A single protein may be holding back CAR T cancer therapy

 Researchers from Columbia University and University Hospital Tübingen have discovered a protein that appears to play a major role in weakening CAR T cells over time. By disabling the protein, known as NFIL3, the scientists found that these engineered immune cells remained active longer and were better able to attack tumors. The findings, published in Cancer Discovery, could help improve CAR T-cell therapy, particularly against solid tumors that have proven difficult to treat.

CAR T-cell therapy is one of the most advanced forms of personalized cancer treatment. The approach involves collecting a patient's own immune cells, genetically modifying them to recognize cancer, and then returning them to the body to seek out and destroy tumor cells.

The therapy has produced remarkable results for some blood cancers. However, it has been far less successful against solid tumors. An international team led by Prof. Michel Sadelain, MD, PhD, of Columbia University, working with Prof. Judith Feucht, MD, of University Hospital Tübingen, set out to better understand why. Sadelain is widely recognized as one of the pioneers of CAR T-cell therapy and has played a key role in its development and clinical use.

NFIL3 Linked to CAR T-Cell Exhaustion

To identify factors that limit CAR T-cell performance, the researchers conducted a large-scale analysis of roughly 400 transcription factors, proteins that control which genes are switched on or off inside cells.

Their investigation pointed to NFIL3 as a major contributor to CAR T-cell exhaustion, a process in which the cells gradually lose their ability to function effectively. When the researchers removed NFIL3, the CAR T cells stayed active for longer periods, multiplied more efficiently, and maintained stronger anti-tumor effects.

The team used CRISPR/Cas9 gene-editing technology to disable the gene responsible for producing NFIL3. Often described as genetic scissors, CRISPR allows scientists to precisely cut and modify DNA.

"Switching off NFIL3 could be a decisive step toward significantly improving the long-term potency of CAR T cells," explains Prof. Feucht.

Stronger Tumor Control in Animal Studies

The benefits of removing NFIL3 were demonstrated across several mouse models. CAR T cells lacking the protein were more effective at controlling tumors and helped extend survival.

The results suggest a possible path toward improving treatment for cancers that currently respond poorly to CAR T-cell therapy, particularly solid tumors.

"Our goal is to improve the effectiveness of CAR T cells in solid tumors as well," says Celina May, co-first author of the study and a member of Prof. Feucht's research group. "We expect this to open up new possibilities in the treatment of cancer patients," adds Feucht.

Bridging Laboratory Research and Patient Care

Prof. Feucht combines cancer research with hands-on clinical care. She conducts research within Germany's only Cluster of Excellence in oncology, iFIT (Image Guided and Functionally Instructed Tumor Therapies), while also treating children and adolescents at the Department of Pediatrics at University Hospital Tübingen.

Her work follows the "bench-to-bedside" approach, which focuses on translating scientific discoveries into treatments that can directly benefit patients. Although additional research will be needed before this strategy can be tested and used in people, the findings provide encouraging evidence that targeting NFIL3 could strengthen CAR T-cell therapy and potentially expand its usefulness against a wider range of cancers.

Source: ScienceDaily

The secret to pigeons’ incredible navigation was hiding in their liver

 How pigeons can travel hundreds of miles and still find their way home has puzzled scientists for decades. New research suggests the answer may lie in an unexpected place: the liver.

According to a study published in Science, pigeons may use specialized immune cells in their livers to detect Earth's magnetic field, providing them with an internal navigation system.

Researchers found that these cells, called macrophages, accumulate iron while breaking down old red blood cells. The iron gives the cells unique magnetic properties that could allow them to respond to the planet's magnetic field. When the cells were removed, pigeons struggled to find their way home, pointing to a previously unknown role in navigation.

"We didn't expect immune cells to act like sensors for magnetic fields at all. Our results reveal a previously unknown mechanism for magnetic perception in animals," says Prof. Christian Kurts, Director at the Institute of Molecular Medicine and Experimental Immunology at the University Hospital Bonn, and one of the study's co-senior authors.

"What looks like a 'gut feeling' in bird navigation may actually have a physical basis," adds Prof. Martin Wikelski, Director at the Max Planck Institute of Animal Behavior and the other co-senior author of the study.

