Using mice, the team discovered that zinc is needed for the development of disease-fighting immune cells called T cells and prompts regeneration of the thymus, the immune organ that produces T cells.

“This study adds to our knowledge of what zinc is actually doing in the immune system and suggests a new therapeutic strategy for improving recovery of the immune system,” said senior author Dr. Jarrod Dudakov, an immunologist at Fred Hutch.

The study also revealed that an experimental compound that mimics zinc’s action in this organ works even better than the natural mineral to promote immune recovery.

“We are now looking into how zinc may fit in with our other discoveries of how the immune system repairs itself and could eventually lead to therapies to improve immune function for people who receive a blood stem cell transplant for a blood cancer or people with chronic immune decline that accompanies aging,” Dudakov said.

Thymic regeneration and immune function, and zinc

Previously, Dudakov and his team have outlined the molecular pathways and cell types that govern how the immune system’s thymus repairs itself after injury. Such treatments could improve vaccine efficacy and hasten thymic regeneration after stressors like chemotherapy, blood stem cell transplant and radiation exposure.

Dudakov began studying zinc a few years ago when Dr. Lorenzo Iovino, the study’s first author and a research associate at Fred Hutch, joined Dudakov’s lab. Since the scientists knew that low levels of zinc are linked to fewer infection fighting T cells and a shrunken thymus, where T cells develop, Dudakov and Iovino explored how to supplement with zinc in mouse models where the immune system is damaged.

Iovino, who’s also a blood stem cell transplant physician, had shown in a previous study that zinc could boost immune recovery in patients undergoing stem-cell transplants for the blood cancer multiple myeloma.

But the study didn’t explain why zinc was helping.

Zinc is critical for T-cell development and thymic regeneration

As in humans, Iovino and Dudakov found that the thymuses of mice deprived of dietary zinc shrink and produce notably fewer mature T cells, even after as little as three weeks of a no-zinc diet. Iovino was able to show that without zinc, T cells cannot fully mature.

He also found that zinc deficiency slows recovery of T-cell numbers after mice receive immune-destroying treatments akin to those given to patients about to receive a blood stem cell transplant.

Conversely, extra zinc speeds this process, and T cells recover faster than normal. The team saw a similar result in a mouse model of blood stem cell transplant.

“So we had a consistent result of a better reconstitution of the thymus and also a better reconstitution of T cells in the peripheral blood after zinc supplementation,” Iovino said. “But we still didn’t know how exactly zinc was working.”

Iovino discovered that it was the change in zinc levels around cells that release a key regenerative factor that seemed to kick off the thymus’ renewal processes. T cells accumulate zinc as they develop, but release it after a damaging event — like a burst of radiation — kills them off.

Cells use a molecule called GPR39 to sense a change in external zinc, and Iovino found that an experimental compound that mimics rising external zinc levels by stimulating GPR39 could also promote renewal factor release and thymic regeneration.

“What we think is going on is, as you give zinc supplementation, that gets accumulated within the developing T cells. It gets stored and stored and stored, then the damage comes along and the zinc is released,” Dudakov said. “Now you have more zinc than you normally would, and it can instigate this regenerative pathway. With the experimental compound we can just directly target GPR39 and basically get the same effect without any of that pretreatment.”

Getting to the clinic

There’s still a lot to learn before they can turn their findings to therapeutic strategies, the scientists said.

Transplant patients already receive mineral supplements, so if extra zinc were to be incorporated into their treatment regimens, it would be important to make sure that anyone receiving it is truly zinc-deficient. Iovino thinks many patients might be, but right now there isn’t a good test to assess this. He’s currently working on developing one, which would first be used to help researchers determine whether patients’ zinc status correlates with immune recovery after blood stem cell transplant.

Dudakov will pursue GPR39-stimulating compounds as therapies to improve thymic recovery after acute injuries like pre-transplant radiation. The team is currently screening similar compounds to find any that may be more effective.

