New Study Highlights First Infection of Human Cells During Spaceflight (Biology)

Astronauts face many challenges to their health, due to the exceptional conditions of spaceflight. Among these are a variety of infectious microbes that can attack their suppressed immune systems.

Now, in the first study of its kind, Cheryl Nickerson, lead author Jennifer Barrila and their colleagues describe the infection of human cells by the intestinal pathogen Salmonella Typhimurium during spaceflight. They show how the microgravity environment of spaceflight changes the molecular profile of human intestinal cells and how these expression patterns are further changed in response to infection. In another first, the researchers were also able to detect molecular changes in the bacterial pathogen while inside the infected host cells.

The results offer fresh insights into the infection process and may lead to novel methods for combatting invasive pathogens during spaceflight and under less exotic conditions here on earth.

The results of their efforts appear in the current issue of the Nature Publishing Group journal npj Microgravity.

Mission control

In the study, human intestinal epithelial cells were cultured aboard Space Shuttle mission STS-131, where a subset of the cultures were either infected with Salmonella or remained as uninfected controls.

The new research uncovered global alterations in RNA and protein expression in human cells and RNA expression in bacterial cells compared with ground-based control samples and reinforces the team’s previous findings that spaceflight can increase infectious disease potential.

Nickerson and Barrila, researchers in the Biodesign Center for Fundamental and Applied Microbiomics, along with their colleagues, have been using spaceflight as a unique experimental tool to study how changes in physical forces, like those associated with the microgravity environment, can alter the responses of both the host and pathogen during infection. Nickerson is also a professor in the School of Life Sciences at ASU. 

In an earlier series of pioneering spaceflight and ground-based spaceflight analogue studies, Nickerson’s team demonstrated that the spaceflight environment can intensify the disease-causing properties or virulence of pathogenic organisms like Salmonella in ways that were not observed when the same organism was cultured under conventional conditions in the laboratory.  

The studies provided clues as to the underlying mechanisms of the heightened virulence and how it might be tamed or outwitted.  However, these studies were done when only the Salmonella were grown in spaceflight and the infections were done when the bacteria were returned to Earth.

“We appreciate the opportunity that NASA provided our team to study the entire infection process in spaceflight, which is providing new insight into the mechanobiology of infectious disease that can be used to protect astronaut health and mitigate infectious disease risks,” Nickerson says of the new study. “This becomes increasingly important as we transition to longer human exploration missions that are further away from our planet.”

Probing a familiar adversary

Salmonella strains known to infect humans continue to ravage society, as they have since antiquity, causing around 1.35 million foodborne infections, 26,500 hospitalizations, and 420 deaths in the United States every year, according to the Centers for Disease Control. The pathogen enters the human body through the ingestion of contaminated food and water, where it attaches and invades into intestinal tissue. The infection process is a dynamic dance between host and microbe, its rhythm dictated by the biological and physical cues present in the tissue’s environment.

Despite decades of intensive research, scientists still have much to learn about the subtleties of pathogenic infection of human cells. Invasive bacteria like Salmonella have evolved sophisticated countermeasures to human defenses, allowing them to flourish under hostile conditions in the human stomach and intestine to stealthily evade the immune system, making them highly effective agents of disease.

The issue is of particular medical concern for astronauts during spaceflight missions. Their immune systems and gastrointestinal function are altered by the rigors of space travel, while the effects of low gravity and other variables of the spaceflight environment can intensify the disease-causing properties of hitchhiking microbes, like Salmonella. This combination of factors poses unique risks for space travelers working hundreds of miles above the earth—far removed from hospitals and appropriate medical care.

As technology advances, it is expected that space travel will become more frequent—for space exploration, life sciences research, and even as a leisure activity (for those who can afford it). Further, extended missions with human crews are on the horizon for NASA and perhaps space-voyaging companies like SpaceX, including trips to the Moon and Mars. A failure to keep bacterial infections at bay could have dire consequences.

Hide and Seq

In the current study, human intestinal epithelial cells, the prime target for invasive Salmonella bacteria, were infected with Salmonella during spaceflight. The researchers were keen to examine how the spaceflight setting affected the transcription of human and bacterial DNA into RNA, as well as the expression of the resulting suite of human proteins produced from the RNA code, products of a process known as translation.

The research involved the close examination of transcriptional profiles of both the pathogenic Salmonella and the human cells they attack, as well as the protein expression profiles of the human cells to gauge the effects of the spaceflight environment on the host-pathogen dynamic.

To accomplish this, researchers used a revolutionary method known as dual RNA-Seq, which applied deep sequencing technology to enable their evaluation of host and pathogen behavior under microgravity during the infection process and permitted a comparison with the team’s previous experiments conducted aboard the Space Shuttle.

The host and pathogen data recovered from spaceflight experiments were compared with those obtained when cells were grown on earth in identical hardware and culture conditions (e.g., media, temperature).

