They also showed that aspirin was able to improve hormone deficiency symptoms in mice with this condition.

People with mutations in a gene called Sox3 develop hypopituitarism, where the pituitary gland doesn’t make enough hormones. It can result in growth problems, infertility and poor responses of the body to stress.

In research published today in PLOS Genetics, the scientists at the Crick removed Sox3 from mice, causing them to develop hypopituitarism around the time of weaning (starting to eat solid food).

They found that mutations in Sox3 largely affect the hypothalamus in the brain, which instructs the pituitary gland to release hormones. However, the gene is normally active in several brain cell types, so the first task was to ask which specific cells were most affected by its absence.

The scientists observed a reduced number of cells called NG2 glia, suggesting that these play a critical role in inducing the pituitary gland cells to mature around weaning, which was not known previously. This could explain the associated impact on hormone production.

The team then treated the mice with a low dose of aspirin for 21 days. This caused the number of NG2 glia in the hypothalamus to increase and reversed the symptoms of hypopituitarism in the mice.

Although it’s not yet clear how aspirin had this effect, the findings suggest that it could be explored as a potential treatment for people with Sox3 mutations or other situations where the NG2 glia are compromised.

An incidental discovery revealed the role of gut bacteria in hormone production

When the National Institute for Medical Research (NIMR) merged with the Crick in 2015, mouse embryos were transferred from the former building to the latter, and this included the mice with Sox3 mutations.

When these mice reached the weaning stage at the Crick, the researchers were surprised to find that they no longer had the expected hormonal deficiencies.

After exploring a number of possible causes, lead author Christophe Galichet compared the microbiome — bacteria, fungi and viruses that live in the gut — in the mice from the Crick and mice from the NIMR, observing several differences in its makeup and diversity. This could have been due to the change in diet, water environment, or other factors that accompanied the relocation.

He also examined the number of NG2 glia in the Crick mice, finding that these were also at normal levels, suggesting that the Crick-fed microbiome was somehow protective against hypopituitarism.

To confirm this theory, Christophe transplanted faecal matter retained from NIMR mice into Crick mice, observing that the Crick mice once again showed symptoms of hypopituitarism and had lower numbers of NG2 glia.

Although the exact mechanism is unknown, the scientists conclude that the make-up of the gut microbiome is an example of an important environmental factor having a significant influence on the consequences of a genetic mutation, in this case influencing the function of the hypothalamus and pituitary gland.

Christophe Galichet, former Senior Laboratory Research Scientist at the Crick and now Research Operations Manager at the Sainsbury Wellcome Centre, said: “It was a huge surprise to find that changes in the gut microbiome reversed hypopituitarism in the mice without Sox3. It’s reinforced to me how important it is to be aware of all variable factors, including the microbiome, when working with animals in research and how nurture can influence nature.”

Robin Lovell-Badge, Group Leader of the Stem Cell Biology and Developmental Genetics Laboratory at the Crick, said: “Hypopituitarism can result from trauma as well as rare mutations, and it can have some profound effects on health in general. As well as suggesting potential options for treatment, our work reinforces how important the gut-brain link is. The next step for this research will be to work out exactly how aspirin and the microbiome influence NG2 glia, and then study this effect in people so we can see if these relatively accessible interventions could help treat hypopituitarism.”

They published their findings today (Sept. 26) in JAMA Network Open.

“The cause of SUID is believed to be multi-factorial. Even with education about safe sleep environments and the back-to-sleep campaign encouraging parents to put babies to sleep on their backs, there’s still a high rate of SUID,” said Emma Guare, a fourth-year medical student at Penn State College of Medicine and first author of the paper. “It’s been hypothesized that there might be a link between infection and SUID and we wanted to better understand that connection, particularly as endemic infection rates shifted during the pandemic.”

In 2022, approximately 3,700 infants died unexpectedly in the United States, according to the Centers for Disease Control and Prevention (CDC). SUID is an umbrella term for unexpected death of an infant under the age of one year from known and unknown causes. SIDS is a type of SUID that occurs during sleep and where the cause of death is not known, even after a full investigation, and accounts for roughly one-third of SUID cases.