The Long Search for Birds' Magnetic Sense

Scientists have long known that homing pigeons and migratory birds use Earth's magnetic field as one of several tools for navigation. However, exactly how animals detect that field has remained one of biology's biggest mysteries.

Over the years, researchers proposed several possibilities. Some theories suggested birds could detect magnetic fields through light-sensitive molecules in their eyes. Others pointed to tiny magnetic particles in their beaks. Despite years of investigation, neither idea has received strong experimental confirmation.

The new study offers a different explanation, combining expertise from immunology, physics, and animal behavior. The research team included scientists from the University of Bonn, the University Hospital Bonn, the University of Duisburg-Essen, and the Max Planck Institute of Animal Behavior (MPI-AB).

Iron-Rich Liver Cells Show Strong Magnetic Properties

To determine where magnetic sensing might occur, the researchers examined multiple organs that have previously been linked to magnetoreception, including the eyes, beak, and brain. They also analyzed the liver and spleen using techniques known as "vibrating sample magnetometry" and "magnetic cell separation."

"We had some clues that the liver and spleen have magnetic properties, because they break down red blood cells and so store much iron in the body," says first author Dr. Clivia Lisowski, from the University of Bonn and the University Hospital Bonn, who led the immunological work.

The results were striking. Among all the tissues studied, the liver contained the highest concentration of iron and produced the strongest magnetic response.

"Iron is crystallized in oxide nanoparticles making the cells superparamagnetic and reactive to magnetic fields. We found by far the strongest magnetic response in liver tissue," adds Prof. Ulf Wiedwald, from the University of Duisburg-Essen.

Further investigation revealed that liver macrophages were responsible for these magnetic properties.

Navigation Experiments Reveal a Critical Role

The researchers then tested whether the macrophages actually influence navigation.

At the MPI-AB in Konstanz, Germany, pigeons had been trained to return to their aviary from locations more than twenty kilometers away. Scientists removed the liver macrophages and monitored how the birds performed.

The results depended on the weather. On overcast days, when the sun was hidden, pigeons that lacked the macrophages lost their sense of direction and had difficulty navigating home. On sunny days, however, they successfully returned, likely relying on the sun as a navigational cue instead of Earth's magnetic field.

These findings suggest that birds use magnetic information alongside solar cues to orient themselves during flight.

How Magnetic Signals May Reach the Brain

After establishing a link between the liver cells and navigation, the researchers looked for a way the information could travel to the brain.

Source: Sciencedaily

Why cancer spreads more in middle age than in old age

 Cancer becomes more common with age and is often harder to treat in older adults. Yet most cancer studies in mice do not reflect that reality. Fewer than 10% of mouse experiments use aged animals, with researchers typically relying on mice that roughly correspond to humans in their early 20s.

That gap may help explain why many cancer therapies that perform well in laboratory studies ultimately fail in human clinical trials.

New findings from Fox Chase Cancer Center, presented at the American Association for Cancer Research annual meeting, suggest that melanoma does not behave the same way throughout the aging process. Researchers found that cancer spread was lowest in young mice, reached its highest level in middle aged mice, and then declined again in very old mice.

"The vast majority of studies are done in these very young mice that have a healthy and intact immune system," said Mitchell Fane, PhD, a cancer biologist who specializes in aging and cancer, and lead investigator of the study. "Right now, it's easy to personalize care for someone who's young and fit, who's potentially not going to experience as many toxicities; understanding how therapies affect older patients would give us more and better treatment options."

Immune Cells May Hold the Key

The researchers believe a specialized group of immune cells known as gamma delta (γδ) T cells may help explain the surprising pattern.

These cells act as an early defense system, helping prevent cancer from spreading throughout the body. Young mice and very old mice had higher levels of these protective immune cells, and their tumors were more likely to remain dormant or spread less aggressively.

Middle aged mice told a different story. They had fewer γδ T cells, and melanoma was much more likely to spread to organs such as the lungs and liver.

The team also discovered that melanoma cells can actively weaken the immune system as animals age. In middle aged mice, the cancer released molecules that suppressed or exhausted γδ T cells. As those defenses weakened, previously dormant cancer cells were able to become active and spread more aggressively.

Additional experiments reinforced the importance of these immune cells. When researchers removed γδ T cells from young and very old mice, melanoma spread increased significantly. Conversely, blocking the signals that suppress immune activity restored protection and reduced cancer spread in middle aged mice, although the same effect was not seen in the younger or older groups.