Earth and sky

Earlier studies by Nickerson and her colleagues demonstrated that ground-based spaceflight analogue cultures of Salmonella exhibited global changes in their transcriptional and proteomic (protein) expression, heightened virulence, and improved stress resistance—findings similar to those produced during their experiments on STS-115 and STS-123 Space Shuttle missions.

However, these previous spaceflight studies were done when only the Salmonella were grown in spaceflight and the infections were done when the bacteria were returned to Earth.

Jennifer Barrila, lead author of the new study, is a researcher in the Biodesign Center for Fundamental and Applied Microbiomics.  © ASU

In contrast, the new study explores for the first time, a co-culture of human cells and pathogen during spaceflight, providing a unique window into the infection process. The experiment, called STL-IMMUNE, was part of the Space Tissue Loss payload carried aboard STS-131, one of the last four missions of the Space Shuttle prior to its retirement. 

The human intestinal epithelial cells were launched into space (or maintained in a laboratory at the Kennedy Space Center for ground controls) in three-dimensional (3-D) tissue culture systems called hollow fiber bioreactors. The hollow fiber bioreactors each contained hundreds of tiny, porous straw-like fibers coated with collagen upon which the intestinal cells attached and grew. These bioreactors were maintained in the Cell Culture Module, an automated hardware system which pumped warm, oxygenated cell culture media through the tiny fibers to keep the cells healthy and growing until they were ready for infection with Salmonella. 

Once in orbit, astronauts aboard STS-131 activated the hardware. Eleven days later, S. Typhimurium cells were automatically injected into a subset of the hollow fiber bioreactors, where they encountered their target—a layer of human epithelial cells.

The RNA-Seq and proteomic profiles showed significant differences between uninfected intestinal epithelial cultures in space vs those on earth. These changes involved major proteins important for cell structure as well as genes important for maintaining the intestinal epithelial barrier, cell differentiation, proliferation, wound healing and cancer.  Based on their profiles, uninfected cells exposed to spaceflight may display a reduced capacity for proliferation, relative to ground control cultures.

Infections far from home

Human intestinal epithelial cells act as critical sentinels of innate immune function. The results of the experiment showed that spaceflight can cause global changes to the transcriptome and proteome of human epithelial cells, both infected and uninfected.

During spaceflight, 27 RNA transcripts were uniquely altered in intestinal cells in response to infection, once again establishing the unique influence of the spaceflight environment on the host-pathogen interaction. The researchers also observed 35 transcripts which were commonly altered in both space-based and ground-based cells, with 28 genes regulated in the same direction. These findings confirmed that at least a subset of the infection biosignatures that are known to occur on Earth also occur during spaceflight.  Compared with uninfected controls, infected cells in both environments displayed gene regulation associated with inflammation, a signature effect of Salmonella infection.

Bacterial transcripts were also simultaneously detected within the infected host cells and indicated upregulation of genes associated with pathogenesis, including antibiotic resistance and stress responses.

Cheryl Nickerson is a researcher in the Biodesign Center for Fundamental and Applied Microbiomics and a professor in the School of Life Sciences at ASU. 

The findings help pave the way for improved efforts to safeguard astronaut health, perhaps through the use of nutritional supplements or probiotic microbes. Ongoing studies of this kind, to be performed aboard the International Space Station and other space habitats, should further illuminate the many mysteries associated with pathogenic infection and the broad range of human illnesses for which they are responsible.

“Before we began this study, we had extensive data showing that spaceflight completely reprogrammed Salmonella at every level to become a better pathogen,” Barrila says. “Separately, we knew that spaceflight also impacted several important structural and functional features of human cells that Salmonella normally exploits during infections on earth. However, there was no data showing what would happen when both cell types met in the microgravity environment during infection. Our study indicates that there are some pretty big changes in the molecular landscape of the intestinal epithelium in response to spaceflight, and this global landscape appears to be further altered during infection with Salmonella.”     

This work was done in collaboration with scientists from the NASA Johnson Space Center, NASA Ames Research Center, Japanese Aerospace Exploration Agency (JAXA), Tissue Genesis, and the Department of Defense (DoD).

Featured image: Infection of human intestinal epithelial cells by Salmonella Typhimurium during spaceflight aboard NASA Space Shuttle mission STS-131. Graphic by Shireen Dooling for the Biodesign Institute at Arizona State University


Reference: Barrila, J., Sarker, S.F., Hansmeier, N. et al. Evaluating the effect of spaceflight on the host–pathogen interaction between human intestinal epithelial cells and Salmonella Typhimurium. npj Microgravity 7, 9 (2021). https://www.nature.com/articles/s41526-021-00136-w https://doi.org/10.1038/s41526-021-00136-w


Provided by ASU

X Marks The Spot: How Genes On The Sex Chromosomes Are Controlled (Biology)

Researchers from the University of Tsukuba find that genes on the X chromosome in male fruit fly germ cells are regulated differently from other cells

Because human females have two X chromosomes and males have one X and one Y, somatic cells have special mechanisms that keep expression levels of genes on the X chromosome the same between both sexes. This process is called dosage compensation and has been extensively studied in the fruit fly Drosophila. Now, researchers at the University of Tsukuba (UT) continued work with Drosophila to show that dosage compensation does not occur in the germ cells of male flies.

