Publisher Health

The quest to create safer, more successful pregnancies is one of the top goals of modern science. While pregnancy is better understood today than ever before, with improvements in technology helping to lower the risk of negative outcomes, there is much researchers still don’t know about a vital part of the pregnancy process: uterine fluid.
Secreted by glands in the uterus during pregnancy, uterine fluid is believed to play an important role in supporting a developing embryo by sending information from the uterus to the embryo, along with a host of other speculated functions. But studying this fluid in women presents myriad dilemmas, given that studies might require invasive monitoring or experimentation during an active pregnancy.
Now, in a new study published in the Proceedings of the National Academy of Sciences (PNAS), researchers at the University of Missouri have found a way to study uterine fluid in the lab, thereby avoiding invasive procedures during pregnancy, while at the same time developing a potential model for using precision medicine to improve pregnancy outcomes.
“Using stem cell-derived organoids, we were able to isolate an analogue to uterine fluid in the lab,” said Constantine Simintiras, a postdoctoral research fellow in the College of Agriculture, Food and Natural Resources Division of Animal Sciences. “For such an understudied element of human pregnancy, being able to grow and study this fluid in the lab makes it much easier to advance our understanding of this important function of the uterus.”
Working in National Academy of Sciences member Thomas Spencer’s lab, Simintiras and his colleagues used “organoids” — simplified versions of the tissue that forms the lining of the uterus, grown from stem cells — as the source for a fluid that closely resembles uterine fluid. Inside the body, uterine glands secrete this fluid to support sperm migration and the early development of embryos.
Using organoids as a model not only sidesteps potential issues with extracting samples during pregnancy, but it also paves the way for a precision medicine approach to maintaining a healthy pregnancy. The hope is that by obtaining stem cells from expectant mothers, even before they conceive, researchers could study the composition of their uterine fluid to determine if any issues are present. For example, a deficit in NAD+ — a “coenzyme” considered crucial for metabolism — has been linked to birth defects and miscarriage.
“We know the composition of uterine fluid is extremely important, so we need to understand how that composition is regulated,” Simintiras said. “In women it is likely influenced by hormones, but are there other factors at play? This model for lab study gives us a means to tackle such questions, and in the future, this could help us detect and correct problems with uterine fluid before they lead to complications.”
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Materials provided by University of Missouri-Columbia. Note: Content may be edited for style and length.

In 2020, stores sold out of garden seed, coops and rabbit cages. Now, we have an idea how much protein people can grow in their backyards.
The 2020 meat shortages led many to wonder what to eat for protein when supply chains are disrupted. Some people turned to gathering eggs, raising animals and growing their own food. A team from Michigan Technological University and the University of Alaska Fairbanks found that the work is well worth it. In a new study published in Sustainability, the researchers looked at how a typical household with a typical backyard can raise chickens, rabbits or soybeans to meet its protein needs.
People eat a lot of protein in the U.S. and the average person needs 51 grams of protein every day, according to the National Institutes of Health (NIH) Dietary Reference Intakes (DRI). That comes to 18,615 grams each year or, for an average household of 2.6 people, 48,399 grams per year. Americans love burgers, but few people have room to raise a steer next to the garage — and most city ordinances quake at the mere thought of a rogue cowpie. But small animals are more efficient protein producers and are often allowed within city limits. The average backyard provides plenty of space, typically 800 to 1,000 square meters or about 8,600 to 10,700 square feet.
“You don’t have to convert your entire backyard into a soybean farm. A little goes a long way,” said Joshua Pearce, one of the study co-authors and Michigan Tech’s Richard Witte Endowed Professor of Materials Science and Engineering and professor of electrical and computer engineering. “I’m a solar engineer; I look at surface area and think of photovoltaic production. Many people don’t do that — they don’t treat their backyards as a resource. In fact, they can be a time and money sink that they have to mow and pour fertilizer on. But we can actually be very self-reliant when we treat our yards as an asset.”
Pearce’s co-authors are interdisciplinary and include Michigan Tech students Theresa Meyer and Alexis Pascaris, along with David Denkenberger of the University of Alaska. The lab group originally came together to do an agrovoltaics study to assess raising rabbits under solar panels. But when they sought to purchase cages in spring 2020, they discovered animal equipment and home garden supply shortages throughout the country. Like many labs, the group pivoted and refocused their work to address impacts of the pandemic.
They found that using only backyard resources to raise chickens or rabbits offset protein consumption up to 50%. To reach full protein demand with animals and eggs required buying grain and raising 52 chickens or 107 rabbits. That’s more than most city ordinances allow, of course, and raising a critter is not as simple as plopping down a planter box. While pasture-raised rabbits mow the lawn for you, Pearce says the “real winner is soy.” Consuming plant protein directly instead of feeding it to animals first is far more efficient. The plant-based protein can provide 80% to 160% of household demand and when prepared as edamame, soy is like a “high-protein popcorn.” The team’s economic analyses show that savings are possible — more so when food prices rise — but savings depend on how people value food quality and personal effort.
“It does take time. And if you have the time, it’s a good investment,” Pearce said, pointing to other research on building community with gardens, mental health benefits of being outside and simply a deeper appreciation for home-raised food. “Our study showed that many Americans could participate in distributed food production and help make the U.S. not only more sustainable, but more resilient to supply chain disruptions.”
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Materials provided by Michigan Technological University. Original written by Allison Mills. Note: Content may be edited for style and length.

