Searching for subtypes of immune cells seen only in the most serious, grade 4 brain tumors, called glioblastomas, and using a recently developed technology called spatial genomics, the researchers found that glioblastoma stem cells were co-localized with a type of immunosuppressive cell called myeloid-derived suppressor cell (MDSC), and that these two cells symbiotically feed off of each other to promote tumor growth and aggressiveness. A description of the work was published Jan. 17 in the journal Science. “Tumor stem cells represent only 5% to 10% of the tumor, but they’re the critical cells that are renewing and generating the rest of the tumor and are essentially responsible for the aggressiveness of the tumor,” says senior study author Drew Pardoll, M.D., Ph.D., the Martin D. Abeloff Professor of Cancer Research , co-director of the Mark Foundation Center for Advanced Genomics and Imaging, and director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy. “We found that the myeloid-derived suppressor cells and tumor stem cells literally were in the same place — a region described by pathologists in the 1980s as the pseudopalisading region. There was a very intimate connection.”

To better characterize the cellular components of brain cancer, investigators performed single-cell RNA sequencing on tissue samples from 33 types of brain tumors spanning from low to high grade, finding two populations of MDSCs in IDH-WT glioblastoma. Then, using a technique called spatial transcriptomics to look at patterns of gene expression of over 750,000 immune cells and more than 350,000 tumor and associated cells in these samples, they found MDSCs were co-located with the tumor stem cells.

“Glioblastoma is a highly aggressive brain tumor with remarkable ability to evade the immune system, which has made immune-based therapies largely ineffective to this point,” said first and co-corresponding author, Christina Jackson, M.D., an assistant professor of neurosurgery at the Perelman School of Medicine at the University of Pennsylvania, who was at Johns Hopkins at the time the research was conducted. “Our study revealed a distinct subset of immune cells, known as myeloid-derived suppressor cells that promote glioblastoma growth, providing new insights into how the tumor interacts with the immune system. By identifying these cells and their role, we hope to uncover new therapeutic targets andlay the groundwork for more effective treatments.”

In their studies, investigators discovered that the two types of cells were feeding each other in the brain tumors. Tumor stem cells were producing chemical signals called chemokines that attracted the MDSCs, and making growth factors and activation factors for the MDSCs. In turn, the MDSCs were producing growth factors for the tumor cells.

The researchers were able to further ascertain what specific molecules tumor stem cells were producing to attract and activate MDSCs. Two of the key ones identified by the team were IL (interleukin)-6 and IL-8, which play a role in inflammatory responses, and for which MDSCs have receptors.

“IL-8 is one of the major attractants to bring the MDSCs to the tumor, and IL-6 is one of the major activators of the MDSCs,” Pardoll says.

On the flip side, the team found that MDSCs secreted a growth factor called fibroblast growth factor 11 (FGF11) to feed the stem cells, a molecule never before known to be involved in brain or other cancers.

Along the way, Jackson, Pardoll and colleagues found that tumors with a mutation in the IDH1 gene, which are less aggressive, had almost no MDSCs and far fewer cancer stem cells. This led them to look across all brain cancers at the correlation between MDSC infiltration and survival. Using the National Cancer Institute’s Cancer Genome Atlas (TCGA) database of cancer samples, they indeed found that very tight correlation — the fewer cancer stem cells and fewer MDSCs a person had in their tumors, the better they did.

While additional studies are needed to further understand these cellular interactions, the work is exciting in that it suggests additional potential targets to block in treatment of these aggressive brain tumors, Pardoll says. For example, Jamie Spangler, Ph.D., an associate professor of biomedical engineering at Johns Hopkins, has developed an investigational bispecific antibody that binds to the receptors for IL-6 and IL-8, blocking their signaling.

Study co-authors were Christopher Cherry, Sadhana Bom, Arbor Dykema, Rulin Wang, Elizabeth Thompson, Ming Zhang, Runzhe Li, Zhicheng Ji, Wenpin Hou, Wentao Zhan, Hao Zhang, John Choi, Ajay Vaghasia, Landon Hansen, Kate Jones, Fausto Rodriguez, Jon Weingart, Calixto-Hope Lucas, Jonathan Powell, Jennifer Elisseeff, Srinivasan Yegnasubramanian, Chetan Bettegowda and Hongkai Ji of Johns Hopkins. Other researchers contributing to the work were from Stanford University School of Medicine in California.

The research was supported by the National Institutes of Health (grants #F32NS108580, #R01HG010889, R01HG009518, RA37CA230400, U07CA230691), the Neurosurgery Research Education Foundation, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the Mark Foundation for Cancer Research, a Burroughs Wellcome Career Award for Medical Scientists, the Commonwealth Foundation, the Maryland Cigarette Restitution Fund and the NIH Pioneer Award.