The research team examined the rate of both SUID and SIDS during the COVID-19 pandemic and compared it to the immediate period prior to the pandemic. Between March 1, 2018, and Dec. 31, 2021, there were 14,308 cases of SUID, based on national data on mortality provided by the CDC.

The research team found that the risk of SUID and SIDS increased during the pandemic when they compared monthly cases to the pre-pandemic period. The greatest increase was observed in 2021 when rates for SUID and SIDS increased 9% and 10%, respectively, compared to the pre-pandemic period. There was a notable shift in SUID rates from June to December 2021, when the monthly rate of SUID increased between 10% and 14% compared to pre-pandemic levels.

Measures put in place to mitigate the pandemic also interrupted the spread of respiratory illnesses like RSV, keeping rates low during 2020. However, as these measures were lifted during the second year of the pandemic, seasonal respiratory viruses began to circulate more widely at unexpected times and with more intensity.

While there were few RSV-related hospitalizations in 2020, cases surged between June and December 2021, an “off-season” for RSV, which typically is active between October and April. This seasonal shift in RSV closely mirrored the monthly changes in SUID that were observed in 2021.

“We don’t know what makes babies who die from SUID or SIDS more vulnerable, whether it’s genetics or something else. It could be that infections like RSV amplify those factors and make them more vulnerable,” said co-author Erich Batra, associate professor of pediatrics and family and community medicine at Penn State College of Medicine. “With RSV in particular, there have been questions about whether RSV causes more apnea, when you stop breathing temporarily, than other viruses and if that contributes to an environment conducive to SUID.”

The team noted that further research is needed to better understand the role of infection in SUID and SIDS and whether infections like RSV may contribute to a portion of SUID and SIDS cases.

“Practicing safe sleep practices is just as important, if not more important when babies are sick,” Batra said. He encouraged caregivers to continue to place babies to sleep on their backs, avoid soft bedding and not share a bed.

Other Penn State College of Medicine authors on the paper include Catharine Paules, associate professor of medicine; Vernon Chinchilli, Distinguished Professor of Public Health Sciences; Paddy Ssentongo, assistant professor of public health sciences; and Rong Zhao, doctoral student in biostatistics.

A team led by scientists at UC Riverside, UC Irvine, and Yale School of Medicine has now designed a new drug against malaria and identified its mechanism of action. The researchers found the drug, called MED6-189, is effective against drug-sensitive and drug-resistant P. falciparum strains in vitro as well as in a humanized mouse model (the mice were engineered to have human blood).

The researchers report in the journal Science this week that MED6-189 works by targeting and disrupting not only the apicoplast, an organelle found in P. falciparum cells, but also the vesicular trafficking pathways. They found that this dual mode of action prevents the pathogen from developing resistance, making the drug a highly effective antimalarial compound and a promising new lead in the fight against malaria.

“Disruption of the apicoplast and vesicular trafficking blocks the parasite’s development and thus eliminates infection in red blood cells and in our humanized mouse model of P. falciparum malaria,” said Karine Le Roch, a professor of molecular, cell and systems biology at UCR and the paper’s senior author. “We found MED6-189 was also potent against other zoonotic Plasmodium parasites, such as P. knowlesi and P. cynomolgi.“

MED6-189 is a synthetic compound inspired by a compound extracted from marine sponges. The lab of Christopher Vanderwal, a professor of chemistry and pharmaceutical sciences at UC Irvine, synthesized the compound.

“Many of the best antimalarial agents are natural products, or are derived from them,” he said. “For example, artemisinin, initially isolated from the sweet wormwood plant, and analogues thereof, are critically important for treatment of malaria. MED6-189 is a close relative of a different class of natural products, called isocyanoterpenes, that seem to target multiple pathways in P. falciparum. That is beneficial because had only one pathway been targeted, the parasite could develop resistance to the compound more quickly.”

When researchers at GSK, a pharmaceutical company in Spain, administered MED6-189 to the mice infected with P. falciparum, they found it cleared the mice of the parasite. In collaboration with Choukri Ben Mamoun, a professor of medicine and microbial pathogenesis at the Yale School of Medicine, the team also tested the compound against P. knowlesi, a parasite that infects monkeys, and found it worked as intended, clearing the monkey’s parasite-infected red blood cells.