Why Researchers Need More Aged Mouse Models

One reason aging studies remain uncommon is practical. Young mice are easier and less expensive to obtain, while aged mice require long term care and breeding. Researchers must typically wait 18 to 24 months before mice reach an age suitable for aging research.

To address that challenge, Fane and colleague Yash Chabra, PhD, both Assistant Professors in the Cancer Signaling and Microenvironment Research Program, helped establish an aged mouse facility at Fox Chase Cancer Center.

The goal is to make older animal models more accessible and encourage scientists to test whether their findings hold true across different stages of life.

"Now we have a facility with established aged mouse colonies, which lowers the cost and time barriers to aging research," he said. "It allows us to tell colleagues, 'Your model is interesting, why not test it in aged mice?'"

Rethinking the Link Between Cancer and Aging

Understanding how aging affects cancer could lead to more effective treatments for older adults. Fane's laboratory is particularly interested in the observation that the relationship between age and cancer does not appear to follow a simple straight line.

Although cancer risk generally rises with age, rates unexpectedly decline among people over 80 to 85 years old.

"While risk increases steadily as people age, it abruptly decreases after ages 80-85," said Fane. "We want to explain the mechanism of why very old patients are getting less cancer, but middle-aged patients are getting more."

The new findings suggest that changes in the immune system over the course of aging may play an important role in determining when cancer is most likely to spread. They also highlight the importance of including older animals in cancer research to better reflect the patients most affected by the disease.

Source: ScienceDaily

Human organoids reveal how to reverse “irreversible” nerve damage

 Scientists at the University of Cambridge have created tiny lab-grown brain and spinal cord systems that mimic how movement signals travel through the human nervous system. Using this model, the team discovered that nerve damage once believed to be permanent may actually be reversible under certain conditions.

As the human body develops from an embryo into a fetus and eventually an infant, neurons form complex communication networks between the brain and spinal cord. These signals travel through axons, the long nerve fibers that allow neurons to send messages and control muscle movement.Over time, however, the central nervous system largely loses its ability to regrow damaged axons. As a result, injuries to the brain or spinal cord often become permanent, leading to serious disabilities such as paralysis or loss of movement. This loss of regenerative ability is also linked to neurological diseases including motor neurone disease and multiple sclerosis.

Mini Human Brain and Spinal Cord Models

In 2021, Dr. András Lakatos and his colleagues at the University of Cambridge developed miniature human brain models using stem cells taken from patients. These pea-sized "brain organoids" resembled parts of the cerebral cortex and allowed researchers to study molecular changes linked to motor neurone disease and explore ways to prevent them.

Now, in a new study published in Cell Reports, the researchers expanded on that work by building a miniature version of the connected human brain and spinal cord system.

Because the brain and spinal cord are separate but connected structures in the body, the team kept the organoids physically apart in the lab. They then observed axons from the brain tissue growing across the gap and connecting with the spinal cord tissue. The resulting neural circuit was functional enough to trigger contractions in tiny clusters of muscle cells.

Nerve Regrowth Declines During Development

The scientists maintained these miniature systems in the lab for more than a year. They discovered that until about day 150 of development, roughly corresponding to the middle stage of pregnancy, damaged axons could still regrow. After that point, the neurons showed a major decline in their ability to regenerate.

George Gibbons from the Department of Clinical Neurosciences at the University of Cambridge and first author of the study said: "Neurons taken from less mature organoids regrew long fibers after injury, but those from more mature organoids showed a sharp drop in their ability to regrow. In other words, poor regeneration is built into human neurons as they mature in the central nervous system."

Source: ScienceDaily

Vitamin B12 and folate deficiencies linked to chronic fatigue

 Chronic fatigue has become increasingly common in modern life as people juggle heavier workloads and less downtime. While exhaustion is often blamed on stress or lack of sleep, researchers say poor nutrition may also play an important role.