Bettegowda is a consultant for Bionaut Labs, Privo Technologies, Haystack Oncology and Depuy-Synthes. He also is a co-founder of OrisDx and Belay Diagnostics. Yegnasubramanian has received grant support through Johns Hopkins from Bristol Myers Squibb and Janssen and grants and personal fees from Cepheid. He is a co-founder of Digital Harmonic and Brahm Astra Therapeutics. Elisseeff is founder of Aegeria Soft Tissue. Powell is an employee of Calico but was not when this research was performed. Pardoll is a consultant for Amgen, Arcturus Therapeutics, ATengen, Bristol Myers Squibb, Compugen, Dragonfly Therapeutics, Immunomic Therapeutics, Normunity, PathAI, RAPT Therapeutics, Regeneron, Takeda Pharmaceuticals and Tizona. He has received grant support through Bristol Myers Squibb, Compugen, Enara Bio and Immunomic Therapeutics, and owns stock in Dracen Pharmaceuticals, Dragonfly Therapeutics, Enara Bio, RAPT Therapeutics and Tizona. Pardoll is on the board of directors of Clasp Therapeutics and Dracen Pharmaceuticals and has patent royalties with Bristol Myers Squibb and Immunomic Therapeutics. These relationships are managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.

In reality, research has shown that human bodily responses and cognitive shifts affect each other in both directions. We feel sorry because we cry, but also cry when feeling sorry. So how then for our primate cousins? To date, their connections have remained largely unexplored.

Now a team of researchers at Kyoto University has led a study on six Japanese macaques living in KyotoU’s Center for the Evolutionary Origins of Human Behavior, in Aichi prefecture. The researchers focused on self-scratching — a bodily response linked to negative emotions like anxiety and fear — and its relationship to pessimistic judgment bias, which is the tendency to expect a negative outcome when faced with ambiguous information.

By presenting the monkeys with a white rewarding button and a black non-rewarding button, together with a gray ambiguous button, the researchers were able to estimate each monkey’s degree of pessimism. They also videoed the monkeys to identify the timing of self-scratching, analyzing the relationship between self-scratching and pessimism.

“Bodily responses associated with negative emotions can predict subsequent cognitive pessimism,” says corresponding author Sakumi Iki, “but not the other way around.”

In other words, the monkeys were more likely to make pessimistic judgments — avoiding the gray button — immediately after self-scratching, yet making a pessimistic judgment did not necessarily lead to self-scratching. This stands in contrast to humans, for whom evidence suggests a pessimistic way of thinking can cause bodily responses. That this influence did not appear in the macaques suggests that their emotional bodily responses may precede cognitive changes.

From an evolutionary standpoint, the coping strategy of first addressing immediate needs through bodily responses and then engaging in cognitive information processing is probably adaptive for dealing with challenges in natural habitats. Thus, this mechanism might have existed long before humans and macaques diverged, pointing to an evolutionarily conserved system.

“In humans, the relationship between mind and body may have evolved in a distinctive way, influenced by our use of language and advanced introspection,” adds Iki.

“But it might be observable in monkeys if different bodily reactions or cognitive processes are examined.”

Future research involving a wider range of primates and other animals could shed more light on the evolutionary origins of human emotions, and deepen our understanding of the connection between the mind and the body.

However, satellite measurements of the flow speed of ice streams show that such simulations are inaccurate and have shortcomings to correctly reflect reality. This leads to considerable uncertainties in estimates of how much mass the ice streams are losing and how quickly and how high sea levels will rise.

Ice streams both judder and flow

Now, a team of researchers led by ETH professor Andreas Fichtner has made an unexpected discovery: deep within the ice streams, there are countless weak quakes taking place that trigger one another and propagate over distances of hundreds of metres. This discovery helps to explain the discrepancy between current simulations of ice streams and satellite measurements, and the new findings should also impact the way ice streams are simulated in the future.

“The assumption that ice streams only flow like viscous honey is no longer tenable. They also move with a constant stick-slip motion,” says Fichtner. The ETH professor is confident that this finding will be integrated into simulations of ice streams, making estimates of changes in sea level more accurate.

Riddles relating to ice cores resolved

Moreover, the ice quakes explain the origin of numerous fault planes between ice crystals in ice cores obtained from great depths. These fault planes are the result of tectonic shifts and have been known to scientists for decades, although no explanation had been found for them until now.

“The fact that we’ve now discovered these ice quakes is a key step towards gaining a better understanding of the deformation of ice streams on small scales,” explains Olaf Eisen, Professor at the Alfred Wegener Institute and one of the study’s co-authors.

The study by this international research team led by ETH Zurich has just been published in the journal Science and also involved researchers from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI), the University of Strasbourg, the Niels Bohr Institute (NBI), the Swiss Federal Institute WSL and other universities.