Next, the team plans to continue the optimization of MED6-189 and further confirm the modified compound’s mechanisms of action using a systems biology approach. Systems biology is a biomedical research approach to understanding the larger picture of a biological system. It offers researchers a way to examine how different living organisms and cells interact at larger scales.

Le Roch, Vanderwal, and Ben Mamoun were joined in the research by fellow scientists at the Stowers Institute for Medical Research in Kansas City, Missouri; GSK; and the University of Georgia.

The research was supported by a grant to Le Roch, Vanderwal, and Ben Mamoun and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. At UCR, Le Roch directs the Center for Infectious Disease and Vector Research.

The title of the research paper is “A Potent Kalihinol Analogue Disrupts Apicoplast Function and Vesicular Trafficking in P. falciparum Malaria.”

As one of the world’s most densely population cities, Dhaka deals with a high burden of diarrheal diseases. While some studies have looked at how weather affects diarrhea in Bangladesh, few have examined the future impact of climate change. A warmer climate is expected to worsen this public health issue by making the city hotter and exacerbating water quality issues.

In the new study, researchers estimated the risks posed by diarrheal diseases under various global warming scenarios. They looked to see if daily rainfall, humidity and temperature in Dhaka affected rates of hospitalizations from diarrheal disease, using data from about 3 million diarrhea cases treated at a major hospital in Dhaka from 1981 to 2010. Statistical analysis revealed that higher daily temperatures significantly increased the risk of diarrhea for all age groups. Assuming that the planet warms by 1.5 °C to 2 °C on average, hospitalizations due to diarrheal disease are expected to increase by 4.5% to 7.4% in all age groups by the end of the century. Children under five may be especially hard hit, with hospitalization rates estiated to increase by 5.7% to 9.4%.

Under the Paris Agreement, an international treaty on climate change, countries agreed to set global warming targets to under 2°C. The new study shows that even if these targets are met, hospitalizations from diarrhea will increase substantially in Dhaka. These findings underscore the importance of better preparing the city to prevent and manage diarrheal diseases.

The authors add: “Diarrhoea hospitalisation will increase significantly in Dhaka by 4.5 — 7.4% in all age groups by the 2100s even if the global warming targets adopted by the Paris Agreement is reached. This underscores the importance of preparing the city for management and prevention of diarrhoeal diseases.”

“This is a fish that grew legs using the same genes that contribute to the development of our limbs and then repurposed these legs to find prey using the same genes our tongues use to taste food — pretty wild,” says Nicholas Bellono of Harvard University in Cambridge, MA.

Bellono, along with David Kingsley of Stanford University and their colleagues, didn’t set out to study sea robins at all. They came across these creatures on a trip to the Marine Biological Laboratory in Woods Hole, MA. After learning that other fish follow the sea robins around, apparently due to their skills in uncovering buried prey, the researchers became intrigued and took some sea robins back to the lab to find out more. They confirmed that the sea robins could indeed detect and uncover ground-up and filtered mussel extract and even single amino acids.

As reported in one of the two new studies, they found that sea robins’ legs are covered in sensory papillae, each receiving dense innervation from touch-sensitive neurons. The papillae also have taste receptors and show chemical sensitivity that drives the sea robins to dig.

“We were originally struck by the legs that are shared by all sea robins and make them different from most other fish,” Kingsley says. “We were surprised to see how much sea robins differ from each other in sensory structures found on the legs. The system thus displays multiple levels of evolutionary innovation from differences between sea robins and most other fish, differences between sea robin species, and differences in everything from structure and sensory organs to behavior.”

Through further developmental studies, the researchers confirmed that the papillae represent a key evolutionary innovation that has allowed the sea robins to succeed on the seafloor in ways other animals can’t. In the second study, they looked deeper into the genetic basis of the fish’s unique legs. They used genome sequencing, transcriptional profiling, and study of hybrid species to understand the molecular and developmental basis for leg formation.

Their analyses identified an ancient and conserved transcription factor, called tbx3a, as a major determinant of the sea robins’ sensory leg development. Genome editing confirmed that they depend on this regulatory gene to develop their legs normally. The same gene also plays a critical role in the formation of sea robins’ sensory papillae and their digging behavior.

