A multinational team led by Josef Penninger (MedUni Vienna, IMBA — Institute of Molecular Biotechnology, Vienna, University of British Columbia, Canada, Helmholtz Centre for Infection Research, Germany) observed that the intestinal villi reorganise during pregnancy and breastfeeding and significantly enlarge, doubling their surface area. The studies were carried out in genetically modified mice and intestinal organoids from mice and humans — self-organised three-dimensional tissues derived from stem cells in the intestine. Mechanistically, the researchers identified the RANK receptor/RANK ligand (RANK/RANKL) system as the key to the villous enlargement of the small intestine during reproduction, which is regulated by sex and lactation hormones. When mice were engineered to lack the RANK/RANKL system in the intestine, the villous expansion during pregnancy and breastfeeding was significantly impaired.

Fundamental importance for evolution

For decades, researchers have studied the RANK/RANKL system as a key facilitator of essential, evolutionarily conserved processes. The Penninger group has already identified key functions of the RANK/RANKL system in bone turnover, in the biology of the mammary gland, in breast cancer, and in immune tolerance in pregnancy, contributing to the development of drugs against bone loss used by millions of people and clinical trials for breast cancer prevention and cancer immunotherapies are underway. The researchers now discovered that these intestinal changes, which appear to be completely reversible when nursing is stopped, are important for proper feeding and nourishment of the babies. “Our study shows that the impairment of this intestinal expansion by the lack of the RANK/RANKL system during pregnancy changes the milk of the nursing mothers. This results in lower weights of the babies and transgenerational long-term metabolic consequences,” states the lead author Masahiro Onji. “Mothers need to eat for themselves and their babies. These new studies provide for the first time a molecular and structural explanation of how and why the intestine changes to adapt to enhanced nutrient demand of mothers, which is probably the case in all pregnant and nursing mammals,” adds study leader Josef Penninger.

How mothers adapt to the demands of pregnancy and breastfeeding remains a central question of evolution and human health. During this phase, female hormones influence multiple organs to control and change their structure and functions, which is crucial for the health of the mother and the development of the offspring. It was known that pregnant women have enhanced nutrient demands. However, this fundamental aspect has not been well studied until now: “By identifying the RANK/RANKL system as the driving force behind intestinal adaptation during pregnancy and lactation, our study contributes to a deeper understanding of biological processes that are of fundamental importance for evolution and human health,” says Josef Penninger, summarising the impact of the findings.

This massive expansion is controlled by sex and pregnancy hormones, which change the stem cells in the gut via the RANK/RANKL system and then give the intestinal cell a survival signal to grow much larger. This growth then leads to a near doubling of the intestinal surface area, which also increases the molecular machinery for the uptake of sugar, protein, and fat, and even leads to a profound architectural change in the intestinal villi, which probably slows down the flow of food, again maximising the uptake of nutrients. Josef Penninger: “Our team has discovered an amazing new way how mother’s bodies change to keep babies healthy. Hardly anybody knew about this, apart from a few old studies that have largely been forgotten. We have also found that this system, via stem cells, can directly affect tumours in the intestine; maybe we can learn from pregnant and nursing mothers to reversibly rewire this system to develop new treatments and a better understanding of intestinal cancer or gut regeneration.”

The study was a close collaboration between the Medical University of Vienna, the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna, the Life Sciences Institute in Vancouver, the Helmholtz Centre for Infection Research, Braunschweig, the Hubrecht Institute, Utrecht, and the Kiel University. Researchers from the University of Tokyo and the University of Cambridge also participated.

The use of natural and minimally processed ingredients in many modern diets has decreased, more often being replaced with ingredients that have been industrially processed, artificially flavored, colored or chemically altered.

Foods such as breakfast cereals, margarines/spreads, packaged snacks, hot dogs, soft drinks and energy drinks, candies and desserts, frozen pizzas, ready-to-eat meals, mass-produced packaged breads and buns, and more, include synthesized ingredients and are highly processed.

These ultra-processed foods usually have longer shelf lives and are highly appealing, as they are convenient and contain a combination of sugar, fat, salt and carbohydrates which affect the brain’s reward system, making it hard to stop eating.

For the study, researchers set out to assess the association of ultra-processed food intake and their relationship to intramuscular fat in the thigh.

“The novelty of this study is that it investigates the impact of diet quality, specifically the role of ultra-processed foods in relation to intramuscular fat in the thigh muscles assessed by MRI,” said author Zehra Akkaya, M.D., researcher and former Fulbright Scholar in the Department of Radiology and Biomedical Imaging at the University of California, San Francisco. “This is the first imaging study looking into the relationship between MRI-based skeletal muscle quality and quality of diet.”