In a study recently published in Nature, University of Minnesota Medical School researchers found that senescent immune cells are the most dangerous type of senescent cell.
Cells become senescent when they are damaged or stressed in the body, and they accumulate in our organs as we age. Senescent cells drive inflammation and aging as well as most age-related diseases.
The research team — led by Laura Niedernhofer, MD, PhD, a professor in the Department of Biochemistry, Molecular Biology and Biophysics — discovered that senescent immune cells drive tissue damage all over the body and shorten lifespan. Therefore, senescent immune cells are detrimental and should be targeted with senolytics.
U of M researchers, including Niedernhofer and collaborators at the Mayo Clinic, previously identified a new class of drugs in 2015 and coined them as senolytics, which selectively remove senescent cells from your body. However, senolytic drugs have to be targeted to a specific cell type, so one senolytic drug is not able to kill a senescent brain cell and a senescent liver cell.
“Now that we have identified which cell type is most deleterious, this work will steer us towards developing senolytics that target senescent immune cells,” said Niedernhofer, who is also the director for the Institute on the Biology of Aging and Metabolism at the U of M Medical School, one of the state-sponsored Medical Discovery Teams. “We also hope that it will help guide discovery of biomarkers in immune cell populations that will help gauge who is at risk of tissue damage and rapid aging, and therefore who is at most need of senolytic therapy.”
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Materials provided by University of Minnesota Medical School. Original written by Kelly Glynn. Note: Content may be edited for style and length.

If you did not catch the flu this year — and there is an overwhelming chance that you did not — you have COVID-19 to thank.
It’s a small consolation, given the enormously disruptive scope of the pandemic. But it’s the focus of a new paper published in the journal Frontiers in Public Health by two Concordia researchers and their colleagues that studies the 2020 influenza figures from Canada, the United States, Australia and Brazil. The authors show there is a clear relationship between the implementation of COVID-mitigation measures such as hand-washing, masking and social distancing and the spread of the annual flu.
They write that these preventive measures all but eliminated the flu in countries where it can kill tens of thousands of people a year, even as cases of COVID-19 soared.
“With the introduction of COVID-19 mitigation measures, we saw a steep decline in influenza cases in the northern hemisphere,” says Jovana Stojanovic, a postdoctoral fellow in the Department of Health, Kinesiology and Applied Physiology and the lead author of the paper.
“Then we also observed that as COVID-19 cases went up and down in different ways, influenza was basically annulled across both the north and south hemispheres. That speaks volumes about how contagious COVID-19 is compared to influenza.”
Simon Bacon, a professor of health, kinesiology and applied physiology, co-authored the paper, along with Vincent Boucher and Kim Lavoie at UQAM as well as Jacqueline Boyle and Joanne Enticott of Monash University in Australia.

