Culture

In an upcoming study to be published in Gastroenterology, researchers at the Icahn School of Medicine at Mount Sinai and the University of North Carolina School of Medicine report on the clinical course of COVID-19 and risk factors for adverse outcomes in a large cohort of patients with IBD collected through an international registry.

When the Covid epidemic started to unfold around the country, the researchers collaborated to form an international registry of patients who have Inflammatory Bowel Disease (IBD) and COVID-19. The registry, Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD), to date includes 528 patients from 33 countries.

"We established the registry to better characterize the clinical course of COVID-19 within the IBD patient population and evaluate the association between demographics, clinical characteristics, and IBD treatments on COVID-19 outcomes," says study co-author, Erica Brenner, MD, Pediatric Gastroenterology Fellow, UNC Children's Hospital.

The researchers conclude that increasing age, comorbidities, and corticosteroids are associated with severe COVID-19 among IBD patients, although a causal relationship cannot be definitively established. Notably, TNF antagonists do not appear to be associated with severe COVID-19.

"One of our main takeaways for the IBD patient population is that maintaining remission with steroid-sparing treatments will be important through this pandemic. Our finding that TNF antagonist therapy is not associated with severe COVID-19 is reassuring news in light of the large number of patients who require this therapy, currently the most commonly prescribed biologic therapy for IBD patients," says study co-author, Ryan Ungaro, MD, Assistant Professor, Icahn School of Medicine at Mount Sinai and a gastroenterologist with Mount Sinai Hospital's Feinstein IBD Center.

What The Study Did: National health care survey data were used to assess the amount of money spent on primary care relative to other areas of health care spending in the U.S. from 2002 to 2016.

Authors: Andrew W. Bazemore, M.D., M.P.H., of the American Board of Family Medicine in Washington, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamainternmed.2020.1360)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

What The Study Did: Researchers compared the risk of suicide by firearm based on sociodemographic characteristics of U.S. adults.

Authors: Mark Olfson, M.D., M.P.H., of Columbia University in New York, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamainternmed.2020.1334)

Editor's Note: The article includes funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

Crown-of-thorns starfish are on the menu for many more fish species than previously suspected, an investigation using fish poo and gut goo reveals.

The finding suggests that some fish, including popular eating and aquarium species, might have a role to play in keeping the destructive pest population under control.

The native starfish (Acanthaster solaris) is responsible for widespread damage to the Great Barrier Reef. Since 1962 its population has surged to plague proportions on three occasions, each time causing the loss of large amounts of hard coral. A fourth outbreak is currently underway.

Increasing the amount of predation on starfish has long been touted as a potential solution to preventing outbreaks. However, aside from a mollusc called the Giant Triton (Charonia tritonis), identifying what eats it has been a challenging task.

Now, a team of scientists led by Dr Frederieke Kroon from the Australian Institute of Marine Science in Townsville, Australia, has applied a genetic marker unique for crown-of-thorns, developed at AIMS, to detect the presence of starfish DNA in fish poo and gut contents.

Over three years, Dr Kroon's team used it on samples taken from 678 fish from 101 species, comprising 21 families, gathered from reefs experiencing varying levels of starfish outbreak.

"Our results strongly indicate that direct fish predation on crown-of-thorns may well be more common than is currently appreciated," said Dr Kroon.

The study, published in the journal Scientific Reports, confirms that at least 18 coral reef fish species - including Spangled Emperor (Lethrinus nebulosus), Redthroat Emperor (Lethrinus miniatus) and Blackspotted Puffer (Arothron nigropunctatus) - consume young or adult starfish on the reef.

Among the species were nine which had not been previously reported to feed on crown-of-thorns. These include the Neon Damsel (Pomacentrus coelistis), Redspot Emperor (Lethrinus lentjan), and the Blackspot Snapper (Lutjanus fulviflama).

"Our findings might also solve a mystery - why reef areas that are closed to commercial and recreational fishing tend to have fewer starfish than areas where fishing is allowed," said Dr Kroon.

She and colleagues from AIMS worked with researchers from CSIRO Land and Water and managers from the Great Barrier Reef Marine Park Authority to conduct the study.

"This innovative research sheds new light on the extent that coral reef fishes eat crown-of-thorns starfish," said Mr Darren Cameron, co-author of the paper, and Director of the COTS Control Program at the Great Barrier Reef Marine Park Authority.

"A number of the fish species shown to feed on these starfish are caught by commercial and recreational fisheries, highlighting the importance of marine park zoning and effective fisheries management in controlling crown-of-thorns starfish across the Great Barrier Reef."

When there's a vexing problem to be solved, people sometimes offer metaphorical advice such as "stretching the mind" or engaging in "flexible" thinking, but in confronting a problem facing many biomedical research labs, a team of MIT researchers has engineered a solution that is much more literal. To make imaging cells and molecules in brain and other large tissues easier while also making samples tough enough for years of handling in the lab, they have come up with a chemical process that makes tissue stretchable, compressible and pretty much indestructible.