For the study, researchers analyzed data from 666 individuals who participated in the Osteoarthritis Initiative who were not yet affected by osteoarthritis, based on imaging. The Osteoarthritis Initiative is a nationwide research study, sponsored by the National Institutes of Health, that helps researchers better understand how to prevent and treat knee osteoarthritis.

“Research from our group and others has previously shown that quantitative and functional decline in thigh muscles is potentially associated with onset and progression of knee osteoarthritis,” Dr. Akkaya said. “On MRI images, this decline can be seen as fatty degeneration of the muscle, where streaks of fat replace muscle fibers.”

Of the 666 individuals, (455 men, 211 women) the average age was 60 years. On average, participants were overweight with a body mass index (BMI) of 27. Approximately 40% of the foods that they ate in the past year were ultra-processed.

The researchers found that the more ultra-processed foods people consumed, the more intramuscular fat they had in their thigh muscles, regardless of energy (caloric) intake.

“In an adult population at risk for but without knee or hip osteoarthritis, consuming ultra-processed foods is linked to increased fat within the thigh muscles,” Dr. Akkaya said. “These findings held true regardless of dietary energy content, BMI, sociodemographic factors or physical activity levels.”

Targeting modifiable lifestyle factors — mainly prevention of obesity via a healthy, balanced diet and adequate exercise — has been the mainstay of initial management for knee osteoarthritis, Dr. Akkaya noted.

“Osteoarthritis is an increasingly prevalent and costly global health issue. It is the largest contributor to non-cancer related health care costs in the U.S. and around the world,” Dr. Akkaya said. “Since this condition is highly linked to obesity and unhealthy lifestyle choices, there are potential avenues for lifestyle modification and disease management.”

By exploring how ultra-processed food consumption impacts muscle composition, this study provides valuable insights into dietary influences on muscle health.

“Understanding this relationship could have important clinical implications, as it offers a new perspective on how diet quality affects musculoskeletal health,” Dr. Akkaya said.

Co-authors are Gabby B. Joseph, Ph.D., Katharina Ziegeler, M.D., Wynton M. Sims, John A. Lynch, Ph.D., and Thomas M. Link, M.D., Ph.D.

“Two years ago, we demonstrated an aquatic soft robot that was able to reach average speeds of 3.74 body lengths per second,” says Jie Yin, corresponding author of a paper on the work and an associate professor of mechanical and aerospace engineering at North Carolina State University. “We have improved on that design. Our new soft robot is more energy efficient and reaches a speed of 6.8 body lengths per second. In addition, the previous model could only swim on the surface of the water. Our new robot is capable of swimming up and down throughout the water column.”

The soft robot has fins shaped like those of a manta ray, and is made of a material that is stable when the fins are spread wide. The fins are attached to a flexible, silicone body that contains a chamber that can be pumped full of air. Inflating the air chamber forces the fins to bend — similar to the down stroke when a manta flaps its fins. When the air is let out of the chamber, the fins spontaneously snap back into their initial position. 

“Pumping air into the chamber introduces energy into the system,” says Haitao Qing, first author of the paper and a Ph.D. student at NC State. “The fins want to return to their stable state, so releasing the air also releases the energy in the fins. That means we only need one actuator for the robot and allows for more rapid actuation.”

Studying the fluid dynamics of manta rays also played a key role in controlling the vertical movement of the soft robot.

“We observed the swimming motion of manta rays and were able to mimic that behavior in order to control whether the robot swims toward the surface, swims downward, or maintains its position in the water column,” says Jiacheng Guo, co-author of the paper and a Ph.D. student at the University of Virginia. “When manta rays swim, they produce two jets of water that move them forward. Mantas alter their trajectory by altering their swimming motion. We adopted a similar technique for controlling the vertical movement of this swimming robot. We’re still working on techniques that will give us fine control over lateral movements.”

“Specifically, simulations and experiments showed us that the downward jet produced by our robot is more powerful than its upward jet,” says Yuanhang Zhu, co-author of the paper and an assistant professor of mechanical engineering at the University of California, Riverside. “If the robot flaps its fins quickly, it will rise upward. But if we slow down the actuation frequency, this allows the robot to sink slightly in between flapping its fins — allowing it to either dive downward or swim at the same depth.”

“Another factor that comes into play is that we are powering this robot with compressed air,” Qing says. “That’s relevant because when the robot’s fins are at rest, the air chamber is empty, reducing the robot’s buoyancy. And when the robot is flapping its fins slowly, the fins are at rest more often. In other words, the faster the robot flaps its fins, the more time the air chamber is full, making it more buoyant.”