Scientists have for the first time revealed the structure surrounding important receptors in the brain’s hippocampus, the seat of memory and learning.
The study, carried out at Oregon Health & Science University, published today in the journal Nature.
The new study focuses on the organization and function of glutamate receptors, a type of neurotransmitter receptor involved in sensing signals between nerve cells in the hippocampus region of the brain. The study reveals the molecular structure of three major complexes of glutamate receptors in the hippocampus.
The findings may be immediately useful in drug development for conditions such as epilepsy, said senior author Eric Gouaux, Ph.D., senior scientist in the OHSU Vollum Institute, Jennifer and Bernard Lacroute Endowed Chair in Neuroscience Research and an Investigator with the Howard Hughes Medical Institute.
“Epilepsy or seizure disorders can have many causes,” he said. “If one knows the underlying cause for a particular person’s seizure activity, then you may be able to develop small molecules to modulate that activity.”
Working with a mouse model, the OHSU researchers made the breakthrough by developing a chemical reagent based on monoclonal antibodies to isolate the receptor and the complex of subunits surrounding it. They then imaged the assemblage using state-of-the-art cryo-electron microscopy at the Pacific Northwest Cryo-EM Center, housed in OHSU’s South Waterfront campus in Portland.
Gouaux anticipates the technique will transform structural biology.
“It really opens the door to specifically target the molecules that need to be targeted in order to treat a particular condition,” he said. “A great deal of drug development is structure-based, where you see what the lock looks like and then you develop a key. If you don’t know what the lock looks like, then it’s much harder to develop a key.”
Previously, scientists had to rely on mimicking the actual receptors by artificially engineering receptors by combining DNA segments in tissue culture. However, that technique has obvious shortcomings.
“It doesn’t work perfectly because the real receptors are surrounded by a constellation of additional, sometimes previously unknown, subunits,” Gouaux said.
The new monoclonal antibody reagents, also developed at OHSU, enabled scientists to isolate actual glutamate receptors from the brain tissue of mice. They then were able to image those samples in near-atomic detail using cryo-EM, which allowed them to capture the entire assemblage of three types of glutamate receptors along with their auxiliary subunits.
“Previously, it’s been impossible to do this because we had no good way to isolate molecules and no way to see what they looked like,” Gouaux said. “So this is a super exciting development.”
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Materials provided by Oregon Health & Science University. Original written by Erik Robinson. Note: Content may be edited for style and length.

Severe symptoms of COVID-19, leading often to death, are thought to result from the patient’s own acute immune response rather than from damage inflicted directly by the virus. Immense research efforts are therefore invested in figuring out how the virus manages to mount an effective invasion while throwing the immune system off course. A new study, published today in Nature, reveals a multipronged strategy that the virus employs to ensure its quick and efficient replication, while avoiding detection by the immune system. The joint labor of the research groups of Dr. Noam Stern-Ginossar at the Weizmann Institute of Science and Dr. Nir Paran and Dr. Tomer Israely of the Israel Institute for Biological, Chemical and Environmental Sciences, this study focused on understanding the molecular mechanisms at work during infection by SARS-CoV-2 at the cellular level.
During an infection, our cells are normally able to recognize that they’re being invaded and quickly dispatch signaling molecules, which alert the immune system of the attack. With SARS-CoV-2 it was apparent early on that something was not working quite right — not only is the immune response delayed, enabling the virus to quickly replicate, unhindered, but once this response does occur it’s often so severe that instead of fighting the virus it causes damage to its human host.
“Most of the research that has addressed this issue so far concentrated on specific viral proteins and characterized their functions. Yet not enough is known today about what is actually going on in the infected cells themselves,” says Stern-Ginossar, of the Molecular Genetics Department. “So we infected cells with the virus and proceeded to assess how infection affects important biochemical processes in the cell, such as gene expression and protein synthesis.”
When cells are infected by viruses, they start expressing a series of specific anti-viral genes — some act as first-line defenders and meet the virus head on in the cell itself, while others are secreted to the cell’s environment, alerting neighboring cells and recruiting the immune system to combat the invader. At this point, both the cell and the virus race to the ribosomes, the cell’s protein synthesis factories, which the virus itself lacks. What ensues is a battle between the two over this precious resource.
The new study has elucidated how SARS-CoV-2 gains the upper hand in this battle: It is able to quickly, in a matter of hours, take over the cell’s protein-making machinery and at the same time to neutralize the cell’s anti-viral signaling, both internal and external, delaying and muddling the immune response.
The researchers showed that the virus is able to hack the cell’s hardware, taking over its protein-synthesis machinery, by relying on three separate, yet complementary, tactics. The first tactic the virus uses is to reduce the cell’s capacity for translating genes into proteins, meaning that less proteins are synthesized overall. The second tactic is that it actively degrades the cell’s messenger RNAs (mRNA) — the molecules that carry instructions for making proteins from the DNA to the ribosomes — while its own mRNA transcripts remain protected. Finally, the study revealed that the virus is also able to prevent the export of mRNAs from the cell’s nucleus, where they are synthesized, to the cell’s main chamber, where they normally serve as the template for protein synthesis.
“By employing this three-way strategy, which appears to be unique to SARS-CoV-2, the virus is able to efficiently execute what we call ‘host shutoff’ — where the virus takes over the cell’s protein-synthesis capacity,” Stern-Ginossar explains. “In this way, messages from important anti-viral genes, which the cell rushes to produce upon infection, do not make it to the factory floor to be translated into active proteins, resulting in the delayed immune response we are seeing in the clinic.” The good news is that this study was also successful in identifying the viral proteins involved in the process of host shutoff by SARS-CoV-2, which could spell new opportunities for developing effective COVID-19 treatments.
Study authors also included Yaara Finkel, Avi Gluck, Aharon Nachshon, Dr. Roni Winkler, Tal Fisher, Batsheva Rozman, Dr. Orel Mizrahi and Dr. Michal Schwartz, who are all members of Dr. Noam Stern-Ginossar’s group; Dr. Yoav Lubelsky and Binyamin Zuckerman from Prof. Igor Ulitsky’s group in the Department of Biological Regulation; Dr. Boris Slobodin from the Department of Biomolecular Sciences — as well as Dr. Yfat Yahalom-Ronen and Dr. Hadas Tamir from the Israel Institute for Biological, Chemical and Environmental Sciences.
Stern-Ginossar’s research is supported by Skirball Chair in New Scientists; Knell Family Center for Microbiology; American Committee for the Weizmann Institute of Science 70th Anniversary Lab; Ben B. and Joyce E. Eisenberg Foundation; Maurice and Vivienne Wohl Biology Endowment; and Miel de Botton.