He and Iovino are also working to determine whether such compounds could help with thymic regeneration in other settings. Unfortunately, our thymuses also slowly shrink and reduce their T-cell output as we age. Dudakov and Iovino would also like to know whether this chronic degeneration could be slowed by boosting the organ’s regenerative processes.

“Our lab is continuing to piece together the molecular players that contribute to thymus regrowth,” Dudakov said. “Ultimately, we aim to develop therapies that trigger natural regeneration and restore immune health.”

The study was funded by the National Institutes of Health, the American Society of Hematology and The Rotary Foundation.

In an endeavor to make a more efficient product immune to ice for such demanding industries and consumers, Sushant Anand, UIC assistant professor of mechanical engineering, and Rukmava Chatterjee, a UIC Ph.D. student, have developed a longer-lasting alternative to conventional deicers. They say it could also benefit other industries.

“We questioned the lifetime of the cryoprotectants and looked at new ways to increase their effectivity,” Anand said. “Glycols dissolve very fast in the water and get washed away before the plane takes off, and it’s a serious problem that costs hundreds of millions of dollars — most of which literally ends up in the drain. We thought, why not improve such chemicals themselves, and make alternatives that can last longer while being more biofriendly. And that is what we ended up doing.”

To accomplish their goal, the researchers developed an extensive family of more than 80 anti-freezing coatings, which can be classified as polymeric solutions, emulsions, creams and gels. The formulations can be easily applied to aluminum, steel, copper, glass, plastic or any industrial surface without preconditioning or expensive surface treatments.

“Our coatings are an all-in-one package which can delay formation of frost for extended hours and simultaneously cause any ice formed on its surface to easily shed off by a gentle breeze or simple substrate tilting,” Chatterjee said.

Their work is reported in an Advanced Materials article titled “A family of frost-resistant and icephobic coatings.”

The coatings are a family of phase change material-based formulations and multifunctional coatings which can tailor solid foulant adhesion on functional surfaces, ranging from ice to bacteria, irrespective of their inherent material structure and chemistry. This was engineered by regulating how chemicals leach out of the material system and by creating a lubricating surface layer that is both slippery and non-freezing in nature.

The anti-freezing gels are also transparent, which is critical for applications like traffic signals, runway lights that assist pilots during landings, automotive windshields or building windows.

“Imagine coating your smartwatch with our gel that can inhibit ice accretion in the chilly negatives while simultaneously preventing any bacterial contamination,” Chatterjee said.

“Since our anti-icing sprays are bio-friendly and anti-bacterial, we even think there is a potential to use them in agriculture to prevent crops from being ruined by severe frost,” Anand said. “But that is a pipe dream, and we need to do more studies to see if there will be any long-term adverse effect on the plants.”

A worldwide patent application titled “Compositions and Methods for Inhibiting Ice Formation on Surfaces” has been filed by UIC’s Office of Technology Management.

“There is great potential in these materials for many applications, and I think the day when commercial versions of our materials come out just got closer,” Anand said.

Anand Research Group members Hassan Bararnia and Umesh Chaudhuri collaborated with Chatterjee on the experiments.

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Materials provided by University of Illinois Chicago. Original written by David Staudacher. Note: Content may be edited for style and length.

In a new study published this week in the Journal of Biogeography, researchers from the University of California, Berkeley, provide the first detailed description of the stunning array of fungi that make their home on the Polynesian island of Mo’orea. The collection includes more than 200 species of macrofungi — that is, fungi producing visible, fruiting bodies — many of which may be new to science.

“It’s like a treasure trove,” said study lead author Matteo Garbelotto, cooperative extension specialist and adjunct professor of environmental science, policy and management at UC Berkeley. “It’s truly uncharted territory in evolutionary biology and biodiversity of the fungal kingdom, and this is one the first attempts to generate baseline information on fungal diversity, not just for Mo’orea, but for the entire and vast Insular Oceania region.”