“Although many traits look new, they are usually built from genes and modules that have existed for a long time,” Kingsley said. “That’s how evolution works: by tinkering with old pieces to build new things.”

The findings show that it’s now possible to expand our detailed understanding of complex traits and their evolution in wild organisms, not just in well-established model organisms, according to the researchers. They are now curious to learn more about the specific genetic and genomic changes that led to sea robins’ evolution.

In some mammals, the timing of the normally continuous embryonic development can be altered to improve the chances of survival for both the embryo and the mother. This mechanism to temporarily slow development, called embryonic diapause, often happens at the blastocyst stage, just before the embryo implants in the uterus. During diapause, the embryo remains free-floating and pregnancy is extended. This dormant state can be maintained for weeks or months before development is resumed, when conditions are favorable. Although not all mammals use this reproductive strategy, the ability to pause development can be triggered experimentally. Whether human cells can respond to diapause triggers remained an open question.

Now, a study by the labs of Aydan Bulut-Karslioğlu at the Max Planck Institute for Molecular Genetics in Berlin and Nicolas Rivron at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences in Vienna, an ERC grantee, has identified that the molecular mechanisms that control embryonic diapause also seem to be actionable in human cells. Their results were published on September 26th in the journal Cell.

Stem cell-derived models to study embryonic diapause in humans

In their research, the scientists did not carry out experiments on human embryos and instead used human stem cells and stem cell-based blastocyst models called blastoids. These blastoids are a scientific and ethical alternative to using embryos for research. The researchers discovered that modulation of a specific molecular cascade, the mTOR signaling pathway, in these stem cell models induces a dormant state remarkably akin to diapause. “The mTOR pathway is a major regulator of growth and developmental progression in mouse embryos,” says Aydan Bulut-Karslioğlu. “When we treated human stem cells and blastoids with an mTOR inhibitor we observed a developmental delay, which means that human cells can deploy the molecular machinery to elicit a diapause-like response.”

This dormant state is characterized by reduced cell division, slower development and a decreased ability to attach to the uterine lining. Importantly, the capacity to enter this dormant stage seems to be restricted to a brief developmental period. “The developmental timing of blastoids can be stretched around the blastocyst stage, which is exactly the stage where diapause works in most mammals,” says shared first author Dhanur P. Iyer. Moreover, this dormancy is reversible, and blastoids resume normal development when the mTOR pathway is reactivated.

The ability to alter the timing of embryonic development has implications for IVF

The authors concluded that humans, like other mammals, might possess an inherent mechanism to temporarily slow down their development, even though this mechanism may not be used during pregnancy. “This potential may be a vestige of the evolutionary process that we no longer make use of,” says Nicolas Rivron. “Although we have lost the ability to naturally enter dormancy, these experiments suggest that we have nevertheless retained this inner ability and could eventually unleash it.” For basic research, the question arises as to whether human and other mammalian cells enter the dormant state via similar or alternative pathways and use it for the same purposes, for example either pausing or timing their development and implantation.

The team’s discoveries could have implications for reproductive medicine: “On the one hand, undergoing faster development is known to increase the success rate of in vitro fertilization (IVF), and enhancing mTOR activity could achieve this,” Nicolas Rivron explains. “On the other hand, triggering a dormant state during an IVF procedure could provide a larger time window to assess embryo health and to synchronize it with the mother for better implantation inside the uterus.”

Overall, the new findings provide unforeseen insights into the processes governing our earliest development, which might open new avenues for enhancing reproductive health. “This exciting collaboration is a testimony to how complex biological questions can be tackled by bringing together respective expertise,” says Heidar Heidari Khoei, postdoctoral fellow in the lab of Nicolas Rivron and the study’s co-first author. “I believe this work not only underscores the importance of collaboration in advancing science but also opens up further possibilities for understanding how various signals are perceived by cells as they prepare for their developmental journey.”

Nicolas Rivron is a group leader at IMBA and funded by an ERC Consolidator Grant.

Genomic research led by the University of California, Davis, reveals clues about montane red foxes’ distant past that may prove critical to their future survival. The study, published in the journal Molecular Biology and Evolution, examines the potential for genetic rescue to help restore populations of these mountain-dwelling red foxes. The research is especially relevant for the estimated 30 or fewer native red foxes living in the Lassen Peak region of California.