"ELAST" technology, described in a new paper in Nature Methods, provides scientists a very fast way to fluorescently label cells, proteins, genetic material and other molecules within brains, kidneys, lungs, hearts and other organs. That's because when such tissues can be stretched out or squished down thin, labeling probes can infuse them far more rapidly. Several demonstrations in the paper show that even after repeated expansions or compressions to speed up labeling, tissues snap back to their original form unaltered except for the new labels.

The lab of Kwanghun Chung, an associate professor of chemical engineering and a member of MIT's Institute for Medical Engineering and Science, and Picower Institute for Learning and Memory, developed ELAST amid work on a five-year project, funded by the National Institutes of Health, to make the most comprehensive map yet of the entire human brain. That requires being able to label and scan every fine cellular and molecular detail in the thickest slabs possible to preserve 3D structure. It also means the lab must be able to keep samples perfectly intact for years, even as they must accomplish numerous individual rounds of labeling quickly and efficiently. Each round of labeling - maybe a particular kind of neuron one day, or a key protein the next - will tell them something new about how the brain is structured and how it works.

"When people donate their brain, it is like they are donating a library," said Chung. "Each one contains a library worth of information. You cannot access all the books in the library at the same time. We have to repeatedly be able to access the library without damaging it. Each of these brains is an extremely precious resource."

Former lab postdoc Taeyun Ku, now an assistant professor at the Korea Advanced Institute of Science and Technology, is the study's lead author. He said the particular difficulty of working with human tissues, which of course are much larger than those of lab animals like mice, inspired him to take this new engineering approach. Late one night in the lab around Christmas 2017, he said, he was mulling over how to transform tissue for quicker labeling and began to tinker with repeated compression of an elastic gel.

"We changed our way of thinking: biological tissue doesn't need to be very biological," Ku said. "If our goal is not to image living events but to image appearances, we can change the material type of the tissue while maintaining the appearances. Our work shows how higher-level engineering of the brain enables us to better look into what inside the brain."

Entangled links

The team's efforts to engineer ELAST came down to finding the right formulation of a gel-like chemical called polyacrylamide. In the past Chung has used the substance in a different formulation with crosslinking chemicals to make tissues strong but fairly brittle, said study co-author Webster Guan, a chemical engineering graduate student. When that formulation infused the tissues, cells and molecules would become directly attached to a grid-like mesh.

In the new formulation, the team used a high concentration of acrylamide with much less crosslinker and initiator. The result was an entanglement of long polymer chains with links that are able to slip around, giving the gel a structural integrity but with much more flexibility. Moreover, rather than attaching to the chains, Guan said, the cells and molecules of the tissue just become entangled within it, adding further to the ability of the acrylamide-infused tissues to withstand stretching or squashing without anything becoming torn or permanently displaced in the process.

In the study the team reports stretching human or mouse brain tissues to twice their width and length simultaneously or compressing their thickness by 10 times with virtually no distortion after returning to their regular size.

"These results demonstrate that ELAST enables fully reversible tissue shape transformation while preserving structural and molecular information in the tissue," they wrote.

Fully integrating the polyacrylamide into a large amount of tissue to achieve the elasticity can take as long as 21 days, they report, but from then on, any individual labeling step, such as labeling a particular kind of cell to determine its abundance, or a specific protein to see where it is expressed, can proceed far more quickly than with prior methods.

In one case, by repeatedly compressing a 5-milimeter thick cross section of a human brain, the team needed only 24 hours to label it all the way through. For comparison, back in 2013 when Chung and colleagues debuted "CLARITY," a method of making brain tissue transparent and fixing it with an acrylamide gel, they needed 24 hours to label a slice only a tenth as thick. Because labeling time is estimated by squaring the depth that probes must penetrate, calculations suggest labeling with ELAST proceeds 100 times faster than with CLARITY.

Though Chung's lab mostly focuses on brains, the applicability to other organs can aid in other cell mapping efforts, Chung said. He added that even if labeling tissue isn't a goal at all, having an easy new way to make a durable, elastic gel could have other applications, for instance in creating soft robotics. Resources for learning more about ELAST are available at Chung's website.

The mystery of some lava-like flows on Mars has been solved by scientists who say they are caused not by lava but by mud.

There are tens of thousands of these landforms on the Martian surface, often situated where there are massive channels scoured into the surface by ancient liquids flowing downstream.

These channels are extremely long, extending many hundreds of kilometres in length and usually more than dozens of kilometres wide. They are believed to be the result of massive floods involving huge bodies of water comparable to the largest floods ever known to have occurred on Earth. When the water seeps into the subsurface it can emerge again as mud.

A European team of researchers has now simulated the movement of mud on the surface of Mars, with the results published in Nature Geoscience.