As part of the Mo’orea Biocode Project, the study team spent months trekking across the island in search of new species of fungi, ultimately gathering a total of 553 fungal specimens and sequencing the DNA of 433 of them. Because only a handful of the sequenced specimens have exact genetic matches with other known species, the Mo’orea collections are likely to contain completely new species.

By comparing the DNA sequences of these fungi to those of other species around the world, the team was also able to piece together where the fungal biodiversity on the remote island may have originated. The findings suggest that the majority of the species, or their ancestors, were carried by easterly winds from Australia or other South Pacific islands, though a small number may have been brought to Mo’orea by humans from far-flung locations like East Asia, Europe and South America.

“We were really interested in the biodiversity of the island,” said study first author Todd Osmundson, who completed the work as a postdoctoral researcher at UC Berkeley. “Mo’orea is an island in the middle of the ocean, and it’s a geologically young volcanic island. It’s never touched another piece of land. How did fungi get there, and where did they come from?”

Understanding both the biodiversity of fungi on the island and how different species have traveled around the world to arrive at this remote location can help as scientists grapple with the ongoing impacts of global travel and trade on biodiversity.

“The Mo’orea BioCode project was the first all-taxa-survey of a tropical island to include DNA vouchers and other associated information. It included all organisms from marine and terrestrial habitats and everything larger than bacteria,” said George Roderick, William Muriece Hoskins Professor of environmental science, policy and management at UC Berkeley. “Since, the data has proven to be enormously valuable in monitoring the impacts of global change on Mo’orea but also on other tropical Pacific Islands.”

‘Every day we had a different challenge’

The Mo’orea Biocode Project was led by Neil Davies, executive director of UC Berkeley’s Gump South Pacific Research Station, and ran from 2007 to 2010. One of the motivations for the project was to create a model ecosystem that could be used to answer fundamental questions about how ecosystems work.

“Fungi are really important parts of ecosystems,” said Osmundson, who is currently a professor of biology at the University of Wisconsin-La Crosse. “They act as primary decomposers, and in some cases (as) pathogens that break down decaying organic matter and recycle the nutrients into forms that other organisms can use. They’re also really important as symbionts. They live with other organisms and benefit that organism in exchange for other things. For instance, some fungi will attach to the roots of plants and exchange nutrients with them.”

To collect the specimens, the research team spent months on Mo’orea, beginning before dawn each day to gather samples of fungi from all corners of the ecosystem, including the soil, the roots and leaves of plants, and even the air.

As the heat and humidity rose throughout the day, the outdoor conditions would often become inhospitable to both the scientists and the delicate fruiting bodies of the fungi they had collected. By early afternoon, they would take their samples back to the lab and begin the process of documenting and culturing the specimens they had found, often staying up late into the night to complete their work.

“The terrain on the island is incredibly steep, and when it rains it becomes incredibly muddy, and a lot of areas are not managed. So, every day we had a different challenge,” Garbelotto said. “There are some slopes that you can only really explore on ropes. I remember being attached to a rope with my hands sticking out on the precipice, trying to collect a mushroom that was growing on a little outcrop where you couldn’t possibly walk.“

Each of the specimens was photographed and dried for storage in the University Herbarium and compared to databases of known species. As part of the biocode project, the research team also obtained DNA sequences of a specific gene that can be used as a unique “barcode” to differentiate one species from another.

“In many ways, Mo’orea is not a pristine island, and that actually makes it more interesting to me,” Garbelotto said. “The island has completely pristine areas and also has areas that have been inhabited and deeply changed by humans, starting with the arrival of Polynesians 3,000 years ago and continuing until relatively recently with the arrival of the French, the English and the Americans. Compared to places that are completely pristine, Mo’orea is more interesting to me because it’s more representative of what the world actually is.”

Additional co-authors of the paper are Sarah E. Bergemann of Middle Tennessee State University and Rikke Rasmussen, who worked on DNA sequencing as a volunteer at UC Berkeley. The Moorea Biocode Project was supported by the Gordon and Betty Moore Foundation.