Brown bears that are more inclined to grate and rub against trees have more offspring and more mates, according to a University of Alberta study. The results suggest there might be a fitness component to the poorly understood behaviour.
“As far as we know, all bears do this dance, rubbing their back up against the trees, stomping the feet and leaving behind odours of who they are, what they are, what position they’re in, and possibly whether they are related,” said Mark Boyce, an ecologist in the Department of Biological Sciences.
“What we were able to show is that both males and females have more offspring if they rub, more surviving offspring if they rub and they have more mates if they rub.”
The research team led by Boyce and post-doctoral fellow Andrea Morehouse identified and collected bear hair samples from 899 bear rub spots, which included trees, fence posts and power poles, in the Alberta Rocky Mountains south of Highway 3 for a period of four years starting in 2011.
The team genotyped 213 individual brown bears (118 males, 95 females). Building on the work of Curtis Strobeck, who realized a decade earlier that emerging DNA methods could be used to identify individual bears, the team used previously collected data for more 2,043 individual brown bears in the area to create a family tree.
What the results showed was that bears that rub more frequently and at more sites do better.

Researchers at the Francis Crick Institute and the Latvian Institute of Organic Synthesis have designed a drug-like compound which effectively blocks a critical step in the malaria parasite life cycle and are working to develop this compound into a potential first of its kind malaria treatment.
While drugs and mosquito control have reduced levels of malaria over recent decades, the parasite still kills over 400,000 people every year, infecting many more. Worryingly, it has now developed resistance to many existing antimalarial drugs, meaning new treatments that work in different ways are urgently needed.
In their research, published in PNAS, the scientists developed a set of compounds designed to stop the parasite being able to burst out of red blood cells, a process vital to its replication and life cycle. They found one compound in particular was highly effective in human cell tests.
“Malaria parasites invade red blood cells where they replicate many times, before bursting out into the bloodstream to repeat the process. It’s this cycle and build-up of infected red blood cells which causes the symptoms and sometimes fatal effects of the disease,” says Mike Blackman, lead author and group leader of the Malaria Biochemistry Laboratory at the Crick.
“If we can effectively trap malaria in the cell by blocking the parasite’s exit route, we could stop the disease in its tracks and halt its devastating cycle of invading cells.”
The compound works by blocking an enzyme called SUB1, which is critical for malaria to burst out of red blood cells. Existing antimalarials work by killing the parasite within the cell, so the researchers hope this alternative drug action will overcome the resistance the parasite has acquired.
Importantly the compound is also able to pass through the membranes of the red blood cell and of the compartment within the cell where the parasites reside.
The team is continuing to optimise the compound, making it smaller and more potent. If successful, it will need to be tested in further experiments and in animal and human trials to show it is safe and effective, before being made available to people.
Chrislaine Withers-Martinez, author and researcher in the Malaria Biochemistry Laboratory, says: “Many existing antimalarial drugs are plant derived and while they’re incredibly effective, we don’t know the precise mechanisms behind how they work. Our decades of research have helped us identify and understand pathways crucial to the malaria life cycle allowing us to rationally design new drug compounds based on the structure and mechanism of critical enzymes like SUB1.
“This approach, which has already been highly successful at finding new treatments for diseases including HIV and Hepatitis C, could be key to sustained and effective malaria control for many years to come.”
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Materials provided by The Francis Crick Institute. Note: Content may be edited for style and length.