The research was led by the Institute of Geophysics at the Czech Academy of Sciences, and involved Lancaster University, the Open University and the Rutherford Appleton Laboratory in the UK, CNRS in France, DLR and Münster University in Germany, and CEED in Norway.

Using the Mars Chamber at the Open University, the scientists recreated the surface temperature and atmospheric pressure on Mars as part of a simulation of conditions on both Earth and Mars.

Lionel Wilson, Emeritus Professor of Earth and Planetary Sciences at Lancaster University, said: "We performed experiments in a vacuum chamber to simulate the release of mud on Mars. This is of interest because we see many flow-like features on Mars in spacecraft images, but they have not yet been visited by any of the roving vehicles on the surface and there is some ambiguity about whether they are flows of lava or mud."

The scientists performed experiments at low pressure and at extremely cold temperatures (-20°C) to recreate the Martian environment. They found that free flowing mud under Martian conditions behaves differently from on Earth, because of rapid freezing and the formation of an icy crust. This is because water is not stable and begins to boil and evaporate. The evaporation removes latent heat from the mud, eventually causing it to freeze.

Under Martian conditions, the experimental mud flows formed similar shapes to "pahoehoe" lava frequently occurring on Hawaii or Iceland on Earth, which cools down to form smooth undulating surfaces. In the experiment, this happened when liquid mud spilled from ruptures in the frozen crust, then refroze.

However, under terrestrial atmospheric pressure, the experimental mud flows did not form lava shapes, did not expand, and had no icy crust, even under very cold conditions.

This "sedimentary volcanism" has also been proposed for the dwarf planet Ceres which lies in the asteroid belt between Mars and Jupiter and may have a muddy water ocean beneath an icy crust.

Dr Petr Brož, the leading author of the study, said: "We suggest that mud volcanism can explain the formation of some lava-like flow morphologies on Mars, and that similar processes may apply to eruptions of mud on icy bodies in the outer Solar System, like on Ceres."

CAMBIDGE, MA -- MIT neuroscientists have discovered that an enzyme called HDAC1 is critical for repairing age-related DNA damage to genes involved in memory and other cognitive functions. This enzyme is often diminished in both Alzheimer's patients and normally aging adults.

In a study of mice, the researchers showed that when HDAC1 is lost, a specific type of DNA damage builds up as the mice age. They also showed that they could reverse this damage and improve cognitive function with a drug that activates HDAC1.

The study suggests that restoring HDAC1 could have positive benefits for both Alzheimer's patients and people who suffer from age-related cognitive decline, the researchers say.

"It seems that HDAC1 is really an anti-aging molecule," says Li-Huei Tsai, the director of MIT's Picower Institute for Learning and Memory and the senior author of the study. "I think this is a very broadly applicable basic biology finding, because nearly all of the human neurodegenerative diseases only happen during aging. I would speculate that activating HDAC1 is beneficial in many conditions."

Picower Institute research scientist Ping-Chieh Pao is the lead author of the study, which appears today in Nature Communications.

DNA repair and aging

There are several members of the HDAC family of enzymes, and their primary function is to modify histones -- proteins around which DNA is spooled. These modifications control gene expression by blocking genes in certain stretches of DNA from being copied into RNA.

In 2013, Tsai's lab published two papers that linked HDAC1 to DNA repair in neurons. In the current paper, the researchers explored what happens when HDAC1-mediated repair fails to occur. To do that, they engineered mice in which they could knock out HDAC1 specifically in neurons and another type of brain cells called astrocytes.

For the first several months of the mice's lives, there were no discernable differences in their DNA damage levels or behavior, compared to normal mice. However, as the mice aged, differences became more apparent. DNA damage began to accumulate in the HDAC1-deficient mice, and they also lost some of their ability to modulate synaptic plasticity -- changes in the strength of the connections between neurons. The older mice lacking HCAC1 also showed impairments in tests of memory and spatial navigation.

The researchers found that HDAC1 loss led to a specific type of DNA damage called 8-oxo-guanine lesions, which are a signature of oxidative DNA damage. Studies of Alzheimer's patients have also shown high levels of this type of DNA damage, which is often caused by accumulation of harmful metabolic byproducts. The brain's ability to clear these byproducts often diminishes with age.

An enzyme called OGG1 is responsible for repairing this type of oxidative DNA damage, and the researchers found that HDAC1 is needed to activate OGG1. When HDAC1 is missing, OGG1 fails to turn on and DNA damage goes unrepaired. Many of the genes that the researchers found to be most susceptible to this type of damage encode ion channels, which are critical for the function of synapses.

Targeting neurodegeneration

Several years ago, Tsai and Stephen Haggarty of Harvard Medical School, who is also an author of the new study, screened libraries of small molecules in search of potential drug compounds that activate or inhibit members of the HDAC family. In the new paper, Tsai and Pao used one of these drugs, called exifone, to see if they could reverse the age-related DNA damage they saw in mice lacking HDAC1.