The study found that inbreeding is impacting the Lassen red fox population. Thousands of years ago — long before unregulated trapping and poison knocked back their populations in the 1890s and early 1900s — red foxes were not only abundant in these mountains, they were also more connected to neighboring foxes in Oregon, the Rocky Mountains and Washington Cascades than they are today. This positions them well for genetic rescue should managers decide to pursue it and reconnect the populations.

“Nothing we found disqualifies red foxes from genetic rescue,” said lead author Cate Quinn, who conducted the research as a UC Davis postdoctoral researcher with the Mammalian Ecology and Conservation Unit within the School of Veterinary Medicine. She is now a research biologist with the USDA Forest Service Rocky Mountain Research Station. “The study suggests that genetic rescue could be a viable option for the Lassen population.”

Rescue workers

Genetic rescue is a conservation tool to reverse the effects of inbreeding depression, which is when inbreeding reduces an animal’s fitness and ability to reproduce. Genetic rescue involves bringing new individuals to a population to introduce genetic variation and spur growth.

The tool is not considered lightly, and managers first must understand the severity of inbreeding, the historical baseline genetic rescue seeks to restore, and the deeper evolutionary relationships the foxes share with each other.

To fill those knowledge gaps, the scientists sequenced 28 whole genomes from the four subspecies of montane red foxes. These include small, isolated populations in the Pacific mountains, Oregon Cascades, Lassen Cascades and the Sierra Nevada, as well as a larger population in the Rocky Mountains and a subspecies in the Sacramento Valley. Using genomic technology, the authors could peer back in time to see if a population was always isolated, to what extent, and when that began to change.

Abundant, connected and diverse

The study found high levels of recent inbreeding in Lassen and Sierra Nevada red fox populations, with the Lassen red foxes a high priority for intervention. Only one montane red fox is known to have entered the Lassen population in more than 20 years of monitoring, the study said.

The data also revealed that 10,000 to 12,000 years ago, montane red foxes in the Western United States were abundant, connected and genetically diverse. The Lassen population was likely connected to the Oregon red foxes within the last century, breaking from each other relatively recently, Quinn said.

A hopeful way forward

Combined, these findings point to a hopeful way forward for Lassen’s red foxes, and for other red foxes facing similar challenges.

“We think trapping drove their population down, but we didn’t know what was keeping them small,” said senior author Ben Sacks, director of the Mammalian and Ecology Conservation Unit at the UC Davis School of Veterinary Medicine. “Now we see that what kept them small appears to be inbreeding depression. If what drove their decline is gone, can we bring them back? There is hope here.”

Quinn agrees: “Not too long ago, this was an abundant, connected, diverse population. That diversity still exists. If we were to restore them as a group, these foxes may still have a lot of adaptive potential.”

She cautions, however, that true genetic “rescue” requires reconnecting the whole subspecies — not just growing one population.

“If we only consider each small pocket individually, they’re in trouble, but if we look at the whole montane system, restoration is still possible,” Quinn said.

Additional coauthors include Sophie Preckler-Quisquater of UC Davis and Michael Buchalski of the California Department of Fish and Wildlife.

The study was funded by the U.S. Fish and Wildlife Service, California Department of Fish and Wildlife, and UC Davis.

Researchers working at reefs in Moorea, French Polynesia found that the network of dead coral skeletons left in place by bleaching events caused critical processes to break down, ultimately preventing reefs from recovering. The complex landscape protects seaweed from herbivores, enabling it to quickly colonize the reef and outgrow young coral. The results appear in the journal Global Change Biology.

Dynamic ecosystems

Coral reefs are busy ecosystems undergoing constant change. Every now and again, a larger disturbance will rock the reef, like a storm, an influx of coral predators, or a bleaching event. While all of these can deal a blow to the ecosystem, small nuances can drastically affect the reef’s recovery.

Historically, tropical storms and cyclones have been the biggest disruptors to Moorea’s reefs. “They tend to scrape all the coral off the reef and leave behind a flat surface,” said lead author Kai Kopecky, a former doctoral student in UCSB’s Department of Ecology, Evolution, and Marine Biology. But bleaching and predation are on the rise, and these events kill coral, but leave the reef’s structure intact.