Fire and ice are related

The fact that these ice quakes cannot be observed at the surface and have therefore remained undiscovered until now is due to a layer of volcanic particles located 900 metres below the surface of the ice. This layer stops the quakes from propagating to the surface. Analysis of the ice core showed that these volcanic particles originate from a massive eruption of Mount Mazama in what is now Oregon (USA) some 7,700 years ago. “We were astonished by this previously unknown relationship between the dynamics of an ice stream and volcanic eruptions,” Fichtner recalls.

The ETH professor also noticed that the ice quakes start from impurities in the ice. These impurities are also leftovers from volcanoes: tiny traces of sulphates that entered the atmosphere in volcanic eruptions and flew halfway around the world before being deposited on the Greenland ice sheet in snowfall. These sulphates reduce the stability of the ice and favour the formation of microfissures.

A 2,700-metre borehole in the ice

The researchers discovered the ice quakes using a fibre-optic cable that was inserted into a 2,700-metre-deep borehole and recorded seismic data from inside a massive ice stream for the first time. This borehole was drilled into the ice by researchers from the East Greenland Ice-core Project (EastGRIP), led by the Niels Bohr Institute and strongly supported by the Alfred Wegener Institute, resulting in the extraction of a 2,700-metre-long ice core. Once drilling work was complete, the researchers took the opportunity to lower a fibre-optic cable 1,500 metres into the borehole and record signals from inside the ice stream continuously for 14 hours.

The research station and borehole are located on the North East Greenland Ice Stream (NEGIS), around 400 kilometres from the coast. The NEGIS is the biggest ice stream of the Greenland ice sheet, whose retreat is a large contributor to current rising sea levels. In the area of the research station, the ice is moving towards the sea at a speed of around 50 metres per year.

As ice quakes occur frequently over a wide area in the researchers’ measurements, ETH researcher Fichtner believes it is also plausible that they occur in ice streams everywhere, all the time. To verify this, however, it will be necessary to take seismic measurements of this kind in other boreholes — and there are already plans to do just that.

The research team, led by Dr Sara Mederos and Professor Sonja Hofer, mapped out how the brain learns to suppress responses to perceived threats that prove harmless over time.

“Humans are born with instinctive fear reactions, such as responses to loud noises or fast-approaching objects,” explains Dr Mederos, Research Fellow in the Hofer Lab at SWC. “However, we can override these instinctive responses through experience — like children learning to enjoy fireworks rather than fear their loud bangs. We wanted to understand the brain mechanisms that underlie such forms of learning.”

Using an innovative experimental approach, the team studied mice presented with an overhead expanding shadow that mimicked an approaching aerial predator. Initially, the mice sought shelter when encountering this visual threat. However, with repeated exposure and no actual danger, the mice learned to remain calm instead of escaping, providing researchers with a model to study the suppression of fear responses.

Based on previous work in the Hofer Lab, the team knew that an area of the brain called the ventrolateral geniculate nucleus (vLGN) could suppress fear reactions when active and was able to track knowledge of previous experience of threat. The vLGN also receives strong input from visual areas in the cerebral cortex, and so the researchers explored whether this neural pathway had a role in learning not to fear a visual threat.

The study revealed two key components in this learning process: (1) specific regions of the visual cortex proved essential for the learning process, and (2) a brain structure called the ventrolateral geniculate nucleus (vLGN) stores these learning-induced memories.

“We found that animals failed to learn to suppress their fear responses when specific cortical visual areas where inactivated. However, once the animals had already learned to stop escaping, the cerebral cortex was no longer necessary,” explained Dr Mederos.

“Our results challenge traditional views about learning and memory,” notes Professor Hofer, senior author of the study. “While the cerebral cortex has long been considered the brain’s primary centre for learning, memory and behavioural flexibility, we found the subcortical vLGN and not the visual cortex actually stores these crucial memories. This neural pathway can provide a link between cognitive neocortical processes and ‘hard-wired’ brainstem-mediated behaviours, enabling animals to adapt instinctive behaviours.”

The researchers also uncovered the cellular and molecular mechanisms behind this process. Learning occurs through increased neural activity in specific vLGN neurons, triggered by the release of endocannabinoids — brain-internal messenger molecules known to regulate mood and memory. This release decreases inhibitory input to vLGN neurons, resulting in heightened activity in this brain area when the visual threat stimulus is encountered, which suppresses fear responses.

The implications of this discovery extend beyond the laboratory. “Our findings could also help advance our understanding of what is going wrong in the brain when fear response regulation is impaired in conditions such as phobias, anxiety and PTSD. While instinctive fear reactions to predators may be less relevant for modern humans, the brain pathway we discovered exists in humans too,” explains Professor Hofer. “This could open new avenues for treating fear disorders by targeting vLGN circuits or localised endocannabinoid systems.”

