top layer of non-lesional, healthy-appearing skin between children with atopic dermatitis and food allergy compared with children with atopic dermatitis alone. Non-lesional skin from children with atopic dermatitis and food allergy was more prone to water loss, had an abundance of the bacteria Staphylococcus aureus, and had gene expression typical of an immature skin barrier. These abnormalities also were seen in skin with active atopic dermatitis lesions, suggesting that skin abnormalities extend beyond the visible lesions in children with atopic dermatitis and food allergy but not in those with atopic dermatitis alone.

“Our team sought to understand how healthy-looking skin might be different in children who develop both atopic dermatitis and food allergy compared to children with atopic dermatitis alone,” said Dr. Leung. “Interestingly, we found those differences not within the skin rash but in samples of seemingly unaffected skin inches away. These insights may help us not only better understand atopic dermatitis, but also identify children most at risk for developing food allergies before they develop overt skin rash and, eventually, fine tune prevention strategies so fewer children are affected.”

Allergy experts consider atopic dermatitis to be an early step in the so-called “atopic march,” a common clinical progression found in some children in which atopic dermatitis progresses to food allergies and, sometimes, to respiratory allergies and allergic asthma. Many immunologists hypothesize that food allergens may reach immune cells more easily through a dysfunctional skin barrier affected by atopic dermatitis, thereby setting off biological processes that result in food allergies.

The journey from egg and sperm to a fully grown body requires more than just multiplication. Plants, animals, and people are all made of trillions of cells, carefully organized into larger structures like tissues and organs. Somehow, each cell knows where it belongs — the left side of the heart, the inner lining of the colon, and so on — and generally stays put.

“It’s close to impossible to dissect what’s happening while cells position themselves in multicellular organisms because there are so many players: different cell types, different molecules inside cells, different chemical signals outside the cells, cell growth, programmed cell death,” said Professor Satoshi Sawai from the University of Tokyo, an expert in biological physics, a field that uses the principles of physics to understand living systems.

The slime mold system

Slime molds provide a simpler system to understand cell positioning. Slime molds are amoebas, but are similar in size and shape to human white blood cells and share the fundamental aspects of cell dynamics, such as migration and engulfment of disease-causing pathogens.

Individual cells of the slime mold Dictyostelium discoideum can exist independently, living freely in the soil and eating bacteria and fungi. When food is scarce, independent slime mold cells clump together and function as a multicellular organism.

When slime mold cells clump together, sometimes 100 cells, other times 10,000 cells, they differentiate into two distinct types.

The first type, pre-stalk cells, eventually forms a column that supports a sphere composed of the second type, pre-spore cells. Researchers call this two-part structure a fruiting body. The pre-stalk cells will die as the pre-spore cells eventually float off in the wind to a better environment where they can grow and divide again as independent amoebas.

Inside the clump, before the fruiting body takes shape, cells attach to form long trains and swirl around, immersed in a chemical signal that they secrete. First identified in the 1970s, this diffusive chemical, called cAMP, attracts cells.

Traditionally, the degree of attraction to cAMP signals was thought to separate the cells into pre-stalk and pre-spore cells. More recent genetic experiments revealed, however, that molecules related to adhesion, or cell-to-cell touch, may also be important.

“What’s great about slime mold is that you can take individual cells out of the larger structure and they still do their thing by behaving naturally in a relatively simple setup that mimics the multicellular environment,” said Sawai.

Two types of signals

In their new experiments, the researchers took cells out of a multicellular clump and tracked how the individual cells migrate in response to artificial touch and cAMP signals.

When cell trains formed, the leader cell moved in the direction of cAMP. The follower cells were not pulled along, but rather actively pushed leader cells forward.

“Cell-cell contact activates processes for cell movement. The follower cells are the engine and the leader cells are the steering wheel, always pointing in the direction of the chemical signal,” said Sawai.

Researchers also placed individual pre-stalk or pre-spore cells with beads coated with an adhesion molecule that appears to function in the tail end of cells. All cells attached to follow the bead as in a cell train. Researchers then added cAMP to the experiment. Pre-stalk cells released the bead and moved towards the cAMP source. Pre-spore cells, however, ignored cAMP and held fast to the bead.

Sawai’s research team demonstrated that head-to-tail touch between cells directs their migration, but cAMP somehow overrides this contact only in pre-stalk cells.

“Many people think you have to go to Mars to look for the fundamental rules of what makes life. But we can look at all the still-unexplored branches of the tree of life here on Earth. Slime mold gives us hints at what to look for to understand the mechanistic logics underlying more complex species,” said Sawai.