In an article published in Scientific Reports, the UT researchers investigated this phenomenon in fly primordial germ cells (PGCs), which are present in embryos and are the precursor cells to what ultimately become sperm and eggs in adults. Previous reports on dosage compensation in this cell type were controversial.

Genetic research in somatic cells has shown that expression of X-linked genes in male fruit flies is upregulated to reach equivalent levels to that of their female counterparts. A group of proteins, called the male-specific lethal (MSL) complex, is responsible for carrying out this role. These findings made the UT group interested in if this mechanism also occurs in the male germ cells. Distinct molecular events occur in the PGCs during embryonic development between male and female fruit flies. Because results shown in earlier publications did not align, the researchers chose to address their main question differently.

“The MSL complex leaves a signature mark, called acetylation, on a specific amino acid of the histone H4 protein of the X chromosome,” says Professor Satoru Kobayashi, senior author of the study. “The acetyl group being added tells the cell to express the X-linked genes at a higher level, which results in dosage compensation.”

To address their questions, the researchers used a process called transcriptome analysis to compare gene expression levels between male and female fruit fly PGCs. They also examined the histone H4 protein to determine if acetylation had occurred.

“We found that X-linked gene expression in male PGCs was about half that of female PGCs,” describes Professor Kobayashi. “We also could not detect the acetylation signature of the MSL complex.”

The authors also determined that the main components of the MSL complex are only present in very low amounts in the fly PGCs. Interestingly, they then created transgenic flies that were engineered to express higher levels of the MSL complex proteins. Male PGCs in these flies showed greater activation of X-linked genes, as well as the acetylation signature.

The researchers believe that the findings of this study have high biological significance, possibly suggesting that the absence of dosage compensation affects sex determination in Drosophila PGCs. This work provides novel insight that will be crucial for further investigation of embryo development and germ cell maturation.


Reference: Ota, R., Hayashi, M., Morita, S. et al. Absence of X-chromosome dosage compensation in the primordial germ cells of Drosophila embryos. Sci Rep 11, 4890 (2021). https://www.nature.com/articles/s41598-021-84402-7 https://doi.org/10.1038/s41598-021-84402-7


Provided by University of Tsukuba

An Epic Walk: 15 Million Years Needed For Dinosaurs To Get From South America to Greenland (Paleontology)

For the first time, two researchers—one from the University of Copenhagen and the other from Columbia University—have accurately dated the arrival of the first herbivorous dinosaurs in East Greenland. Their results demonstrate that it took the dinosaurs 15 million years to migrate from the southern hemisphere, as a consequence of being slowed down by extreme climatic conditions. Their long walk was only possible because as CO2 levels dropped suddenly, the Earth’s climate became less extreme.

A snail could have crawled its way faster. 10,000 km over 15 million years—that’s how long it took the first herbivorous dinosaurs to make their way from Brazil and Argentina all the way to East Greenland. This, according to a new study by Professor Lars Clemmensen of the University of Copenhagen’s Department of Geosciences and Natural Resource Management and researcher Dennis Kent of New York’s Columbia University.

The herbivorous dinosaurs first appeared in Brazil and Argentina roughly 230 million years ago. This was during the early part of the Late Triassic period, the Norian, when the world consisted of one supercontinent called Pangæa, without any seas in between. The supercontinent allowed dinosaurs to disperse, unhindered from south to north. So, what took them so long to get to Greenland?

Professor Lars Clemmensen from University of Copenhagen and Nils Natorp from Geocenter Møns Klint on expedition in Greenland  © KU

The answer lies in unique rock deposits consisting of a 350-meter-long unbroken layer series of fossil sediments with bones from about 10 herbivorous dinosaurs that the researchers found on expeditions in East Greenland, and for which Lars Clemmensen and Dennis Kent have now made an accurate dating of.

Drastic fall in atmospheric CO2 levels

Using studies of these ancient sedimentary deposits to help them, the two researchers were able to see that the herbivorous dinosaurs reached East Greenland exactly 214 million years ago. Interestingly, their timing coincides with a major climatic shift that most probably helped them move along. The event? A drastic decrease in atmospheric CO2 levels 215 million years ago.

-“We are able to see that during the period leading up to the dinosaurs’ migration, there was ten times as much CO2 in the atmosphere than there is today. This made it difficult for them to disperse from their original habitat in the southern hemisphere, as higher levels of CO2 produce more extreme climatic conditions. The desert areas they needed to traverse were excruciatingly hot and dry and the humid equatorial areas were tremendously unstable and wet. As such, climate was most likely a barrier that delayed the dinosaurs’ northbound dispersion,” explains Professor Lars Clemmensen from the Department of Geosciences and Natural Resource Management.

The dating was performed using magnetostratigraphic studies. Here, the researchers read the Earth’s ancient magnetic fields in ancient lake deposits and compare them to similar, well-dated sedimentary sea deposits from elsewhere in the world. Even on a global scale, the researchers’ access to a 350-meter thick unbroken layered series of fossils which includes early herbivorous dinosaurs and other contemporaneous vertebrates is extraordinarily unique. The unbroken layer series has allowed them to accurately read changes in Earth’s ancient magnetic fields and made dating the layers safe.