The research team is now planning to collaborate with clinical researchers to study these brain circuits in humans, with the hope of someday developing new, targeted treatments for maladaptive fear responses and anxiety disorders.

This research was funded by the Sainsbury Wellcome Centre core grant from the Gatsby Charity Foundation and Wellcome (090843/F/09/Z); a Wellcome Investigator Award (219561/Z/19/Z); an EMBO postdoctoral fellowship (EMBO ALTF 327-2021) and a Wellcome Early Career Award (225708/Z/22/Z).

Northwestern University researchers have discovered how mantis shrimp remain impervious to their own punches. Their fists, or dactyl clubs, are covered in layered patterns, which selectively filter out sound. By blocking specific vibrations, the patterns act like a shield against self-generated shockwaves.

The study will be published on Friday (Feb. 7) in the journal Science.

The findings someday could be applied to developing synthetic, sound-filtering materials for protective gear as well as inspire new approaches to reducing blast-related injuries in military and sports.

“The mantis shrimp is known for its incredibly powerful strike, which can break mollusk shells and even crack aquarium glass,” said Northwestern’s Horacio D. Espinosa, the study’s co-corresponding author. “However, to repeatedly execute these high-impact strikes, the mantis shrimp’s dactyl club must have a robust protection mechanism to prevent self-damage. Most prior work has focused on the club’s toughness and crack resistance, treating the structure as a toughened impact shield. We found it uses phononic mechanisms — structures that selectively filter stress waves. This enables the shrimp to preserve its striking ability over multiple impacts and prevent soft tissue damage.”

An expert on bio-inspired materials, Espinosa is the James N. and Nancy J. Farley Professor in Manufacturing and Entrepreneurship and a professor of mechanical engineering at Northwestern’s McCormick School of Engineering, where he directs the Institute for Cellular Engineering Technologies. Espinosa led the study in partnership with M. Abi Ghanem of the Institute of Light and Matter, a joint research unit between Claude-Bernard-Lyon-I University and the Center for National Scientific Research in France.

A devastating blow

Living in shallow, tropical waters, mantis shrimp are armed with one hammer-like dactyl club on each side of its body. These clubs store energy in elastic, spring-like structures, which are held in place by latch-like tendons. When the latch is released, the stored energy, too, is released — propelling the club forward with explosive force.

With a single blow, mantis shrimp can slaughter prey or defend their territory from interloping competitors. As the punch rips through surrounding water, it creates a low-pressure zone behind it, causing a bubble to form.

“When the mantis shrimp strikes, the impact generates pressure waves onto its target,” Espinosa said. “It also creates bubbles, which rapidly collapse to produce shockwaves in the megahertz range. The collapse of these bubbles releases intense bursts of energy, which travel through the shrimp’s club. This secondary shockwave effect, along with the initial impact force, makes the mantis shrimp’s strike even more devastating.”

Protective patterns

Surprisingly, this force does not damage the shrimp’s delicate nerves and tissues, which are encased within its armor.

To investigate this phenomenon, Espinosa and colleagues used two advanced techniques to examine the mantis shrimp’s armor in fine detail. First, they applied transient grating spectroscopy, a laser-based method that analyzes how stress waves propagate through materials. Second, they employed picosecond laser ultrasonics, which provide further insights into the armor’s microstructure.

Their experiments revealed two distinct regions — each engineered for a specific function — within the mantis shrimp’s club. The impact region, responsible for delivering crushing blows, consists of mineralized fibers arranged in a herringbone pattern, giving it resistance to failure. Beneath this layer, the periodic region features twisted,corkscrew-like fiber bundles. These bundles form a Bouligand structure, a layered arrangement, in which each layer is progressively rotated relative to its neighbors.

While the herringbone pattern reinforces the club against fractures, the corkscrew arrangement governs how stress waves travel through the structure. This intricate design acts as a phononic shield, selectively filtering high-frequency stress waves to prevent damaging vibrations from propagating back into the shrimp’s arm and body.

“The periodic region plays a crucial role in selectively filtering out high-frequency shear waves, which are particularly damaging to biological tissues” Espinosa said. “This effectively shields the shrimp from damaging stress waves caused by the direct impact and bubble collapse.”

In this study, the researchers analyzed 2D simulations of wave behavior. Espinosa said 3D simulations are needed to fully understand the club’s complex structure.

“Future research should focus on more complex 3D simulations to fully capture how the club’s structure interacts with shockwaves,” Espinosa said. “Additionally, designing aquatic experiments with state-of-the-art instrumentation would allow us to investigate how phononic properties function in submerged conditions.”

The study, “Does the mantis shrimp pack a phononic shield?” was supported by the Air Force Office of Scientific Research, the Office of Naval Research and the National Science Foundation.