Bleaching occurs when stress — usually heat — causes corals to expel the symbiotic algae that provide them with food. Coral can recover from this if conditions quickly return to their liking, but often the colony simply dies, especially in the presence of other stressors like pollution.

A cyclone walloped Moorea’s reefs in 2010. “It removed basically every single coral colony off the fore reef,” Kopecky said. “But within about five years, it recovered back to the amount of coral it had before the storm had hit.”

The reef experienced a big bleaching event in 2019, a year after Kopecky began working on the island. “It basically just cooked and killed about half the corals on the reef,” he recalled. But unlike the storm, this disturbance left all the dead coral structure in place.

Kopecky and his colleagues at the NSF-funded Long Term Ecological Research (LTER) site at Moorea Coral Reef noticed that the reef didn’t experience the same remarkable recovery in the following years. Instead, coral continued to die, and macroalgae, commonly known as seaweed, began to proliferate. Kopecky was curious how the differences between the two events affected reef recovery processes. In 2023, he and his coauthors published a mathematical model of the system, and this new field study focuses on describing the mechanisms at work.

“This combination of time series data on long term responses of ecosystems, mathematical modeling and field experimentation greatly enriches our scientific understanding and ability to devise practical solutions,” said co-author Professor Russ Schmitt, lead principal investigator at the Moorea Coral Reef LTER site.

“The multi-decadal, site-based research focus makes the LTER network both unique and of immense value in our rapidly changing world,” said LTER co-principal investigator Professor Sally Holbrook, who is also one of the study’s authors.

“The current project was led by Kai, a Ph.D. student at the time, and involved UCSB undergraduate researchers who made important contributions in addition to those of senior ecologists. It is a prime example of how the Moorea Coral Reef project fosters and trains the next generation of environmental scientists,” Schmitt added.

Investigating the reefscape

The team prepared small patches of the reef to create a blank slate for their experiment. They then cemented a controlled number of dead coral skeletons in each patch and plugged healthy young coral into the reef in a way that each could be periodically removed and measured as they grew. They also added trays of macroalgae to compare herbivory within the bleached skeletons to consumption out in the open.

“We found that dead coral skeletons prevent herbivores from being able to remove macroalgae, enabling growth and preventing new corals from being able to settle and survive on the reef,” Kopecky said.

Protection by dead coral skeletons could theoretically help young coral, if new recruits settle on the reef shortly after a bleaching event. Unfortunately, corals tend to spawn only once a year, while many algae reproduce continually, giving the seaweeds the advantage in colonizing the newly available substrate.

Macroalgae compete with coral for space, light and resources. Algae grow faster than coral, so without the balancing effect of herbivory they can easily overrun a reef, preventing new corals from settling and shading out those colonies that do. Young coral recruits are particularly vulnerable to this competition, and once a reef flips from being covered by coral to algae, it can be hard to reverse the change, as the team showed in previous research.

Considering long-term shifts

The authors compared the results in their small-scale experiments to the long-term data from the site, and they’ve seen dramatically different trajectories after the different kinds of disturbances. “Coral cover shot up on the reefs after the cyclone, while macroalgae cover went down,” Kopecky said. “After the bleaching event, it was just the opposite.”

The results find context in the concept of ecological memory, which considers how past events can influence the trajectory of an ecosystem. These shifts can produce misalignments between what an ecosystem is used to and what it’s currently experiencing. “As these disturbance regimes change, ecological memory is also changing,” Kopecky explained. Unfortunately, the ecosystem might not be as adapted to cope with the new regime, where vast stands of dead coral skeletons are left behind after a disturbance. This can alter long-standing relationships, such as those between herbivores, algae and coral.

Kopecky wants to know if removing dead skeletons from the reef could stimulate coral recovery, or at least mitigate the impacts of bleaching. “In coral reefs this is a novel idea and strategy,” he said. “But if you look to other ecosystems — like prescribed burns in forests to remove dead wood — people have been increasingly thinking about manipulating dead stuff in ecosystems for management purposes.”