Carnivorous dinosaurs were 600,000 years faster

Herbivorous dinosaurs weren’t alone in East Greenland, which at the time was at the same latitude as the northeastern United States. Therefore, the area had a humid temperate climate.  Small carnivorous dinosaurs had also made their way there. According to the researcher duo, the fossil finds in East Greenland and elsewhere also demonstrate that carnivorous dinosaurs were better at overcoming extreme climate barriers and migrating to new lands compared to their herbivorous relatives. The researchers’ preliminary analyses show that the meat eaters reached East Greenland 600,000 years before herbivorous dinosaurs.

Lars Clemmensen, along with Danish, European and American researchers, has been on seven expeditions. Along the way, he has taken part in the work of discovering bones not only from herbivorous dinosaurs, but from carnivorous dinosaurs, flying lizards, labyrinthodontia and early mammals. The new dating method makes it possible to precisely determine their ages:

“With this new and very precise chronology, we have a tool to better understand the dispersal pattern of many early vertebrates on Pangæa. This holds especially true in the area between Northern Europe and East Greenland. We can go into every layer of soil where we have found bones and precisely determine their age,” says Lars Clemmensen.

The research results are published in PNAS.


Reference: Dennis V. Kent, Lars B. Clemmensen, “Northward dispersal of dinosaurs from Gondwana to Greenland at the mid-Norian (215–212 Ma, Late Triassic) dip in atmospheric pCO2”, Proceedings of the National Academy of Sciences Feb 2021, 118 (8) e2020778118; DOI: 10.1073/pnas.2020778118


Provided by University of Copenhagen

New Therapeutic Approach Discovered For Reducing the Risk of Thrombosis (Medicine)

Thrombotic occlusion of blood vessels, which leads to myocardial infarctions, strokes and venous thromboembolisms, is the major cause of death in the western hemisphere. Therefore, it is of critical importance to understand mechanisms preventing thrombus formation. A new study by the research group of Christoph Binder, Principal Investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and Professor at the Medical University of Vienna, now explains the important role of immunoglobulin-M (IgM) antibodies in preventing thrombosis. The study published in the journal Blood shows that these antibodies recognize microvesicles, which are membrane blebs shed by cells and recognized for their critical role in thrombosis, and therefore prevent their pro-thrombotic effects. These results provide a novel approach to reduce the risk of thrombosis by using IgM antibodies.

Antibodies are an important component of the immune system. On the one hand, these proteins serve in the body to defend against microbes, and on the other hand to remove the body’s own “cell waste”. Naturally occurring antibodies which are present from birth and mostly of the immunoglobulin-M (IgM) type, play an essential role in these processes. In the context of thrombosis, earlier studies demonstrated that people with a low number of IgM antibodies have an increased risk of thrombosis. A research group led by Christoph Binder, Professor of Atherosclerosis Research at the Medical University of Vienna and Principal Investigator at CeMM , previously demonstrated in a study published in 2009 that a high percentage of natural IgM antibodies bind oxidation-specific epitopes, molecular structures that are present on dying cells and serve as “remove-me signals” for the immune system. In this study, Binder’s research group identified the mechanisms explaining anti-thrombotic effects of natural IgM antibodies.

IgM antibodies bind procoagulant microvesicles

Microvesicles, blebs shed from the membrane of cells, are critical mediators of blood coagulation and thrombus formation. The study authors Georg Obermayer and Taras Afonyushkin from Binder’s research group, both affiliated with CeMM and the Medical University of Vienna, have now demonstrated that natural IgM antibodies that bind oxidation-specific epitopes can prevent coagulation and thrombosis induced by microvesicles. This provides a mechanistic explanation for the previously published observation that low levels of these antibodies are associated with an increased risk of thrombosis. “We assume that natural IgM antibodies recognize microvesicles that are particularly proinflammatory and procoagulant,” say the scientists. Both in experiments on the mouse model and directly on human blood samples, the scientists were able to show that the addition of IgM antibodies inhibited blood clotting caused by specific microvesicles and protected mice from lung thrombosis. Conversely, it was also shown that depletion of the IgM antibodies increased blood clotting.

Possible starting point for future therapies

The study authors explain: “The study for the first time provides an explanation why people with a low number of natural IgM antibodies have an increased risk of thrombosis.” Project leader Christoph Binder adds: “The results offer high potential for novel treatments to reduce the risk of thrombosis. Influencing IgM antibody levels in high-risk patients could be a viable addition to the previously established blood thinning treatment, as this is also known to be associated with side effects such as an increased tendency to bleed in the case of injuries.” In addition, the study makes an important contribution to the basic understanding of factor modulating thrombus formation. “Microvesicles are already recognized as an important component of blood coagulation. However, our study created a novel possibility of targeting them therapeutically for the first time,” says Christoph Binder.