This research, published in the Proceedings of the National Academy of Sciences, illustrates the importance of a well-known cytokine called interleukin-13 (IL-13) in protecting cells against SARS-CoV-2, which helps explain the mystery of why people with allergic asthma fair better than the general population despite having a chronic lung condition. The same cannot be said for individuals with other diseases, such as chronic obstructive pulmonary disease (COPD) or emphysema, who are at very high risk of severe COVID.

“We knew there had to be a bio-mechanistic reason why people with allergic asthma seemed more protected from severe disease,” said senior author Camille Ehre, PhD, assistant professor of pediatrics at the UNC School of Medicine and member of the UNC Marsico Lung Institute. “Our research team discovered a number of significant cellular changes, particularly due to IL-13, leading us to conclude that IL-13 plays a unique role in defense against SARS-CoV-2 infection in certain patient populations.”

Although cytokines like IL-13 cannot be used as therapies because they trigger inflammation, it is important to understand natural molecular pathways that cells use to protect themselves from pathogen invasion, as these studies have the potential to reveal new therapeutic targets.

There are many health factors that increase a person’s risk of severe COVID, including chronic lung diseases such as COPD, but as the pandemic went on, epidemiologists found that people with allergic asthma were less susceptible to severe disease.

“These are patients with asthma caused by allergens, such as mold, pollen, and dander,” said Ehre, who is also a member of the UNC Children’s Research Institute. “To find out why they are less susceptible, we investigated specific cellular mechanisms in primary human airway epithelial cell cultures.”

The experiments were led by co-first authors Cameron Morrison, a medical student in the Ehre lab, and Caitlin Edwards, a research assistant and MPH student in the lab of Ralph Baric, PhD, Kenan Distinguished Professor of Epidemiology at the UNC Gillings School of Global Public Health and professor in the UNC Department of Microbiology and Immunology at the UNC School of Medicine.

The researchers used genetic analysis of human airway cell cultures infected with SARS-CoV-2 to discover that the expression of the human protein ACE2 governed which cell types were infected and the amount of virus found in this cell population (also known as “viral load.”)

The scientists then used electron microscopy (EM) to identify an intense exodus of virus from infected ciliated cells, which are cells tasked with moving mucus along the airway surface. EM also revealed severe cytopathogenesis — changes inside human cells due to viral infection. And these changes culminating in ciliated cells (packed with virions) shedding away from the airway surface.

“This shedding is what provides a large viral reservoir for spread and transmission of SARS-CoV-2,” Ehre said. “It also seems to increase the potential for infected cells to relocate to deeper lung tissue.”

Further experiments on infected airway cells revealed that a major mucus protein called MUC5AC was depleted inside cells, likely because the proteins were secreted to try to trap invading viruses. But the virus load kept increasing because the cells tasked with producing MUC5AC were overwhelmed in the face of a rampant viral infection.

The researchers knew from epidemiological studies that allergic asthma patients — known to overproduce MUC5AC- were less susceptible to severe COVID. Ehre and colleagues also knew the cytokine IL-13 increased MUC5AC secretion in the lungs when asthma patients faced an allergen.

The scientists decided to mimic asthmatic airways by treating human airway cells with IL-13. They then measured viral titers, viral mRNA, the rate of infected cell shedding, and the overall number of infected cells. Each one was significantly decreased. They found this remained true even when mucus was removed from the cultures, suggesting other factors were involved in the protective effects of IL-13 against SARS-CoV-2.

Bulk RNA-sequencing analyses revealed that IL-13 upregulated genes that control glycoprotein synthesis, ion transport, and antiviral processes — all of which are important in airway immune defense. They also showed that IL-13 reduced the expression of the viral receptor, ACE2, as well as reducing the amount of virus inside cells and cell-to-cell viral transmission.

Taken together, these findings indicate that IL-13 significantly affected viral entry into cells, replication inside cells, and spread of virus, thus limiting the virus’s ability to find its way deeper into the airways to trigger severe disease.