The researchers used exifone to treat two different mouse models of Alzheimer's, as well as healthy older mice. In all cases, they found that the drug reduced the levels of oxidative DNA damage in the brain and improved the mice's cognitive functions, including memory.

Exifone was approved in the 1980s in Europe to treat dementia but was later taken off the market because it caused liver damage in some patients. Tsai says she is optimistic that other, safer HDAC1-activating drugs could be worth pursuing as potential treatments for both age-related cognitive decline and Alzheimer's disease.

"This study really positions HDAC1 as a potential new drug target for age-related phenotypes, as well as neurodegeneration-associated pathology and phenotypes," she says.

Tsai's lab is now exploring whether DNA damage and HDAC1 also play a role in the formation of Tau tangles -- misfolded proteins in the brain that are a signature of Alzheimer's and other neurodegenerative diseases.

A squad of climate-related factors is responsible for the massive Australian coral bleaching event of 2016. If we're counting culprits: it's two by sea, one by land.

First, El Niño brought warmer water to the Coral Sea in 2016, threatening Australia's Great Barrier Reef's corals. Long-term global warming meant even more heat in the region, according to a new CIRES assessment. And in a final blow that year, a terrestrial heatwave swept over the coast, blanketing the reef system well into the winter, Karnauskas found. The final toll: more than half the coral in some parts of the Great Barrier Reef died.

"When the Great Barrier Reef bleached severely back in 2016, it earned global attention," said Kris Karnauskas, CIRES Fellow, associate professor of atmospheric and oceanic sciences at the University of Colorado Boulder and author on the study out today in Geophysical Research Letters. "Some speculated it was global warming, others thought it was El Niño, but the actual role of those two forces have not really been disentangled. As a physical climate scientist with a bias for the ocean, I thought I should dig in."

Karnauskas dissected the reasons behind the excessively warm water in Northern Australia's Coral Sea--water warm enough to "bleach" and kill coral, especially in the northern Great Barrier Reef. Karnauskas used satellite observations and a mathematical technique to fingerprint what phenomena led to what amount of warming, and when. It was the interaction of two key things, he found, that caused the coral-killing heat: A marine heatwave followed by a terrestrial one, both exacerbated by global warming.

First came a marine heatwave. It was El Niño that initially caused a spike in sea surface temperature by shifting sun-blocking clouds away from the region, but global warming trends increased its intensity and extended it by several months by raising the background temperature. Then, a landborne heatwave moved across eastern Australia and spilled out over the ocean just as the first phase of the marine heatwave was ending.

"It turns out that El Niño did play a role, and the eventual warmth was certainly higher because of the long-term trend, but the reason it lasted so long was actually this terrestrial heatwave lurking over eastern Australia until the marine warming event was just finally waning, and then: bang, the heatwave leaked out over the coastline," Karnauskas said. "That warm air over the ocean changed the way heat is exchanged between the ocean and atmosphere, keeping the ocean warm and bleaching for an extra month or so."

Increased water temperatures off the northeastern Australian coast triggered mass death of corals on an unprecedented scale. The hot water persisted for months, and caused extensive damage to the ecosystem--drastically changing the species composition of the region.

"This new finding reveals that climate variability and change can lead to marine impacts in surprising, compounding ways, including heatwaves both on land and in the ocean," said Karnauskas. "From heatwaves to hurricanes, we need to double down on efforts to understand the complexities of how anthropogenic climate change will influence extreme events in the future."

Neural networks in the visual cortex of the brain do a remarkable job of transforming the patterns of light that fall onto the retina into the vivid sensory experience that we call sight. A critical element of this encoding process depends on neurons that respond selectively to different features in the visual scene. Edges and their orientation in space carry an enormous amount of information about the visual environment, and individual neurons in the visual cortex encode this information by responding selectively to a narrow range of edge orientations; some responding maximally to vertical or horizontal, and others to different orientations in between. But neurons in visual cortex face another challenge in representing visual information: They must bring together the signals that originate from the left and right eyes to create a single unified binocular representation. The association of the inputs from the two eyes occurs in the visual cortex and we know that this is achieved with a high degree of precision such that individual neurons respond selectively to the same orientation with stimulation of either the left or right eye. What has been missing is a clear understanding of the developmental mechanisms that are responsible for uniting the inputs from the two eyes, a gap in knowledge that led Max Planck Florida researchers to a series of experiments that have revealed a critical role for early visual experience in guiding the formation of a unified binocular representation.