The study “Natural IgM antibodies inhibit microvesicle-driven coagulation and thrombosis” was published in the journal Blood, online on 8 December 2020. DOI: https://doi.org/10.1182/blood.2020007155.

Authors: Georg Obermayer*, Taras Afonyushkin*, Laura Göderle, Florian Puhm, Waltraud Schrottmaier, Soreen Taqi1, Michael Schwameis, Cihan Ay, Ingrid Pabinger, Bernd Jilma, Alice Assinger, Nigel Mackman, Christoph J. Binder;
* authors contributed equally

Funding: This study was supported by the SFB-54 “InThro” of the Austrian Science Fund (FWF), the Christian Doppler Laboratory for Innovative Therapy Approaches in Sepsis, and CCHD (Cell Communication in Health and Disease) of the FWF.

Featured image: First authors Taras Afonyushkin (left) and Georg Obermayer (right) with Last author Christoph Binder (middle), © Laura Alvarez/CeMM.


Provided by CEMM

Scientists Discovery Ends Long-standing Photosynthesis Controversy (Botany)

New findings overturn conventional thinking about the location of a key plant enzyme involved in photosynthesis

Scientists have pinpointed the location of an essential enzyme in plant cells involved in photosynthesis, according to a study published today in eLife.

The findings overturn conventional thinking about where the enzyme resides in plant cells and suggest a probable role in regulating energy processes as plants adapt from dark to light conditions.

During photosynthesis, plants convert carbon into energy stores through ‘electron transport’, involving an enzyme called ferredoxin:NADP(H) oxidoreductase, or FNR.

Plants can switch rapidly between two types of electron transport – linear electron flow (LEF) and cyclic electron flow (CEF) in response to environmental conditions. The transfer of FNR between membrane structures in the chloroplast, where photosynthesis takes place, has been linked to this switch.

“Current dogma states that FNR carries out its function in the soluble compartment of the chloroplast, but evidence suggests that the activity of FNR increases when it is attached to an internal membrane,” explains first author Manuela Kramer, a PhD student at the School of Biological and Chemical Sciences, Queen Mary University of London, UK. “We needed to find out precisely where FNR is located in the chloroplast, how it interacts with other proteins, and how this affects its activity in order to understand its role in switching between electron transport processes.”

The researchers used immuno-gold staining to pinpoint FNR in more than 300 chloroplasts from 18 individual Arabidopsis plants. The staining density of FNR was five times higher in the internal membrane system of the chloroplast (thylakoids) than in the soluble compartment (stroma), where it did not rise above background levels. This significantly higher labelling in the membrane proved that chloroplasts contain little soluble FNR, and confirmed for the first time where the enzyme is located.

To understand more about FNR’s location, the team generated plants where the enzyme is specifically bound to different proteins called ‘tether proteins’. In Arabidopsis plants with decreased FNR content, they substituted three versions of FNR from maize, each with a different capacity for binding to the tether proteins TROL and Tic62. They found that rescue with maize FNR types that strongly bound to the Tic62 tether protein resulted in much higher density of gold FNR labelling in specific, lamellar membrane regions of the thylakoids. This suggests that the distribution of FNR throughout the chloroplast in plant cells is dependent on binding to the tether proteins.

Finally, the team tested how FNR location affects electron transport, by comparing electron flow rates when plants were adapted to the dark with electron flow after their acclimatisation to light. In normal dark-adapted plants, a short exposure to light resulted in a switch to higher CEF activity. However, this was not seen in plants lacking strong interaction between FNR and the tether proteins, suggesting these plants lack the ability to switch on CEF. After light acclimatisation, both the wild-type and mutant plants had similar, decreased CEF activity, suggesting that the impact of FNR is related to light-dependent changes in the interactions between the enzyme and tether proteins.

“Our results show a link between the interaction of FNR with different proteins and the activity of an alternative photosynthetic electron transport pathway,” concludes senior author Guy Hanke, Senior Lecturer in Plant Cell and Molecular Biology at the School of Biological and Chemical Sciences, Queen Mary University of London. “This supports a role for FNR location in regulating photosynthetic electron flow during the transition of plants from dark to light.”


Reference:

  1. Plant Biology

Regulation of photosynthetic electron flow on dark to light transition by Ferredoxin:NADP(H) Oxidoreductase interactions“, Manuela Kramer et al. Research Article  Mar 9, 2021.


Provided by Elife

World’s First Dinosaur Preserved Sitting On Nest of Eggs with Fossilized Babies (Paleontology)

The fossil in question is that of an oviraptorosaur, a group of bird-like theropod dinosaurs that thrived during the Cretaceous Period, the third and final time period of the Mesozoic Era (commonly known as the ‘Age of Dinosaurs’) that extended from 145 to 66 million years ago. The new specimen was recovered from uppermost Cretaceous-aged rocks, some 70 million years old, in Ganzhou City in southern China’s Jiangxi Province.

“Dinosaurs preserved on their nests are rare, and so are fossil embryos. This is the first time a non-avian dinosaur has been found, sitting on a nest of eggs that preserve embryos, in a single spectacular specimen,” explains Dr. Shundong Bi.

