Now, new research clarifies the role of these intestinal white blood cells, known as 𝛄𝛅 T cells, in colorectal cancer. It turns out that the cells have a double-edged function: They rein in early-stage tumors but, as the disease progresses, undergo biochemical changes and switch sides, strengthening the tumor. The findings, published in Science, shed further light on the role of 𝛄𝛅 T cells in tumor growth, and may open new paths toward colorectal cancer therapies.

“𝛄𝛅 T cells that live in the gut act to prevent tumor formation,” says Bernardo Reis, a research associate in the laboratory of Daniel Mucida at The Rockefeller University. “But once tumors form, gut 𝛄𝛅 T cell populations change, enter the tumor, and promote tumor growth.”

Altered T cell receptors

The intestinal lining may be the body’s most vulnerable port of entry. Composed of but a single layer of epithelial cells, this busy digestive region must absorb useful substances like nutrients, and reject harmful ones like foodborne pathogens, within a limited working space. 𝛄𝛅 T cells mind the gaps, perpetually scanning the epithelium to maintain the integrity of the intestinal lining and prevent pathogens from invading the rest of the body.

Reis set out to investigate conflicting claims over whether these cells help or hinder the growth of intestinal tumors. But as is often the case in biology, there was no simple answer.

“We had data showing 𝛄𝛅 T cells were protective, but the literature suggested that they also promote tumor growth,” Reis says. “We wanted to understand what these 𝛄𝛅 T cells were really up to.”

Working in a mouse model of colorectal cancer, Reis and colleagues derived 𝛄𝛅 T cells from the intestines of animals with early-stage tumors and from the tumors of mice with advanced cancer. In comparing these two sources of supposedly identical cells, the researchers were surprised to find vast molecular differences between them. For example, the two categories of 𝛄𝛅 T cells boasted different T cell receptors. Moreover, 𝛄𝛅 T cells that had entered the tumor produced IL-17, a cytokine that normally promotes inflammation in response to infection. In the tumor microenvironment, however, IL-17 was promoting disease — spurring tumor growth and recruiting other cells to help hide the tumor from the rest of the immune system.

“The 𝛄𝛅 T cells had completely changed,” Reis says.

To confirm their findings, the team then used CRISPR gene editing technology to selectively remove T cell receptors from the white blood cells, changing the cells from anti-tumor to pro-tumor, or vice versa. In this way, they managed to increase the number and decrease the size of tumors in mouse models. “When we depleted the original 𝛄𝛅 T cells, the mice became sicker,” Reis says. “And when we depleted the tumor invading 𝛄𝛅 T cells, the tumors shrank.”

Hope for human cancers

Reis and colleagues witnessed similar activity in 𝛄𝛅 T cells derived from human colorectal tumors and their environs. Cells inside the tumor resembled the renegade, late-stage 𝛄𝛅 T cells seen in mice, while cells hovering around the outside of the tumor looked more like the original Res. “It almost looked like a fight between these two populations,” Reis says. “Regular cells were trying to contain the tumor while cells inside were promoting tumor growth.”

In the short term, the Mucida lab will focus on shoring up our understanding what promotes 𝛄𝛅 T cells’ shift from the intestine’s stark ally into its source of ruin. Future studies will delve deeper, examining whether it might be possible to modulate normal 𝛄𝛅 T cells to curb the tumor and prevent their cancer-promoting alter egos from dominating the arena. Reis is also interested in exploring ways to manipulate the system by which altered 𝛄𝛅 T cells enter the tumor.

“Perhaps we might one day fashion 𝛄𝛅 T cells into Trojan horses that can act as anti-cancer cells right inside the tumor microenvironment,” he says.

For this purpose, the researchers studied fruit flies of the genus Drosophila, which they had genetically modified in such a way that they cannot form Creld. In the animals, the heart rate was slowed in a characteristic way — a sign of energy deficiency. They also exhibited severe motor disorders. The power plants of the cell, the mitochondria, are responsible for providing energy. Their malfunction can result in the death of nerve cells that are responsible for motor function in humans. The clinical picture is known as Parkinson’s disease.

“So Creld may play an important role not only in impaired heart function, but also in Parkinson’s disease,” says Dr. Nicole Kucharowski of the LIMES Institute, who, along with her colleague Marie Paradis, conducted a key part of the experiments in the study. “The findings of a recent analysis are consistent with this. It suggests that Creld production is often reduced in Parkinson’s patients.” But just how Creld might be related to Parkinson’s was puzzling: The protein is not found in mitochondria at all. It can be detected exclusively in a widely branched network of tubes that serves to produce various molecules in the cell — the endoplasmic reticulum (ER). How can it interfere with the function of cellular power plants from there?