The first issue that Max Planck scientists Jeremy Chang, David Whitney, and David Fitzpatrick wanted to address is whether alignment of the inputs from the two eyes requires visual experience. Does the brain use vision to align the representations? They approached this question in the ferret, a species that has a well-organized visual cortex with a repeating modular structure in which nearby neurons have similar orientation preferences, resulting in distinct patterns of activity across the cortical surface for different orientations. This makes it possible to use imaging techniques that detect calcium signals to visualize the different modular patterns of activity that are associated with different orientations.  Prior to the onset of visual experience, they found that monocular stimulation produced activity patterns that had all the hallmarks of the mature visual cortex except one: the modular patterns of activity produced by stimulation of the left eye with a single orientation, were different from the modular patterns produced by the same stimulus orientation presented to the right eye. In other words, our brains are capable of developing orderly network representations of edge orientation in the absence of visual experience, but these networks lack the binocular alignment that is seen in mature animals. Additional experiments allowed the investigators to uncover a dynamic process that occurs over a short period of time (7-10 days) in which visual experience drives the alignment of these early representations. Importantly, the period when visual experience is capable of supporting alignment was found to be limited to the first week after eye opening, making it clear that early visual experience is critical for proper development of the circuits that support binocular vision for the rest of life.

These results suggested that binocular visual experience early in development is likely to be a key factor in the alignment of the network representations of the two eyes.  This led them to wonder what the patterns of activity in visual cortex would look like for simultaneous stimulation of the two eyes early in development before alignment has been achieved. Surprisingly, they found that binocular stimulation led to the appearance of a third modular representation--one that was distinct from the patterns of activity found for stimulation of the two eyes independently. By tracking these three representations across time they discovered that the early binocular representation was more stable than the others, appearing most similar to the mature, unified representation that emerges with visual experience. Thus, the activation of this binocular representation with the onset of binocular visual experience may guide the reorganization process, ensuring that all three representations become aligned as a single coherent network.

Ultimately, these changes in network structure must reflect changes in the response properties of single neurons, and to probe the process of alignment at the cellular scale, they turned to experiments using two-photon imaging that allowed them to visualize the response properties of individual neurons. Consistent with the network representation observations, individual neurons exhibited mismatched orientation preferences for monocular stimulation prior to the onset of visual experience that are rectified by changes in preferred orientation induced by visual experience. The next steps of this project are to investigate network reorganization at the synaptic scale, to identify precisely which components of the cortical network are changing and the mechanisms that enable the change.

A greater understanding of the mechanisms responsible for the experience-dependent alignment of cortical networks is critical for addressing visual disorders that arise from early abnormalities in visual experience such as amblyopia.  But experience-guided alignment of cortical networks is likely critical for a broad range of brain functions--sensory, motor, and cognitive-- that are optimized to support effective navigation and interaction with our world. Identifying those aspects of brain circuitry that depend on early experience for proper alignment, and understanding the underlying alignment mechanisms could offer insights into a host of neurodevelopmental disorders whose causes are still largely unknown.

White blood cells are known to circulate through the entire body inside blood vessels, acting as a surveillance system. However, a specialized group of these cells are permanently present in tissues like the skin, intestine and lungs, protecting against external invaders, such as microbes. But it is largely unknown how these cells are generated. A new study led by Marc Veldhoen, group leader at Instituto de Medicina Molecular João Lobo Antunes (iMM; Portugal) and published this week in the prestigious Nature Immunology*, shows that the local availability of specific molecules is crucial to generate these tissue resident surveillance cells. The impact of these results extends beyond protective immunity in tissues, as these cells are also efficient when elicited after vaccination and yield more effective anti-tumor immunity.

These tissue resident surveillance cells are a specialized group of T-cells, important to directly attack invading microorganisms. "The tissue resident T-cells develop after an initial infection, as part of immunological memory, and provide protection against future infections", explains Cristina Ferreira, first author of the paper.

Now, Marc Veldhoen and his team, have shown that within another population of T-cells, the regulatory T cells, mainly known for their ability to dampen immune responses to avoid damaging our own tissues, there are cells important for the development of these tissue resident T-cells. Using mouse models lacking this population of regulatory T-cells, the team observed that the number of tissue resident T-cells generated and present in the tissues was much lower. "It´s like the "surveillance system" in the gut, where we looked, was shut down. We could observe that a reduced number of the tissue resident T-cells resulted in less protection against invading pathogens", explains Marc Veldhoen.

But what is the role of the regulatory T-cells in the development of the tissue resident T-cells? "What we observed is that the regulatory T-cells are alerted to move to the site of infection, where they promote the local availability of a specific molecule, TGF-beta. According to our results, this is crucial to generate the tissue resident surveillance cells", explains Cristina Ferreira.

"We believe that learning more about how these cells develop might impact not only on how we look at infection conditions, especially in the gut, but also in cancer. It has been shown that the presence of tissue resident T-cells is important for a good outcome in cancer patients and, in animal models, studies have shown that these cells were most efficacious against cancer. Very likely, the reason is that these cells are specialized to penetrate deep into tissues. The more we know about these cells, the better we are equipped to develop ways to boost treatments in diseases, such as breast cancer", adds Marc Veldhoen, on the importance of these discoveries.