A research team led by Professor Hiroaki Kanouchi from Osaka Metropolitan University's Graduate School of Human Life and Ecology investigated whether deficiencies in certain vitamins could be connected to fatigue and motivation levels. The scientists focused on folate (B9) and vitamin B12, two nutrients that help regulate homocysteine (Hcy), a substance in the blood that tends to rise when these vitamins are lacking.Blood Marker Linked to Fatigue and Motivation

The study included around 600 healthy Japanese adults. Researchers measured blood levels of homocysteine, folate, and vitamin B12, then evaluated participants' fatigue and motivation using the Chalder Fatigue Scale questionnaire and a Visual Analog Scale.

The team found that participants with higher homocysteine levels generally had lower levels of folate and vitamin B12, regardless of sex.

Researchers then looked more closely at how homocysteine levels related to fatigue in men and women separately. Their analysis also accounted for factors that could influence fatigue, including age, sleep duration, workload, and eating habits.

The results showed that men with higher homocysteine levels were more likely to report greater physical fatigue. In women, elevated homocysteine levels were linked to lower motivation.

Vitamin Deficiencies May Affect Energy Levels

"This suggested relationship between vitamin B12, folate, and fatigue in healthy individuals may represent the first report of its kind," said Professor Kanouchi.

"Blood homocysteine levels have traditionally raised concerns in relation to cardiovascular disease, dementia, and fractures. However, our findings suggest that attention should also be paid to fatigue and motivation in the future. To prevent an increase in homocysteine levels, it is important to avoid deficiencies in vitamin B12 and folate. Maintaining a well-balanced diet on a daily basis is essential."

Source: ScienceDaily

Antarctica’s ice sheet hit a climate tipping point 1 million years ago

 A new study published in Nature Geoscience suggests Antarctica's ice sheet underwent a dramatic change about one million years ago, becoming much more responsive to shifts in Earth's climate.

The research, led by scientists at the IBS Center for Climate Physics (ICCP) at Pusan National University in South Korea, offers fresh insight into how massive ice sheets react to long term climate changes and what that could mean for future sea level rise.Today, Antarctica contains the largest mass of ice on the planet and plays a major role in regulating global sea levels. Around one million years ago, Earth experienced a major climate transition in which ice ages became longer, colder, and more intense. Scientists refer to this period as the Mid-Pleistocene Transition. Although researchers have known about this shift for decades, exactly how Antarctica's ice sheet responded has remained uncertain.

Simulating 3 Million Years of Climate History

One of the biggest obstacles has been the lack of realistic long term climate records needed to test ice sheet behavior under ancient conditions.

To solve this problem, the team used an advanced paleoclimate simulation recently developed at the ICCP that reconstructs global climate patterns over the past 3 million years. The simulation provided detailed temperature and precipitation data, which researchers fed into the Penn State University ice-sheet-ice-shelf model.

That model tracks changes in ice sheet movement, thickness, temperature, and elevation across Antarctica and the Northern Hemisphere. It also simulates the behavior of floating ice shelves, including those in the Ross and Weddell Seas.

Using one of South Korea's most powerful supercomputers dedicated to basic science research, the team produced a physically consistent picture of how Earth's major ice sheets evolved as climate conditions changed over time.

Antarctic Ice Reached a Critical Threshold

The simulations revealed that Antarctica entered an entirely different mode of behavior after the Mid-Pleistocene Transition.

Researchers identified a key atmospheric carbon dioxide threshold of roughly 240 parts per million. Once CO2 levels dropped below that point, Antarctic ice volume began responding much more dramatically to changes in atmospheric and ocean temperatures.

"After this transition, the Antarctic ice sheet reacts much more strongly to changes in climate forcing. This indicates that the system does not evolve gradually but instead becomes more responsive after crossing a particular threshold in the climate system," said Dr. Kyung-Sook Yun, researcher at the IBS Center for Climate Physics and lead author of the study.

Why Antarctica's Ice Expanded So Rapidly

According to the simulations, several processes worked together to accelerate Antarctic ice growth after the climate transition around one million years ago.

First, colder ocean temperatures during ice ages reduced melting beneath portions of the Antarctic ice sheet that extend below sea level. At the same time, global sea levels were approximately 50-100 meters lower than today. Lower sea levels reduced pressure on the bedrock beneath Antarctic ice shelves, allowing the land underneath to slowly rise upward. That uplift helped support additional thickening of coastal ice.

Together, these mechanisms helped create the larger and more persistent Antarctic ice sheets that later defined Earth's ice age cycles.