The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) plays an important and previously unknown role in blocking a form of cell death called ferroptosis, according to a new study published today in Nature by researchers at The University of Texas MD Anderson Cancer Center. Preclinical findings suggest that targeting DHODH can restore ferroptosis-driven cell death, pointing to new therapeutic strategies that may be used to induce ferroptosis and inhibit tumor growth.
“By understanding ferroptosis and how cells defend against it, we can develop therapeutic strategies to block those defense mechanisms and trigger cell death,” said senior author Boyi Gan, Ph.D., associate professor of Experimental Radiation Oncology. “We have discovered that DHODH plays a key role in defending against ferroptosis and shown that we can exploit this vulnerability with clinically tested therapies.”
Ferroptosis is a recently identified form of controlled cell death triggered by the toxic accumulation of lipid peroxides in the cell. Because lipid peroxides are generated through normal metabolic activities, cells also have mechanisms in place to defend against ferroptosis. Glutathione peroxidase 4 (GPX4) is one of the key defense mechanisms identified to date.
In this study, the researchers used GPX4 inhibitors to block its activity and to identify new defense mechanisms. Metabolic analyses pointed them to DHODH, a mitochondrial enzyme that normally is involved in the pyrimidine biosynthesis pathway.
In cells with low GPX4 expression, loss of DHODH activity led to the accumulation of lipid peroxides in mitochondria and the activation of ferroptosis. By contrast, cells with high GPX4 expression were able to continue blocking ferroptosis activity in the absence of DHODH. The findings suggest that DHODH and GPX4 work as redundant defense mechanisms in the mitochondria to prevent ferroptosis.
The researchers further clarified DHODH’s role in regulating ferroptosis and then investigated the therapeutic potential of targeting this enzyme in cancer cells. Using extensive preclinical models, they evaluated the DHODH inhibitor brequinar, which has been tested in multiple clinical trials for other indications.
In GPX4-low cancers, brequinar effectively induced ferroptosis and suppressed tumor growth, but the effects were not seen in GPX4-high cancers. However, the combination of brequinar and sulfasalazine, an FDA-approved ferroptosis inducer, resulted in a synergistic effect to overcome high GPX4 expression and to block tumor growth.
“We were able to leverage our understanding of a new ferroptosis defense mechanism into a novel therapeutic strategy that appears promising in preclinical studies,” Gan said. “Because ferroptosis is active across cancer types, we believe this could have broad implications, particularly in cancers with low expression of GPX4.”
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Materials provided by University of Texas M. D. Anderson Cancer Center. Note: Content may be edited for style and length.

Researchers at the Center for Applies Genomics (CAG) at Children’s Hospital of Philadelphia (CHOP) have revealed how variants of a gene responsible for packing and condensing genetic material present a novel cause for certain neurodevelopmental disorders. The findings were published today in Science Advances.
Many neurodevelopmental disorders classified as intellectual disabilities are linked to certain genetic variants. Despite this, the underlying molecular mechanism for most of these patients is unknown. In particular, several neurodevelopmental disorders have been linked to pathogenic variants in genes responsible chromatin remodeling, or the rearrangement of the structure of chromosomes that allows for the transcription of DNA into directions to carry out necessary functions of the cells in the body.
One of these genes responsible for encoding a chromatin remodeling complex is SMARCA5. While there was some preclinical evidence that variants of SMARCA5 may be associated with developmental changes, a specific disorder associated with such variants had never been described.
“Our study is the first to describe how certain germline mutations in SMARCA5 are responsible for a spectrum of neurodevelopmental delays,” said study leader Dong Li, PhD, a research scientist with CAG. “Apart from identifying patients with such germline variants for the first time, our extended translational modeling study efforts to determine the underlying functions for these variants further elucidated their clinical relevance.”
This current study reports on 12 patients (six males and six females) across 10 unrelated families. Clinical features that were similar across these patients included mild developmental delay as well as short stature and microcephaly.
Dr. Li collaborated with Yuanquan Song, PhD, a faculty member from Department of Pathology and Laboratory Medicine at CHOP.
“We used fruit flies to study the effects of losing the function of SMARCA5 and found that this led to smaller body size, reduced the complexity of sensory neuron processes, among other defects in the larvae,” Song said. “In adult flies, the neural knockdown caused decreased brain size and abnormal locomotor function, and mutated SMARCA5 was unable to rescue the cells from this loss of function.”
“Our findings expand the spectrum of neurodevelopmental disorders linked to chromatin remodeling genes,” said Hakon Hakonarson, MD, PhD, Director of the Center for Applied Genomics at CHOP and senior author of the study. “It is very likely that this group of genetic variants may be responsible for other neurodevelopmental disorders and should be a point of focus going forward.”
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Materials provided by Children’s Hospital of Philadelphia. Note: Content may be edited for style and length.