LA JOLLA, CALIF. – May 18, 2020 – Scientists at Sanford Burnham Prebys have discovered that combining immunotherapy with a drug called tumor necrosis factor (TNF) eradicated a deadly type of pediatric brain tumor in mice. The discovery, published in Nature Neuroscience, is expected to lead to a clinical trial to test the benefits of the treatment in patients. The findings also hold implications for other cancers that do not respond to immunotherapy.

“I’ve studied medulloblastoma for more than 20 years. I’ve seen many therapies that prolong survival in mice. But this is first time I have ever seen a therapy essentially melt the tumor away,” says Robert Wechsler-Reya, Ph.D., senior author of the paper, professor and director of the Tumor Initiation and Maintenance Program at Sanford Burnham Prebys, and program director of the Joseph Clayes III Research Center for Neuro-Oncology and Genomics at the Rady Children’s Institute for Genomic Medicine. “We look forward to testing this approach in the clinic and are hopeful that this discovery might be able to save children’s lives.”

One in four children does not survive medulloblastoma, and tumors with mutations in p53, a protein that stops the growth of tumors, are especially deadly. The standard treatments for the disease are surgery, whole brain and spine radiation, and intensive chemotherapy. Although these aggressive treatments can cure some patients, those who survive often suffer devastating long-term side effects, including intellectual disabilities, hormonal disorders and an increased risk of developing cancer later in life. Scientists have been striving to use immunotherapy, which harnesses an individual’s immune system to destroy the cancer, as a safer and more effective treatment for medulloblastoma.

“We are very encouraged by these study results and hope to initiate a Phase 1 clinical trial as soon as possible,” says Sabine Mueller, M.D., Ph.D., co-founder of the Pediatric Pacific Neuro-Oncology Consortium (PNOC), a network of children’s hospitals that aims to advance personalized therapies to children and young adults with brain tumors. “Undergoing chemotherapy and radiation is difficult for adults, and even more so for children. Treatment advances cannot come soon enough for these vulnerable pediatric patients.”

Removing the tumor’s invisibility cloak

In the study, Wechsler-Reya and his colleagues conducted a series of experiments investigating why immune responses differed between two different mouse models of medulloblastoma—one with p53 mutations and one without. Often called the “guardian of the genome,” p53 scans DNA for errors and is the most frequently mutated gene in human cancer.

These experiments revealed that tumors lacking p53 do not display an important protein—called the major histocompatibility complex I (MHC-I)—on their surface. MHC-I allows tumors to be recognized and killed by the immune system; without it, a tumor is invisible to the immune system and continues to grow uninterrupted.

The scientists found that low doses of TNF increased expression of MHC-I on p53-mutant tumors—removing their “invisibility cloak” and allowing them to be detected and destroyed by the immune system. Importantly, when mice with p53-mutant tumors received both TNF and a type of immunotherapy called an immune checkpoint inhibitor, the tumor completely disappeared.

“This work suggests that adding TNF to immunotherapy could benefit medulloblastoma patients with tumors lacking p53,” says Alexandra Garancher, Ph.D., first author of the study and a postdoctoral associate in the Wechsler-Reya lab. “If p53 is missing, low doses of TNF may boost MHC-I to the levels needed for immunotherapy to work.”

The scientists also tested the combination treatment in a mouse model of diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor that has a nearly 100% fatality rate. After receiving the treatment, approximately half of these mice survived the cancer.

“Our findings suggest that some cancers may not respond to immunotherapy because the tumors don’t have sufficient MHC-I levels to trigger an effective immune response,” says Wechsler-Reya. “Our hope is that in the near term, combining immunotherapy with TNF will increase the effectiveness of immunotherapy for children who are battling brain cancer.”

Rockville, MD, May 18, 2020 - Increasing reports of severe COVID-19 illness in children - coupled with the fact that little is known about how and why the disease may behave differently in this younger population - demand that a set of critical steps be taken now to ensure children get the attention they need, according to an article just published in Pediatric Research.

The article, authored by research experts from I-ACT for Children and other leading pediatric researchers, outlines a roadmap for better understanding the disease in children and ensuring that potential treatments and vaccines are developed for children with the same level of urgency given to adults.

"Although the volume and severity of COVID-19 illness in adults has been greater, we cannot afford scientific unknowns for children, especially with mounting reports of severe illness in children.," said Gary Noel, M.D., the study's lead author and I-ACT for Children's Chief Medical Officer. "Studying the infection in children now could lead to valuable information that helps us successfully treat COVID-19 and prevent its further spread."

In early April, the CDC calculated that in the United States, about 1.7% (2,572 of 149,082 for which age was reported) of COVID-19 cases had occurred in children (

The authors outline five key areas of pediatric research that require urgent action:

1. Understanding how COVID-19 infection develops and progresses in children and the impact of a mother's infection during pregnancy on her newborn.

The early suggestion that children are at lower risk of severe disease from COVID-19 infection remains unexplained and has not been confirmed; research aimed at defining the pathophysiology and course of the disease in children is essential for developing the best treatment and prevention strategies to address children's medical needs. This should receive the highest priority in the clinical research community.