Pesticide suspected of causing Parkinson’s disease

To find out, the researchers administered small amounts of a pesticide to healthy fruit flies (i.e., those that can form Creld). It contains the active ingredient rotenone, which is suspected of triggering Parkinson’s disease in humans. Rotenone acts directly in the mitochondria by inhibiting a key step in energy production. After administration of the pesticide, the flies showed motor disorders similar to those of the Creld mutants. “We also found that their mitochondria are very often in contact with the ER,” Bülow explains.

In further experiments, the researchers were able to show that certain classes of lipids are transported from the ER to the mitochondria during this contact. These so-called phospholipids rekindle the step in energy production that is inhibited by rotenone. With assistance from the ER, the mitochondria try to ramp up the energy supply again in this way. “And the availability of Creld seems to be crucial for this transfer of phospholipids,” Bülow points out. “In flies that cannot form Creld, phospholipids accumulate in the contact sites between ER and mitochondria. So they don’t get transported to the mitochondria, but accumulate.”

Creld increases energy production in the cell

Creld is therefore important for increasing energy production in the cell. This is in line with the observation that Drosophila mutants without Creld produce hardly any hydrogen peroxide in their mitochondria — this is a molecule produced as a waste material during the work of the power plants. Hydrogen peroxide can damage cells. Until now, it was thought that it was produced in excessive amounts in people with Parkinson’s or that it was not adequately disposed of. This would gradually poison the nerve cells responsible for motor function.

It is possible, however, that another effect might cause their demise — namely, the chronic undersupply of energy triggered by damage to or underproduction of Creld. “This is a thesis that we now need to investigate further,” says Bülow, who is a member of the Transdisciplinary Research Area “Life and Health” at the University of Bonn.

The current success is also the result of a successful cooperation. For instance, essential parts of the work were carried out at the University of Osnabrück. Dr. Julia Sellin, who originally helped initiate the study, has also recently moved to the University Hospital in Aachen. “The collaboration with Prof. Dr. Christoph Thiele from the Cluster of Excellence Immunosensation2 here at the University of Bonn also went extremely well,” stresses Bülow.

Funding:

Working groups from the Universities of Bonn and Osnabrück, the University Hospital Aachen and the Leuven Center for Brain and Disease Research in Belgium were involved in the study. The work was funded by the German Research Foundation.

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A new study suggests that stem cells are able to integrate cues from their surroundings and coordinate their behavior across the tissue through networks of vasculature in their close vicinity.

Rockefeller scientists found that lymphatic capillaries — fine vessels that transport immune cells and drain fluids from tissues — represent a signaling hub that communicates with stem cells to regulate their activity. With molecular guidance from the lymphatics, the stem cells produce daughter cells to repopulate the intestinal lining or self-renew to restock the stem cell reserve.

The findings, published in the journal Cell Stem Cell, provide new insights about primary intestinal components whose disrupted communication may contribute to intestinal disorders, such as inflammatory bowel disease. “The key to treating these diseases will be to figure out who talks to whom in this ecosystem and how we can reset the communication networks,” says Rachel Niec, a clinical scholar in the laboratory of Elaine Fuchs.

Communications in the crypt

The intestinal stem cells reside in so-called crypts, found at the base of densely packed indentations in the intestinal lining. The stem cells may renew and stay in the crypt, or differentiate into specialized cells, which then migrate out of the crypt to replenish the gut lining. “To understand how stem cells balance self-renewal with differentiation, we needed a more complete picture of crypt niches,” says Marina Schernthanner, a graduate student in the Fuchs lab.

To zoom in on the crypt, the team used a suite of techniques, including single-cell and spatial transcriptomics, which allowed them to identify cell types at specific locations and study their signaling molecules. The results showed that lymphatic capillaries, which form an intimate connection with the stem cells in the crypt, produce a number of proteins known to be important for stem cell functioning.

One previously underappreciated protein, REELIN, emerged as a top candidate for mediating communications between lymphatics and stem cells. By manipulating the amount of REELIN in lab-grown intestinal organoid cultures in some experiments and genetically suppressing it in mice in others, the researchers found that REELIN directly governs the regenerative behavior of intestinal stem cells.

The involvement of the lymphatic system in stem cell functioning is a relatively new concept. A previous study by the Fuchs team revealed that lymphatics are also closely involved with stem cells of the skin and play a key role in hair regeneration. There, however, it is the hair follicle stem cells that signal to lymphatic capillaries. By controlling their interactions with lymphatics, the stem cells synchronize hair regeneration across the tissue. “This suggests that lymphatics may be a conserved feature of stem cell niches, but their relationship to stem cells are likely tailored around the needs of each tissue,” Niec says.

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A new study suggests that indeed, ants as a group behave similar to networks of neurons in a brain.

