Scientists Make Progress Toward a New Potential Treatment for Asthma

Some 24.6 million American adults and children have asthma, which can range from mild to life threatening. A chronic pulmonary disorder, asthma is characterized by inflammation of the lungs, narrowing of the airways, and excessive mucus production—essentially, causing difficulty breathing.

Researchers looking for new drugs to treat this condition at Cincinnati Children’s Hospital Medical Center (CCHMC) have made a recent breakthrough by identifying long-sought transcription factors, proteins responsible for turning genes on or off in the nucleus of cells. These transcription factors are buried deep inside the nucleus of cells where it’s challenging to access or study them.

But the CCHMC researchers managed to identify a small molecule which blocks a key inflammatory transcription factor, FOXM1. FOXM1 stimulates excessive mucus production and inflammation, leading to respiratory distress, and is often found in severe asthma and other pulmonary diseases. Their results were published in the journal Science Signaling.

Asthma is usually triggered by an outside stimulus, ranging from mold to animal fur to pollen. “In response to [a] particular insult from outside, our lungs start to be inflamed, so the cells from the blood come into the lung and start populating our alveoli, which we need to keep clear to breathe,” lead author Vladimir Kalinichenko tells Mental Floss. Kalinichenko is the director for the Center for Lung Regenerative Medicine and a member of the Division of Pulmonary Biology at CCHMC. He explains that in response to an allergen, epithelial (lung) cells start differentiation, or metaplasia, and produce a lot of the goblet cells that secrete the mucus that narrows airways and makes breathing difficult.

Kalinichenko found that inside the lungs, FOXM1 is an important transcription factor responsible for cells becoming mucus-producing goblet cells—a key step in what makes it hard to breathe. His research team’s aim was to find a compound that would specifically target FOXM1, and by blocking its activation, keep the whole process of pro-inflammatory molecules stimulating goblet cells into over-producing mucus from launching.

To do this, the CCHMC researchers screened a database of 50,000 small molecule compounds that have been created in previous scientific research to see if they could find one that inhibited FOXM1. After narrowing it down to 20, they settled on a molecule called RCM-1, which exhibited the inhibiting function they sought.

They first tested RCM-1 on dish-cultured human epithelial cells, with good results; it prevented the transcription factor, FOXM1, from going to the nucleus, says Kalinichenko.

Next they exposed mice that were genetically modified to express high amounts of the FOXM1 transcription factor to dust mites, a common allergen in humans, over the course of two weeks. With repeated exposure to the allergen, the mice began to exhibit asthma symptoms. When they gave the mice just two injections of RCM-1, Kalinichenko says, “The mice would not develop mucus overproduction in the airways and their breathing would be much clearer.”

Then Kalinichenko’s team evoked asthma symptoms in another group of mice, by injecting an inflammatory molecule called interleukin-13—which is normally produced by T-cell lymphocytes as a response to an allergen. Just giving the interleukin-13 to mice (even without the presence of an allergen) causes asthma-like symptoms of lung inflammation, narrowing airways, and difficulty breathing. When the mice were given RCM-1, these symptoms abated, essentially demonstrating a kind of “downstream inflammatory effect” of the immune system.

The team was pleased not to observe any symptoms of toxicity in the mice, which bodes well for human applications, though Kalinichenko cautions that human clinical trials are still far off. First, they’ll have to test the molecule in other animal models, such as non-human primates, assess toxicity levels in different concentrations of the compound, and work on perfecting the compound itself.

“We are just in discovery mode. We have proven in two mouse models of asthma that [RCM-1] works," he notes. "That is a long way to human use.”

Still, Kalinichenko thinks RCM-1 is promising. It could be especially helpful in treating the progressive nature of asthma, which damages the lungs over time from repeat acute attacks. “With every new asthmatic attack, the lungs become much worse. This drug, with others, could be used to prevent these attacks and treat patients in earlier stages, before the lungs get bad,” he says.

However, Kalinichenko says its real value could be in treating serious diseases such as chronic obstructive pulmonary disease, cystic fibrosis, and even lung cancer. “Those diseases are associated with excess mucus production and clogging airways. For those diseases where FOXM1 is expressed in high levels, this drug could be highly beneficial—and even life-saving.”

Scientists Find Fossil of 150-Million-Year-Old Flesh-Eating Fish—Plus a Few of Its Prey

M. Ebert and T. Nohl
M. Ebert and T. Nohl

A fossil of an unusual piranha-like fish from the Late Jurassic period has been unearthed by scientists in southern Germany, Australian news outlet the ABC reports. Even more remarkable than the fossil’s age—150 million years old—is the fact that the limestone deposit also contains some of the fish’s victims.