2. Ensuring the availability of widespread, rapid point-of-care diagnostic testing to assess prevalence, inform prevention strategies.

Identifying infected children more extensively and more rapidly can help define the role children may be playing in spreading the infection, as well as help researchers understand the course of the disease in these children. The authors suggest that limited availability of testing has likely resulted in a significant underestimation of the number of infected children.

3. Conducting widespread antibody testing of children as a marker for susceptibility.

Defining the role specific antibodies play in determining immunity to COVID-19 infection is needed not only to advance vaccine strategies, but also to better understand the extent to which infants and children have responded to these infections, and therefore may be protected from new infections.

4. Establishing a dedicated framework for testing the safety and efficacy of new COVID-19 treatments in children.

As treatments are being developed and tested in adults, including pediatricians in that study planning can help ensure the collection of data that can be used to inform and accelerate pediatric studies, through use of extrapolation and other innovative research methods. Studies of investigational agents in children should begin as soon as deemed ethically appropriate based on risk and benefit assessment.

5. Evaluating vaccines and other preventive measures for children.

As with new treatments, early preparation for inclusion of children in trials of new vaccines and other preventive agents is important - and these trials should not be delayed once careful risk-benefit assessment justifies such inclusion. It is already clear that the risk for serious disease exists, and that the family impact of infection/disease in children can be significant.

"While it appears so far that children represent a small proportion of the total population with serious COVID-19 disease, this should not mean that we are left without the information we need to make well-informed decisions about using new therapies in children who are critically ill," said Edward Connor, M.D., M.B.E., Founder and Chairman of I-ACT for Children and the article's senior author. "We must collaborate to ensure pediatric needs aren't pushed to the edge of the radar."

Drug development in pediatrics has been slow and inefficient for decades. Half the medicines prescribed for children have never been proven effective for them. I-ACT for Children was created to level the playing field by championing and participating in the research needed to ensure children have the same access as adults to effective medicines.

I-ACT for Children has created a public-private pediatric research network that is specifically designed to advance product development in children. It collaborates with similar organizations in Europe, Canada and Japan to provide a global research framework.

A hidden Murray River rockshelter speaks volumes about local Aboriginal and European settlement in the Riverland, with symbols of conflict - including a swastika symbol - discovered in Aboriginal rock art.

The engravings studied in 188 engravings in a remote South Australian rockshelter are a stark reminder of colonial invasion and the strife brewing in Europe ahead of World War Two, Flinders University archaeologists have revealed.

The 'graffiti' has been etched over or adjacent to Aboriginal rock art at a culturally significant rockshelter in limestone cliffs of the Murray River near Waikerie in South Australia.

The engravings reveal the deep Aboriginal significance of the rockshelter, the traumatic period of European invasion, and the frontier conflict and ongoing impacts of colonial settlement, says lead author Flinders Associate Professor Amy Roberts, who works with members of the local Aboriginal community.

The archaeologists from Flinders University, in partnership with the River Murray and Mallee Aboriginal Corporation, have published their observations in a new article in Australian Archaeology.

"Of the 188 motifs identified, only one engraving remained that could be positively identified as a pre-European Aboriginal design - a 'treelike' motif," Associate Professor Roberts says.

"The rest of the identifiable historical inscriptions were the work of members of frontier conflict/punitive expeditions, local European settlers and a non-local Aboriginal man. Of the motifs that can be confidently identified one incorporates a swastika, engraved in 1932."

The first European historical inscriptions were engraved by members of volunteer police parties on punitive expeditions, and were part of a historical trajectory that later culminated in the Rufus River Massacre.

"It is unlikely that police party members were unaware of this deliberate desecration when they added their names to the front of the shelter," says co-author Flinders University Professor Heather Burke.

The authors argue that these historical engravings breach the Aboriginal cultural space and represent the first acts of trespass and desecration.

Fiona Giles, co-chair of the River Murray and Mallee Aboriginal Corporation, says: "We need to tell these stories to protect our history and heritage so that our culture is respected and not lost.

"For us, as traditional owners, this rockshelter is a highly significant and special place. It tells the stories of our ancestors and shows our deep connection to the river and reminds us of how our people lived before Europeans invaded our world," she says.

Imagine a self-repairing rubber, or super-adhesive made entirely from waste materials.

It sounds like science fiction, but researchers have discovered a new kind of rubber and catalyst that together can be used with low energy consumption to make flexible, repairable, sustainable objects - including car tires.

The new rubber material, made from cheap and plentiful industrial waste products sulfur, canola cooking oil and dicyclopentadiene (DCPD) from petroleum refining, can be completely repaired and returned to its original strength in minutes - even at room temperature - with an amine catalyst.

The new type of rubber can be seamlessly repaired if damaged and can also be recycled, says research leader Flinders University Associate Professor Justin Chalker, whose team's breakthrough findings are described in leading international journal Chemical Science.