Rockefeller’s Daniel Kronauer and postdoctoral associate Asaf Gal developed a new experimental setup to meticulously analyze decision-making in ant colonies. As reported in the Proceedings of the National Academy of Sciences, they found that when a colony evacuates due to rising temperatures, its decision is a function of both the magnitude of the heat increase and the size of the ant group.

The findings suggest that ants combine sensory information with the parameters of their group to arrive at a group response — a process similar to neural computations giving rise to decisions.

“We pioneered an approach to understand the ant colony as a cognitive-like system that perceives inputs and then translates them into behavioral outputs,” says Kronauer, head of the Laboratory of Social Evolution and Behavior. “This is one of the first steps toward really understanding how insect societies engage in collective computation.”

A new paradigm

At its most basic level, decision-making boils down to a series of computations meant to maximize benefits and minimize costs. For instance, in a common type of decision-making called sensory response thresholding, an animal has to detect sensory input like heat past a certain level to produce a certain costly behavior, like moving away. If the rise in temperature isn’t big enough, it won’t be worth it.

Kronauer and Gal wanted to investigate how this type of information processing occurs at the collective level, where group dynamics come into play. They developed a system in which they could precisely perturb an ant colony with controlled temperature increases. To track the behavioral responses of individual ants and the entire colony, they marked each insect with different colored dots and followed their movements with a tracking camera.

As the researchers expected, colonies of a set size of 36 workers and 18 larvae dependably evacuated their nest when the temperature hit around 34 degrees Celsius. This finding makes intuitive sense, Kronauer says, because “if you become too uncomfortable, you leave.”

However, the researchers were surprised to find that the ants were not merely responding to temperature itself. When they increased the size of the colony from 10 to 200 individuals, the temperature necessary to trigger the decision to vacate increased. Colonies of 200 individuals, for example, held out until temperatures soared past 36 degrees. “It seems that the threshold isn’t fixed. Rather, it’s an emergent property that changes depending on the group size,” Kronauer says.

Individual ants are unaware of the size of their colony, so how can their decision depend on it? He and Gal suspect that the explanation has to do with the way pheromones, the invisible messengers that pass information between ants, scale their effect when more ants are present. They use a mathematical model to show that such a mechanism is indeed plausible. But they do not know why larger colonies would require higher temperatures to pack up shop. Kronauer ventures that it could simply be that the larger the colony’s size, the more onerous it is to relocate, pushing up the critical temperature for which relocations happen.

In future studies, Kronauer and Gal hope to refine their theoretical model of the decision-making process in the ant colony by interfering with more parameters and seeing how the insects respond. For example, they can tamper with the level of pheromones in the ants’ enclosure or create genetically altered ants with different abilities to detect temperature changes. “What we’ve been able to do so far is to perturb the system and measure the output precisely,” Kronauer says. “In the long term, the idea is to reverse engineer the system to deduce its inner workings in more and more detail.”

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The work, led by UAF Geophysical Institute postdoctoral researcher Alex Witsil, was published recently in the journal Geophysical Research Letters.

Witsil, at the Geophysical Institute’s Wilson Alaska Technical Center, and colleagues created a library of synthetic infrasound explosion signals to train computers in recognizing the source of an infrasound signal. Infrasound is at a frequency too low to be heard by humans and travels farther than high-frequency audible waves.

“We used modeling software to generate 28,000 synthetic infrasound signals, which, though generated in a computer, could hypothetically be recorded by infrasound microphones deployed hundreds of kilometers from a large explosion,” Witsil said.

The artificial signals reflect variations in atmospheric conditions, which can alter an explosion’s signal regionally or globally as the sound waves propagate. Those changes can make it difficult to detect an explosion’s origin and type from a great distance.

Why create artificial sounds of explosions rather than use real-world examples? Because explosions haven’t occurred at every location on the planet and the atmosphere constantly changes, there aren’t enough real-world examples to train generalized machine-learning detection algorithms.

“We decided to use synthetics because we can model a number of different types of atmospheres through which signals can propagate,” Witsil said. “So even though we don’t have access to any explosions that happened in North Carolina, for example, I can use my computer to model North Carolina explosions and build a machine-learning algorithm to detect explosion signals there.”

Today, detection algorithms generally rely on infrasound arrays consisting of multiple microphones close to each other. For example, the international Comprehensive Test Ban Treaty Organization, which monitors nuclear explosions, has infrasound arrays deployed worldwide.

“That’s expensive, it’s hard to maintain, and a lot more things can break,” Witsil said.

Witsil’s method improves detection by making use of hundreds of single-element infrasound microphones already in place around the world. That makes detection more cost-effective.