The fossil consists of an incomplete skeleton of a large, presumably adult oviraptorid crouched in a bird-like brooding posture over a clutch of at least 24 eggs. At least seven of these eggs preserve bones or partial skeletons of unhatched oviraptorid embryos inside. The late stage of development of the embryos and the close proximity of the adult to the eggs strongly suggests that the latter died in the act of incubating its nest, like its modern bird cousins, rather than laying its eggs or simply guarding its nest crocodile-style, as has sometimes been proposed for the few other oviraptorid skeletons that have been found atop nests.

The ~70-million-year-old fossil in question: an adult oviraptorid theropod dinosaur sitting atop a nest of its eggs. Multiple eggs (including at least three that contain embryos) are clearly visible, as are the forearms, pelvis, hind limbs, and partial tail of the adult. Photo by Shundong Bi, Indiana University of Pennsylvania.

“This kind of discovery, in essence fossilized behavior, is the rarest of the rare in dinosaurs,” explains Dr. Lamanna. “Though a few adult oviraptorids have been found on nests of their eggs before, no embryos have ever been found inside those eggs. In the new specimen, the babies were almost ready to hatch, which tells us beyond a doubt that this oviraptorid had tended its nest for quite a long time. This dinosaur was a caring parent that ultimately gave its life while nurturing its young.”

The team also conducted oxygen isotope analyses that indicate that the eggs were incubated at high, bird-like temperatures, adding further support to the hypothesis that the adult perished in the act of brooding its nest. Moreover, although all embryos were well-developed, some appear to have been more mature than others, which in turn suggests that oviraptorid eggs in the same clutch might have hatched at slightly different times. This characteristic, known as asynchronous hatching, appears to have evolved independently in oviraptorids and some modern birds.

One other interesting aspect of the new oviraptorid specimen is that the adult preserves a cluster of pebbles in its abdominal region. These are almost certainly gastroliths, or “stomach stones,” rocks that would have been deliberately swallowed to aid the dinosaur in digesting its food. This is the first time that undoubted gastroliths have been found in an oviraptorid, and as such, these stones may provide new insights into the diets of these animals.

Says Dr. Xu, “It’s extraordinary to think how much biological information is captured in just this single fossil. We’re going to be learning from this specimen for many years to come.”

Featured image: An attentive oviraptorid theropod dinosaur broods its nest of blue-green eggs while its mate looks on in what is now Jiangxi Province of southern China some 70 million years ago. Artwork by Zhao Chuang © Zhao Chuang


Reference:

Bi, S., Amiot, R., de Fabrègues, C.P., Pittman, M., Lamanna, M.C., Yu, Y., Yu, C., Yang, T., Zhang, S., Zhao, Q. and Xu, X., 2020. An oviraptorid preserved atop an embryo-bearing egg clutch sheds light on the reproductive biology of non-avialan theropod dinosaurs. Science Bulletin. 2020, https://doi.org/10.1016/j.scib.2020.12.018.


Provided by Science China Press

Study Identifies A Molecular Process to Explain How Maternal Stress Triggers Idiopathic Preterm Birth (Medicine)

A University of South Florida Health preclinical study indicates that FKBP51-progesterone receptor binding plays a critical role in stress-induced preterm birth

Preterm birth is a leading cause of infant deaths and illness in the U.S. — yet its underlying molecular causes remain largely unclear. About 40 to 50% of preterm births, defined as births before 37 weeks of pregnancy, are estimated to be “idiopathic,” meaning they arise from unexplained or spontaneous labor. And, maternal stress linked to depression and post-traumatic stress disorders as well as fetal stress have been strongly implicated in preterm births with no known cause.

Now, for the first time, a University of South Florida Health (USF Health) preclinical study has uncovered a mechanism to help explain how psychological and/or physiological stress in pregnant women triggers idiopathic preterm birth. A research team at the USF Health Morsani College of Medicine Department of Obstetrics and Gynecology shows how cortisol — the “fight-or-flight” hormone critical for regulating the body’s response to stress — acts through stress-responsive protein FKBP51 binding to progesterone receptors to inhibit receptor function in the uterus. This reduced progesterone receptor activity stimulates labor.

The findings were published online first March 8 in Proceedings of the National Academy of Sciences (PNAS).

“This new study fills in some longstanding mechanistic gaps in our understanding of how normal labor begins and how stress causes preterm birth,” said the paper’s senior author Charles J. Lockwood, MD, senior vice president of USF Health, dean of the USF Health Morsani College of Medicine, and a professor of obstetrics and gynecology specializing in maternal-fetal medicine.

Dr. Lockwood was a co-principal investigator for the study along with the paper’s lead author Ozlem Guzeloglu-Kayisli, PhD, a USF Health associate professor of obstetrics and gynecology. Nihan Semerci, MSc, a senior biological scientist, shares the lead authorship with Dr. Guzeloglu-Kayisli.