The amine catalyst used to trigger the reaction that causes the rubber to self-repair occurs within minutes in some cases and it is all done at room temperature, scientists say.

"This study reveals a new concept in the repair, adhesion and recycling of sustainable rubber," says Associate Professor Chalker, adding too many plastics, rubbers and ceramics are not recyclable.

Each year in Australia, the equivalent of 48 million tires (tyres) reach the end of their life, only 16% of these are domestically recycled. Around two-thirds of used tires in Australia end up in landfill, are stockpiled, illegally dumped or have an unknown fate.

This represents both a waste of resources and creates health and environmental issues. Each passenger car tire contains approximately 1.5kg of steel, 0.5kg of textiles and 7 kg of rubber. - Source: Planet Ark

"It is exciting to see how the underlying chemistry of these materials has such wide potential in recycling, next-generation adhesives, and additive manufacturing."

Researchers from the Chalker Lab at the Flinders University Institute for Nanoscale Science and Technology, with University of Liverpool and University of Western Australia colleagues, say the new rubber can be used as a "latent adhesive".

"The rubber bonds to itself when the amine catalyst is applied to the surface. The adhesion is stronger than many commercial glues," says University of Liverpool researcher Dr Tom Hasell.

"The polymer is also resistant to water and corrosion."

Rubber bricks made out of this polymer can be chemically joined by applying the catalyst.

"In some cases, the amine catalyst causes the rubber to bond in just minutes, and it can be done at room temperature," explains Flinders University lead author Sam Tonkin.

"The rubber can also be used as a latent adhesive, where it bonds to the surface of another piece of rubber when the amine catalyst is applied.

"Basically the rubber is not 'sticky' until the catalyst is applied."

In addition to the highly useful practical applications, the new paper gives detailed fundamental studies on the mechanisms of the rubber repair.

An antibody first identified in a blood sample from a patient who recovered from Severe Acute Respiratory Syndrome in 2003 inhibits related coronaviruses, including the cause of COVID-19.

The antibody, called S309, is now on a fast-track development and testing path at Vir Biotechnology in the next step toward possible clinical trials.

Laboratory research findings on the S309 antibody are reported in the May 18 edition of Nature. The title of the paper is: "Cross-neutralization of SARS-CoV and SARS-CoV2 by a human monoclonal antibody".

The senior authors on the paper are David Veesler, assistant professor of biochemistry at the University of Washington School of Medicine, and Davide Corti of Humabs Biomed SA, a subsidiary of Vir.

The lead authors are Dora Pinto and Martina Beltramello of Humabs, as well as Young-Jun Park and Lexi Walls, research scientists in the Veesler lab, which for several years has been studying the structure and function of the infection mechanisms on a variety of coronaviruses.

"We still need to show that this antibody is protective in living systems, which has not yet been done," Veesler said.

"Right now there are no approved tools or licensed therapeutics proven to fight against the coronavirus that causes COVID-19," he added. If the antibody is shown to work against the novel coronavirus in people, it could become part of the pandemic armamentarium.

Veesler said that his lab is not the only one seeking neutralizing antibodies for COVID 19 treatment. What makes this antibody different is that its search did not take place in people who had COVID-19, but in someone who had been infected 17 years ago during a SARS epidemic.

"This is what allowed us to move so fast compared to other groups," Veesler said.

The scientists identified several monoclonal antibodies of interest from memory B cells of the SARS survivor. Memory B cells form following an infectious illness. Their lineage can last, sometimes for life. They usually remember a pathogen, or one similar to it, that the body has ousted in the past, and launch an antibody defense against a re-infection.

Several of the antibodies from the SARS survivor's memory B cells are directed at a protein structure on coronaviruses. This structure is critical to the coronaviruses' ability to recognize a receptor on a cell, fuse to it, and inject their genetic material into the cell. This infectivity machinery is located in the spikes that crown the coronavirus.

The S309 antibody is particularly potent at targeting and disabling the spike protein that promotes the coronavirus entry into cells. It was able to neutralize SARS CoV-2 by engaging with a section of the spike protein nearby the attachment site to the host cell.

Through their cryo-electronmicroscopy studies and binding assays, the researchers learned that the S309 antibody recognizes a binding site on the coronavirus that is conserved across many sarbocoviruses, not just the SARS and COVID-19 viruses. That is probably why this antibody, instead of being single-minded, is able to act against related coronaviruses.

Combining the S309 antibody with other, though weaker, antibodies identified in the recovered SARS patient enhanced the neutralization of the COVID-19 coronavirus.

This multiple antibody cocktail approach might help limit the coronavirus' ability to form mutants capable of escaping a single-ingredient antibody treatment, according to the researchers.

The scientists noted that they hope these initial results pave the way for using the S309 antibody, alone or in a mixture, as a preventive measure for people at high-risk of exposure to the COVID-19 coronavirus or as post-exposure therapy to limit or treat severe illness.