This discovery of the importance of cell-cell contact to activate cell movement and organization will open new possibilities to study cell-pattern formation in events such as embryo development or spread of breast cancer.

The results are published in the Proceedings of the National Academy of Sciences of the United States of America.

When the body’s immune system has just begun attacking cells of a transplanted organ, the new method’s particles send a fluorescent signal into the urine. In a new study, researchers at the Georgia Institute of Technology and Emory University validated the method in a mouse model, and they have engineered the sensor with highly biocompatible components, which could make the path to potential future trials easier.

A patient may feel fine, and a biopsy may look deceptively clean when T cells have already begun attacking a transplanted organ. The sensor particle, a nanoparticle, detects a T cell weapon, an enzyme called granzyme B, that pushes a transplanted organ’s cells into the self-destruction process called apoptosis.

Earliest detection

“Before any organ damage can happen, T cells have to produce granzyme B, which is why this is an early detection method,” said Gabe Kwong, a co-principal investigator in the study and an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

“This is sensitive enough to possibly detect budding rejection before you see significant injury to the transplanted organ and that could help clinicians treat early to prevent damage,” said Dr. Andrew Adams, co-principal investigator and an associate professor of surgery at Emory University School of Medicine. “Right now, most tests are aimed at organ dysfunction, and sometimes they don’t signal there is a problem until organ function is below 50 percent.”

Kwong and Adams published the study’s results in the journal Nature Biomedical Engineering on February 18, 2019. The research was funded by the National Institutes of Health, the National Science Foundation and the Burroughs Wellcome Fund.

Bristly nanoball

The nanoparticles are put together with iron oxide in the middle like a ball. It is double-coated with dextran, a sugar, and polyethylene glycol, a common ingredient in laxatives, to keep the body from disposing of it too quickly.

Bristles made of amino acids stick out from the iron ball with fluorescent “reporter” molecules attached to their tips.

The particles are injected intravenously. They are too big to accumulate in native tissue or to pass through the kidneys and out of the body but small enough to accumulate in the tissue of struggling transplanted organs, where they keep a lookout for rejection.

Exploiting rejection

Once T cells start secreting granzyme B, it severs amino acid strands in the transplanted organ’s cells, triggering the cells to unravel and die.

“The nanoparticles’ bristles mimic granzyme’s amino acid targets in the cells, so the enzyme cuts the bristles on the nanoparticle at the same time,” said Kwong who directs the Laboratory for Synthetic Immunity in the Coulter Department. “That releases the reporter molecules, which are so small that they easily make it through the kidney’s filtration and go into the urine.”

In the experiment, the animals’ urine glowed and could be seen in their bladders in near-infrared images.

Comprehensive method

The researchers plan to augment their new sensor to detect the other major cause of transplant rejection, attacks by antibodies, which are not living cells but proteins the body creates to neutralize foreign entities.

“Antibodies kill their target cells through similar types of enzymes. In the future, we envision a single sensor to detect both types of rejection,” Kwong said. But there is even more potential.

“This method could be adapted to tease out multiple problems like rejection, infection or injury to the transplanted organ,” Adams said. “The treatments for all of those are different, so we could select the proper treatment or combination of treatments and also use the test to measure how effective treatment is.”

Outdoing biopsies

Biopsies are currently the gold standard in detection but they can go wrong, and the wide, long needle can damage tissue.

“The biggest risk of a biopsy is bleeding and injury to the transplanted organ,” Adams said. “Then there’s the possibility of infection. You’re also just taking a tiny fraction of the transplanted organ to determine what’s going on with the whole organ, and you may miss rejection or misdiagnose it because the needle didn’t hit the right spot.”

The urine test gets a more global reading on the whole organ, and it has other advantages over biopsies.

“The biopsy is not predictive. It’s a static snapshot. It’s like looking at a photo of people in mid-jump. You don’t know if they’re on their way up or on their way down. With a biopsy, you don’t know whether rejection is progressing or regressing,” Kwong said.

“Our method measures biological activity rates, and that tells us where things are going.”

Immunosuppressant medications

That could also allow clinicians to carefully dose powerful immunosuppressant medications that the vast majority of transplant patients receive.

“Adjusting the dose is very difficult but very important because heavy immunosuppression increases occurrence of infections and patients who receive it also get cancer more often,” Kwong said.

For this experiment, the researchers used small skin grafts on mice and got a very clear, timely signal from the nanoparticle sensor. Since organ transplants represent a lot more tissue, the researchers believe that any occurrence of organ rejection would trigger a much larger signal from the sensor.

