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.