Fish with chunks missing from their fins were found near the predator fish, which has been named Piranhamesodon pinnatomus. Aside from the predator’s razor-sharp teeth, though, it doesn’t look like your usual flesh-eating fish. It belonged to an extinct order of bony fish that lived at the time of the dinosaurs, and until now, scientists didn’t realize there was a species of bony fish that tore into its prey in such a way. This makes it the first flesh-eating bony fish on record, long predating the piranha. 

“Fish as we know them, bony fishes, just did not bite flesh of other fishes at that time,” Dr. Martina Kölbl-Ebert, the paleontologist who found the fish with her husband, Martin Ebert, said in a statement. “Sharks have been able to bite out chunks of flesh, but throughout history bony fishes have either fed on invertebrates or largely swallowed their prey whole. Biting chunks of flesh or fins was something that came much later."

Kölbl-Ebert, the director of the Jura Museum in Eichstätt, Germany, says she was stunned to see the bony fish’s sharp teeth, comparing it to “finding a sheep with a snarl like a wolf.” This cunning disguise made the fish a fearful predator, and scientists believe the fish may have “exploited aggressive mimicry” to ambush unsuspecting fish.

The fossil was discovered in 2016 in southern Germany, but the find has only recently been described in the journal Current Biology. It was found at a quarry where other fossils, like those of the Archaeopteryx dinosaur, have been unearthed in the past.

[h/t the ABC]

Could Leonardo da Vinci's Artistic Genius Be Due to an Eye Condition?

Young John the Baptist, Leonardo da Vinci (1513-16, Louvre, Paris).
Young John the Baptist, Leonardo da Vinci (1513-16, Louvre, Paris).
Christopher Tyler, JAMA Ophthalmology (2018)

Leonardo da Vinci was indisputably a genius, but his singular artistic vision may have been the result of seeing the world differently in more ways than one. A new paper argues that he had strabismus, a vision disorder where the eyes are misaligned and don’t look toward the same place at the same time. This disorder, visual neuroscientist Christopher Tyler argues, may have helped the artist render three-dimensional images on flat canvas with an extra level of skill.

Tyler is a professor at City, University of London who has written a number of studies on optics and art. In this study, published in JAMA Ophthalmology, he examined six different artworks from the period when Leonardo was working, including Young John the Baptist, Vitruvian Man, and a self-portrait by the artist. He also analyzed pieces by other artists that are thought to have used Leonardo as a model, like Andrea del Verrocchio’s Young Warrior sculpture. Leonardo served as the lead assistant in the latter artist’s studio, and likely served as the model for several of his works. Leonardo was also a friend of Benedetto da Maiano, and possibly served as a model for his 1480 sculpture of John the Baptist. Tyler also looked at the recently auctioned Salvator Mundi, a painting that not all experts believe can be attributed to Leonardo. (However, at least one scientific team that examined the painting says it’s legit.)

With strabismus, a person’s eyes appear to point in different directions. Based on the eyes in Leonardo’s own portraits of himself and other artworks modeled after him, it seems likely that he had intermittent strabismus. When he relaxed his eyes, one of his eyes drifted outward, though he was likely able to align his eyes when he focused. The gaze in the portraits and sculptures seems to be misaligned, with the left eye consistently drifting outward at around the same angle.

'Vitruvian Man' with the subject's pupils highlighted
Vitruvian Man, Leonardo da Vinci (~1490, Accademia, Venice)
Christopher Tyler, JAMA Ophthalmology (2018)

“The weight of converging evidence suggests that [Leonardo] had intermittent exotropia—where an eye turns outwards—with a resulting ability to switch to monocular vision, using just one eye,” Tyler explained in a press release. “The condition is rather convenient for a painter, since viewing the world with one eye allows direct comparison with the flat image being drawn or painted.” This would have given him an assist in depicting depth accurately.

Leonardo isn’t the first famous artist whose vision researchers have wondered about. Some have speculated that Degas’s increasingly coarse pastel work in his later years may have been attributed to his degenerating eyes, as the rough edges would have appeared smoother to him because of his blurred vision. Others have suggested that Van Gogh’s “yellow period” and the vibrant colors of Starry Night may have been influenced by yellowing vision caused by his use of digitalis, a medicine he took for epilepsy.

We can never truly know whether a long-dead artist’s work was the result of visual issues or simply a unique artistic vision, but looking at their art through the lens of medicine provides a new way of understanding their process.

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