The machine-learning method broadens the usefulness of single-element infrasound microphones by making them capable of detecting more subtle explosion signals in near real-time. Single-element microphones currently are useful only for retroactively analyzing known and typically high-amplitude signals, as they did with January’s massive eruption of the Tonga volcano.

Witsil’s method could be deployed in an operational setting for national defense or natural hazards mitigation.

This work was funded by the Defense Threat Reduction Agency.

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“We found that in some children, illness with COVID-19 is associated with reporting persistent symptoms after 3 months,” said Principal Investigator Stephen Freedman, MDCM, MSc, with the Cumming School of Medicine at University of Calgary, and Alberta Health Services. “Our results suggest that appropriate guidance and follow-up are needed, especially for children at high risk for long COVID.”

The study included 1,884 children with COVID-19 who had 90-day follow-up. Long COVID was found in nearly 10 percent of hospitalized children and 5 percent in children discharged from the ED.

“Reported rates of long COVID in adults are substantially higher than what we found in children,” said Co-Principal Investigator Nathan Kuppermann, MD, MPH, from University of California, Davis School of Medicine, Sacramento. “Our findings can inform public health policy decisions regarding COVID-19 mitigation strategies for children and screening approaches for long COVID among those with severe infections.”

The most reported persistent symptoms in children were fatigue or weakness, cough, difficulty breathing or shortness of breath.

“Our finding that children who had multiple COVID-19 symptoms initially were at higher risk for long COVID is consistent with studies in adults,” said Co-Principal Investigator Todd Florin, MD, MSCE, from Ann & Robert H. Lurie Children’s Hospital of Chicago and Northwestern University Feinberg School of Medicine. “Unfortunately, there are no known therapies for long COVID in children and more research is needed in this area. However, if symptoms are significant, treatment targeting the symptoms is most important. Multidisciplinary care is warranted if symptoms are impacting quality of life.”

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Climate change accelerated by excess CO₂ emissions has been a major concern over the past few years. To deal with this problem, technologies that can not only reduce and remove excess CO₂ emissions but also transform them into value-added chemicals are being developed. One such method is the hydrogenation of CO₂ using renewable hydrogen to produce alternative fuels.

Over the years different strategies have been developed to improve CO₂ hydrogenation in the presence of metallic catalysts. The most promising among them is nonthermal plasma (NTP). It promotes hydrogenation of CO₂ beyond the thermodynamic limit even at low temperatures without deactivating metallic catalysts, which are vulnerable to higher temperatures. Despite the rising popularity of this technique, the interactions between the NTP-activated species and metallic catalysts are still not well understood.

Fortunately, a team of researchers from Tokyo Institute of Technology (Tokyo Tech), Japan, led by Prof. Tomohiro Nozaki, devised a study to overcome this gap in understanding. In their recent breakthrough, published in the Journal of the American Chemical Society, the researchers revealed the reaction dynamics for NTP-assisted CO₂ hydrogenation on the surface of Pd₂Ga/SiO₂ alloy catalysts that lead to the formation of formate. Prof Nozaki explains “Reaction mechanisms like Eley-Rideal or E-R pathway have been proposed to explain efficient CO₂ conversion at lower temperatures and the activation energy for this reaction decreases dramatically. Moreover, NTP produces a copious amount of vibrationally activated CO₂ which is the key to enhancing CO₂ conversion beyond the thermal equilibrium.”

The team investigated the reactions between NTP activated CO₂ and Pd₂Ga/SiO₂ alloy catalysts in a fluidized-bed dielectric barrier discharge reactor  and compared them to conventional thermal catalysis. The results revealed that the CO₂ conversion into formate was more than two-fold in the case of NTP-assisted hydrogenation when compared to thermal conversion. To further establish the mechanics of the mentioned conversion, the scientists adopted in situ spectroscopic analysis and density functional theory (DFT) calculations.

The results revealed that the NTP activation gave rise to vibrationally excited CO₂ molecules which directly react with hydrogen atoms adsorbed by the Pd sites on the catalyst via the E-R pathway. One of the O atoms from the reacted species then got adsorbed at the neighboring Ga site resulting in the formation of monodentate-formate or m-HCOO. The DFT calculations also deduced a decomposition pathway for the same m-HCOO species.

This experimental-theoretical study showed that NTP can promote CO₂ hydrogenation to limits those conventional thermal methods can hardly reach. It also provided mechanistic insights into NTP activated CO₂ and catalyst interaction, which can be utilized to develop better catalysts and improve the hydrogenation process. “With our research, we wanted to accelerate the waste to wealth initiative. Capturing CO₂ and using it as feedstock for synthesis of fuels and valuable chemicals will not only help us deal with climate problem but also slow down fossil fuel depletion to some extent,” concludes Prof. Nozaki.

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