The preclinical study providing molecular insights into maternal stress and preterm birth of unknown cause was led by USF Health’s Charles J. Lockwood, MD, (above) and Ozlem Guzeloglu-Kayisli, PhD. (Below) | Photos by Freddie Coleman and Allison Long, USF Health Communications

Progesterone reduces contractions of the uterus and sustained levels are essential to prevent a baby from being born too early. Reduced uterine progesterone receptor expression and signaling stimulates labor. In the brain, elevated FKBP51 expression has been strongly associated with increased risk for stress-related disorders.

Previous work by the USF Health team showed that normal human labor starting at term (between 37 and 42 weeks of pregnancy) was associated with reduced expression of progesterone receptors and increased expression of FKBP51, specifically in maternal decidual cells (specialized cells lining the uterus).

For the current study focused on maternal stress-induced idiopathic preterm birth, the researchers combined experiments in human maternal decidual cells and a mouse model in which FKBP5, the gene that makes FKBP51, had been removed, or “knocked out.” Altogether, their results revealed a novel functional progesterone withdrawal mechanism, mediated by maternal stress-induced uterine FKBP51 overexpression and enhanced FKPB51-progesterone receptor binding, that decreased progestational effects and triggered preterm birth. The researchers found that Fkbp5 knockout mice (with depletion of the gene encoding for FKBP51) exhibit prolonged gestation and are completely resistant to maternal stress-induced preterm birth.

Among the USF Health team’s key findings:

– FKPB51 levels were greater and FKPB51 binding to progesterone receptors was significantly increased in the decidual cells of women with idiopathic preterm birth, compared to decidual cells of gestational age-matched controls.

– The study reports for the first time that Fkbp5-deficient (knockout) mice are completely resistant to maternal stress-induced preterm birth and exhibit prolonged pregnancies accompanied by slower decline in systemic progesterone levels. This indicates that FKBP51 plays a crucial role in the length of pregnancy and initiation of labor and delivery.

– In contrast, mice with the FKPB5 gene intact and normal levels of FKPB51 protein (wild type mice) delivered earlier when exposed to maternal stress than either non-stressed wild type mice or FKPB5 knockout mice under nonstressed or stressed conditions.

“Collectively, these results suggest that FKBP51 plays a pivotal role both in term labor and stress-associated preterm parturition (birth) and that inhibition of FKBP51 may prove to be a novel therapy to prevent idiopathic preterm birth,” the study authors conclude.

Dr. Guzeloglu-Kayisli (center) in the Ob-Gyn research team’s laboratory, USF Health Morsani College of Medicine, with MCOM maternal-fetal medicine fellow Anthony Kendle, MD (left) and biological scientist Xiaofang Guo (right), who are isolating tissue samples | Photo by Allison Long, USF Health Communications.

Currently, injectable progesterone is the only drug approved to help prevent preterm birth in high-risk women who have had a previous preterm birth. However, its effectiveness was not confirmed by a recent large clinical trial, sparking debate in the health care community.  The authors finding that progesterone receptor activity was reduced in idiopathic preterm birth may explain the apparent lack of effectiveness of supplemental progesterone.

Babies born before 37 weeks, particularly those born before 34 weeks, have more health problems and may face long-term health complications, including childhood lung or heart disease and neurodevelopmental delays, Dr. Guzeloglu-Kayisli said. The likelihood of poor outcomes decreases as gestational age (length of the pregnancy) increases.

“Prevention of idiopathic preterm birth by extending gestation even two or three weeks can benefit the newborn, because it provides critical time needed for the fetus’s lungs and brain to mature,” Dr. Guzeloglu-Kayisli said. “Our research indicates the importance of investigating the potential use of FKBP51 inhibitors as a targeted therapy to reduce the risk of stress-related preterm birth.”

The USF Health study was supported in part by The March of Dimes Prematurity Research Center Ohio Collaborative grant.

Featured image: Babies born before 37 weeks, particularly those born before 34 weeks, have more health problems and may face long-term complications like heart and lung diseases and neurodevelopmental delays. © USF Health


Reference: Ozlem Guzeloglu-Kayisli, Nihan Semerci, Xiaofang Guo, Kellie Larsen, Asli Ozmen, Sefa Arlier, Duygu Mutluay, Chinedu Nwabuobi, Bradley Sipe, Irina Buhimschi, Catalin Buhimschi, Frederick Schatz, Umit A. Kayisli, Charles J. Lockwood, “Decidual cell FKBP51–progesterone receptor binding mediates maternal stress–induced preterm birth”, Proceedings of the National Academy of Sciences Mar 2021, 118 (11) e2010282118; DOI: 10.1073/pnas.2010282118


Provided by USF Health

Bridge Built Between Kähler-Einstein and Chen-Ning Yang’s Equations (Maths)

Recently, Prof. CHEN Gao from Institute of Geometry and Physics of the University of Science and Technology of China has made breakthrough in the field of complex differential geometry. Using mathematical invention, he buildt a new bridge between the relativity of Einstein and quantum mechanics. This work was published in Inventiones Mathematicae.