“We think this research further shows how important it is to treat SARS-CoV-2 infection as early as possible,” Ehre said. “And it shows just how important specific mechanisms involving ACE2 and IL-13 are, as we try our best to protect patients from developing severe infections.”

Other authors of the PNAS paper are Kendall Shaffer, Kenza Araba, Jason Wykoff, Danielle Williams, Takanori Asakura, Hong Dang, Lisa Morton, Rodney Gilmore, Wanda O’Neal, and Ric Boucher, all at UNC-Chapel Hill.

This research was funded through grants from the National Institutes of Health and Vertex Pharmaceuticals.

“The DOE calls sounds of specific events the ‘signs of signature,'” said Misra. “In this case, the signature identified the break or mechanical discontinuity of a rock in the earth’s subsurface, especially as the breaks continued to grow or propagate into fractures.”

Misra and his doctoral candidate Rui Liu published their preliminary findings in the May 2022 issue of the Systems and Signals Processing journal.

Why does Basic Energy Sciences want this signature identified? Sounds are often important clues to environmental and security changes. Threatening noises, such as underground explosions, are hard to mistake. But the small sounds of a high-rise building foundation cracking and failing are just as threatening. So, the fundamental sound of rock undergoing mechanical failure is a basic and critical clue worth finding.

“This research goes to the heart of identifying something specific within a massive data set,” said Misra. “An example is credit card transactions. You cannot monitor the whole data set for fraud because the transactions are so varied. You must find some indicative sign, such as a credit card charge in one city to book an airline flight immediately after that same card pays for an Uber in another city. That discrepancy is a signature.”

Previous attempts to pinpoint underground mechanical failures never brought reliable success, but Misra found that an unusual combination of three research methods — supervised machine learning, causal discovery and rapid simulations — could tackle the problem.

The supervised machine learning began with lab experiments in which a multipoint sensor system was placed on the surface of a rock and recorded sound wave-transmission measurements through the material as it cracked and finally failed. Computers monitored the information and were taught which data signatures meant initial, intermediate and end-stage damage. One tell-tale signature that repeatedly traveled up and down across the zero point between positive and negative measurements caught the computer’s attention, once it knew what to look for.

“I can only see the color or shape of something with my eyes,” said Liu. “But machine learning can pick out so many more characteristics from the data. It picked out those positive and negative turnings, and we used that sign to get further results.”

Misra and Liu searched for the causation of each of these turnings to confirm their source. They couldn’t rely on the computer to complete this step because machine learning is not the best interpreter.

“During the heat of the summer, ice cream sales increase and drowning deaths increase,” said Misra. “If you use machine learning or simple statistical methods, they might say people are drowning because people eat ice cream. That’s a correlation. Though they are both related to the summer heat, they are not connected to each other. They each have a different cause. We are looking for causation for these turnings because that’s when they become meaningful.”

Misra and Liu created a workflow that could generate scenarios of various fracture propagations and measured waveforms. Then, they increased the workflow’s speed to rapidly run up to 20,000 different simulations of possibilities for each event. This allowed the researchers to discover the best cause-and-effect explanations.

“We didn’t control how the discontinuity propagated, so there’s a lot of randomness,” said Misra. “Yet, as the fractures grew, despite the differences in direction or length, results showed a similar increase in amplifications or positive and negative turnings across the zero point in the waveforms. So, this is a definite signature of rock failure, which, to the best of my knowledge, was not known prior to this research.”

While the signature discovery is exciting, the project still has several months to go. Misra intends to explore the limits of the data-driven simulations and causal discovery approach. He will also test other methods to see if similar or different results occur.

“What we need to do as scientists, as engineers, is to find causality, find causation,” said Misra. “We tried a lot of different techniques to discover this signature and its causal relationships. A lot of approaches didn’t work, but one did. Now we need to find the limits of what it can do.”

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Materials provided by Texas A&M University. Original written by Nancy Luedke. Note: Content may be edited for style and length.