These authors contributed to this research: Co-first authors Quoc Mac of the Coulter Department and Dave Mathews of the Emory Transplant Center; Justin Kahla, Claire Stoffers, Olivia Delmas, and Brandon Alexander Holt of the Coulter Department. The research was funded by the Burroughs Wellcome Fund, the National Institutes of Health (awards DP2HD091793, 5T32EB006343 and DK109665) and its National Institute of Allergy and Infectious Diseases (grant U01AI132904); the National Science Foundation (grant DGE-1650044). Any findings, conclusions or recommendations are those of the authors and do not necessarily reflect those of the funding agencies.

For 150 years scientists have been trying to figure out why the wispy upper atmosphere of the Sun — the corona — is over 200 times hotter than the solar surface. This region, which extends millions of miles, somehow becomes superheated and continually releases highly charged particles, which race across the solar system at supersonic speeds.

When those particles encounter Earth, they have the potential to harm satellites and astronauts, disrupt telecommunications, and even interfere with power grids during particularly strong events. Understanding how the corona gets so hot can ultimately help us understand the fundamental physics behind what drives these disruptions.

In recent years, scientists have largely debated two possible explanations for coronal heating: nanoflares and electromagnetic waves. The nanoflare theory proposes bomb-like explosions, which release energy into the solar atmosphere. Siblings to the larger solar flares, they are expected to occur when magnetic field lines explosively reconnect, releasing a surge of hot, charged particles. An alternative theory suggests a type of electromagnetic wave called Alfvén waves might push charged particles into the atmosphere like an ocean wave pushing a surfer. Scientists now think the corona may be heated by a combination of phenomenon like these, instead of a single one alone.

The new discovery of pseudo-shocks adds another player to that debate. Particularly, it may contribute heat to the corona during specific times, namely when the Sun is active, such as during solar maximums — the most active part of the Sun’s 11-year cycle marked by an increase in sunspots, solar flares and coronal mass ejections.

The discovery of the solar tadpoles was somewhat fortuitous. When recently analyzing data from NASA’s Interface Region Imaging Spectrograph, or IRIS, scientists noticed unique elongated jets emerging from sunspots ¬ — cool, magnetically-active regions on the Sun’s surface — and rising 3,000 miles up into the inner corona. The jets, with bulky heads and rarefied tails, looked to the scientists like tadpoles swimming up through the Sun’s layers.

“We were looking for waves and plasma ejecta, but instead, we noticed these dynamical pseudo-shocks, like disconnected plasma jets, that are not like real shocks but highly energetic to fulfill Sun’s radiative losses,” said Abhishek Srivastava, scientist at the Indian Institute of Technology (BHU) in Varanasi, India, and lead author on the new paper in Nature Astronomy.

Using computer simulations matching the events, they determined these pseudo-shocks could carry enough energy and plasma to heat the inner corona.

The scientists believe the pseudo-shocks are ejected by magnetic reconnection — an explosive tangling of magnetic field lines, which often occurs in and around sunspots. The pseudo-shocks have only been observed around the rims of sunspots so far, but scientists expect they’ll be found in other highly magnetized regions as well.

Over the past five years, IRIS has kept an eye on the Sun in its 10,000-plus orbits around Earth. It’s one of several in NASA’s Sun-staring fleet that have continually observed the Sun over the past two decades. Together, they are working to resolve the debate over coronal heating and solve other mysteries the Sun keeps.

“From the beginning, the IRIS science investigation has focused on combining high-resolution observations of the solar atmosphere with numerical simulations that capture essential physical processes,” said Bart De Pontieu research scientist at Lockheed Martin Solar & Astrophysics Laboratory in Palo Alto, California. “This paper is a nice illustration of how such a coordinated approach can lead to new physical insights into what drives the dynamics of the solar atmosphere.”

The newest member in NASA’s heliophysics fleet, Parker Solar Probe, may be able to provide some additional clues to the coronal heating mystery. Launched in 2018, the spacecraft flies through the solar corona to trace how energy and heat move through the region and to explore what accelerates the solar wind as well as solar energetic particles. Looking at phenomena far above the region where pseudo-shocks are found, Parker Solar Probe’s investigation hopes to shed light on other heating mechanisms, like nanoflares and electromagnetic waves. This work will complement the research conducted with IRIS.

“This new heating mechanism could be compared to the investigations that Parker Solar Probe will be doing,” said Aleida Higginson, deputy project scientist for Parker Solar Probe at Johns Hopkins University Applied Physics Laboratory in Laurel, Maryland. “Together they could provide a comprehensive picture of coronal heating.”