In the field of complex differential geometry, there are two crucial physical equations: the Hermitian-Yang-Mills equation, which became the standard model of quantum mechanics, and the Kähler-Einstein equation, which is closely related to relativity. To stably solve these two equations has been at the core of complex differential geometry.

In 1977, Shing-Tung Yau solved the zero curvature Keller-Einstein equation. In 1985, Shing-tung Yau and others solved the Hermitian-Yang-Mills equation under the premise of stability. In 2012, CHEN Xiuxiong, collaborating with others, solved the positive curvature Kähler-Einstein equation under the premise of stability.

Prof. Chen’s work is another important development in this field. He solved the Chen-Donaldson’s J-equation and the supercritical deformed Hermitian-Yang-Mills equation under the premise of stability, and thus connected the Kähler-Einstein equation and the Hermitian-Yang-Mills equation.

Reviewer of Inventiones mathematicae, remarked the work as “CHEN Gao introduced two bold ideas, and solved two important equations, the results of which are very rare.” The paper has attracted the attention of the international mathematical circle and was quoted an academician of the National Academy of Sciences and others at the first time.


Reference: Chen, G. The J-equation and the supercritical deformed Hermitian–Yang–Mills equation. Invent. math. (2021). https://link.springer.com/article/10.1007%2Fs00222-021-01035-3 https://doi.org/10.1007/s00222-021-01035-3


Provided by University of Science and Technology of China

Head Injury 25 Years Later – Penn Study Finds Increased Risk of Dementia (Neuroscience)

Penn Medicine Research Reveals Stronger Associations Between Head Injuries and Dementia Among Women Compared to Men, and Among White Participants as Compared to Black Participants

Head injury in the United States is common, with over 23 million adults age 40 or older reporting a history of head injury with loss of consciousness. Many head injuries can be caused by a host of different situations – from car and motorcycle accidents to sports injuries. What’s more, it has become increasingly recognized that the effects from head injuries are long-lasting. New research led by the Perelman School of Medicine at the University of Pennsylvania shows that a single head injury could lead to dementia later in life. This risk further increases as the number of head injuries sustained by an individual increases. The findings also suggest stronger associations of head injury with risk of dementia among women compared to among men and among white as compared to among Black populations.

The researchers, whose findings were published today in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, conducted the investigation using data from the Atherosclerosis Risk in Communities (ARIC) Study, which aimed to uncover associations between head injury and dementia over the span of 25 years in a diverse population in the United States. Previously, data on traumatic brain injury has been limited to select populations, such as military and medical claims databases. These are among the first findings to specifically investigate head injury and dementia risk in both Black and white populations, as well as among both males and females, in a community-based setting.

“Head injury is a significant risk factor for dementia, but it’s one that can be prevented. Our findings show that the number of head injuries matter – more head injuries are associated with greater risk for dementia,” said lead investigator, Andrea L.C. Schneider, MD, PhD, an assistant professor of Neurology at Penn. “The dose-dependence of this association suggests that prevention of head injury could mitigate some risk of dementia later in life. While head injury is not the only risk factor for dementia, it is one risk factor for dementia that is modifiable by behavior changes such as wearing helmets and seat belts.”

The findings show that compared to participants who never experienced a head injury, a history of a single prior head injury was associated with a 1.25 times increased risk of dementia, and a history of two or more prior head injuries was associated with over 2 times increased risk of dementia compared to individuals without a history of head injury. Overall, 9.5 percent of all dementia cases in the study population could be attributed to at least one prior head injury.

To illustrate the relationship between dementia and head injuries, the authors gathered data from a diverse cohort with a mean baseline age of 54 years, comprised of 56 percent female and 27 percent Black participants from four different communities across the United States. Participants were followed for a median of 25 years through up to six in-person visits and semi-annual telephone follow-ups. Data on head injuries of participants was drawn from hospital records, as well as self-reporting from some participants.

Previous research on dementia and traumatic brain injuries suggests that women are at higher risk for dementia compared to men. Additionally, Black populations overall are at higher risk for dementia compared to people who are white. However, few prior studies have evaluated for possible differences in associations of head injury with dementia risk by sex and race.

This data from the ARIC study found evidence that females were more likely to experience dementia as a result of head injury than males. Further, the study showed that although there is increased dementia risk associated with head injury among both White and Black participants, White participants were at higher risk for dementia after head injury compared to Black participants. The authors conclude that more research is needed to better understand reasons for these observed sex and race differences in the association of head injury with dementia risk.

“Given the strong association of head injury with dementia, there is an important need for future research focused on prevention and intervention strategies aimed at reducing dementia after head injury,” Schneider said. “The results of this study have already led to several ongoing research projects, including efforts to uncover the causes of head injury-related dementia as well as investigations into reasons underlying the observed sex and race differences in the risk of dementia associated with head injury.”

The study was supported by the National Institutes of Health (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I, 2U01-HL-096812, 2U01-HL-096814, 2U01-HL-096899, 2U01-HL-096902, 2U01-HL-096917, and R01-HL-70825).


Provided by Penn Medicine