"Our findings suggest that the Antarctic ice sheet was more sensitive to external forcings than previously assumed. This also raises important questions about its future response to global warming," said Prof. Axel Timmermann, Director of the IBS Center for Climate Physics and co-author of the study.

What the Findings Could Mean for the Future

The study highlights that ice sheets may not always respond to climate change in a slow, predictable way. Instead, they can suddenly shift into a much more sensitive state after crossing critical climate thresholds.

Scientists say understanding these abrupt transitions is essential for improving future projections of Antarctic ice loss and global sea level rise.

Source: ScienceDaily

Twisted graphene reveals a hidden superconductivity switch

 Researchers have uncovered evidence that superconductivity can be controlled by changing a material's surrounding environment, a breakthrough that could eventually lead to more efficient electronics and powerful quantum technologies.

Superconductivity allows certain materials to carry electricity with zero energy loss when cooled below a critical temperature. Even though scientists have studied the phenomenon for decades, many of its underlying mechanisms remain poorly understood. Gaining deeper insight into how superconductivity forms could help researchers design better materials and improve future electronic and quantum devices.

Twisted Graphene Reveals Unusual Behavior

The study, led by Chun Ning (Jeanie) Lau, a physics professor at The Ohio State University, focused on a specially engineered material known as twisted bilayer graphene. The material is made by stacking two sheets of carbon and rotating one slightly relative to the other.

The research team combined the graphene structure with strontium titanate, a synthetic diamond-like material. This setup allowed scientists to observe and influence how electrons interacted inside the system.

Electron interactions play a major role in determining properties such as magnetism and chemical bonding. In superconductors, electrons pair together in a special way that enables electricity to flow without resistance. By tuning the environment around the material, the team found they could strengthen or weaken those interactions and effectively switch superconductivity on and off.

"Electrons normally repel each other, but in superconductors they form pairs; this pair formation is the key to a superconductor's ability to conduct electricity without dissipation," said Lau. "Our evidence suggests that electrons themselves, depending on their sensitivity to their nearby environment, are unexpectedly important for material changes."

Discovery Challenges Traditional Superconductor Theory

The researchers were surprised by one of their findings. As they increased certain adjustments within the material, superconductivity became weaker instead of stronger.

That behavior differs from what scientists typically observe in conventional superconductors, where reducing the repulsive forces between electrons usually strengthens superconductivity. The unexpected result highlights how unusual materials like twisted bilayer graphene may behave very differently from traditional superconductors.

"If you could transmit electricity without energy loss, that would be hugely important for technologies used in our everyday life," said Lau. "Despite the fundamental questions that still need answers, this work basically provides a path toward a new type of physics mechanism."

The discovery may also help researchers move closer to one of the field's biggest goals: developing superconductors that work at much higher temperatures, potentially even room temperature. Achieving that milestone could dramatically reshape electronics, communications systems, and power transmission technologies.

Potential for More Efficient Electronics

The findings, published in Nature Physics, suggest a simpler method for controlling the conditions needed to create superconductivity.

Many high-temperature superconductors currently face limitations that reduce their performance. The researchers believe manipulating the surrounding environment of these materials could provide a new way to improve their capabilities and increase efficiency in future electronics.

According to lead author Xueshi Gao, a PhD student in physics at Ohio State, the team expects the results to become useful for many different experiments and material systems across the field.

"The mechanism of superconductivity in the twisted bilayer graphene system we used is still not well understood," said Gao. "But our result can shed light on and help people to better understand the concept when applying it to future work."

Researchers Plan Further Experiments

The scientists caution that the work represents an early step toward understanding a much broader range of complex electronic interactions. Future research will explore other interaction types and investigate additional physics questions raised by the study.

"We're showing capabilities that we haven't shown before, so many people in the field are getting really excited about this result," said Lau.

Additional co-authors from Ohio State include Aatmaj Rajesh, Emilio Codecido, Daria Sharifi, Zheneng Zhang, Youwei Liu and Marc Bockrath. Collaborators also included Alejandro Jimeno-Pozo, Pierre Pantaleon and Paco Guinea from Imdea Nanoscience in Spain, along with Kenji Watanabe and Takashi Taniguchi from the National Institute for Materials Science in Japan.

Source: ScienceDaily