The researchers have demonstrated the soft robot’s functionality in two different ways. First, one iteration of the robot was able to navigate a course of obstacles arrayed on the surface and floor of a water tank. Second, the researchers demonstrated that the untethered robot was capable of hauling a payload on the surface of the water, including its own air and power source.

“This is a highly engineered design, but the fundamental concepts are fairly simple,” Yin says. “And with only a single actuation input, our robot can navigate a complex vertical environment. We are now working on improving lateral movement, and exploring other modes of actuation, which will significantly enhance this system’s capabilities. Our goal is to do this with a design that retains that elegant simplicity.”

The paper, “Spontaneous Snapping-Induced Jet Flows for Fast, Maneuverable Surface and Underwater Soft Flapping Swimmer,” is published open access in the journal Science Advances. The paper was co-authored by Yinding Chi and Yaoye Hong, former Ph.D. students at NC State; and by Daniel Quinn and Haibo Dong of UVA.

This work was done with support from the National Science Foundation under grants 2126072 and 2329674; and from the Office of Naval Research under grant N00014-22-1-2616.

The study, featured on the Dec. 4 cover of the journal Science Advances, used stable isotope analysis to model the diet of the mother of an infant discovered at a 13,000-year-old Clovis burial site in Montana. Before this study, prehistoric diet was inferred by analyzing secondary evidence, such as stone tools or the preserved remains of prey animals.

The findings support the hypothesis that Clovis people specialized in hunting large animals rather than primarily foraging for smaller animals and plants.

The Clovis people inhabited North America around 13,000 years ago. During that time period, animals like mammoths lived across both northern Asia and the Americas. They migrated long distances, which made them a reliable fat- and protein-rich resource for highly mobile humans.

“The focus on mammoths helps explain how Clovis people could spread throughout North America and into South America in just a few hundred years,” said co-lead author James Chatters of McMaster University.

“What’s striking to me is that this confirms a lot of data from other sites. For example, the animal parts left at Clovis sites are dominated by megafauna, and the projectile points are large, affixed to darts, which were efficient distance weapons,” said co-lead author Ben Potter, an archaeology professor at the University of Alaska Fairbanks.

Hunting mammoths provided a flexible way of life, Potter said. It allowed the Clovis people to move into new areas without having to rely on smaller, localized game, which could vary significantly from one region to the next.

“This mobility aligns with what we see in Clovis technology and settlement patterns,” Potter said. “They were highly mobile. They transported resources like toolstone over hundreds of miles.”

Researchers were able to model the Clovis people’s diet by first analyzing isotopic data published during earlier studies by other researchers of the remains of Anzick-1, an 18-month-old Clovis child. By adjusting for nursing, they were able to estimate values for his mother’s diet.

“Isotopes provide a chemical fingerprint of a consumer’s diet and can be compared with those from potential diet items to estimate the proportional contribution of different diet items,” said Mat Wooller, an author on the study and director of the Alaska Stable Isotope facility at UAF.

The team compared the mother’s stable isotopic fingerprint to those from a wide variety of food sources from the same time period and region. They found that about 40% of her diet came from mammoth, with other large animals like elk and bison making up the rest. Small mammals, sometimes thought to have been an important food source, played a very minor role in her diet.

Finally, the scientists compared the mother’s diet to those of other omnivores and carnivores from the same time period, including American lions, bears and wolves. The mother’s diet was most similar to that of the scimitar cat, a mammoth specialist.

Findings also suggest that early humans may have contributed to the extinction of large ice age animals, especially as environmental changes reduced their habitats.

“If the climate is changing in a way that reduces the suitable habitat for some of these megafauna, then it makes them potentially more susceptible to human predation. These people were very effective hunters,” said Potter.

“You had the combination of a highly sophisticated hunting culture — with skills honed over 10,000 years in Eurasia — meeting naïve populations of megafauna under environmental stress,” said Chatters.

An important aspect of this research, according to Potter and Chatters, is their outreach to Native Americans in Montana and Wyoming about their concerns and interest in this work.

“It is important and ethical to consult with Indigenous peoples on questions relating to their heritage,” they said.

They worked with Shane Doyle, executive director of Yellowstone Peoples, who reached out to numerous tribal government representatives throughout Montana, Wyoming and Idaho. “The response has been one of appreciative consideration and inclusion,” said Doyle.

“I congratulate the team for their astounding discovery about the lifeways of Clovis-era Native people and thank them for being tribally inclusive and respectful throughout their research,” he said. “This study reshapes our understanding of how Indigenous people across America thrived by hunting one of the most dangerous and dominant animals of the day, the mammoth.”

Other authors of the paper include Stuart J. Fiedel, independent researcher; Juliet E. Morrow, University of Arkansas; and Christopher N. Jass, Royal Alberta Museum.