Study Shows How Low-protein Intake During Pregnancy Can Cause Renal Problems in Offspring (Medicine)

In an article published in PLOS ONE, scientists at a FAPESP-supported research center describe the impact of hypoproteinemia on the expression of microRNAs associated with kidney development in rat embryos.

Besides being underweight, babies born to women whose diet lacked sufficient protein during pregnancy tend to have kidney problems resulting from alterations that occurred while their organs were forming during the embryonic stage of their development. 

In a study published in PLOS ONE, researchers affiliated with the University of Campinas (UNICAMP) in the state of São Paulo, Brazil, discovered the cause of the problem at the molecular level and its link to epigenetic phenomena (changes in gene expression due to environmental factors such as stress, exposure to toxins or malnutrition, among others).

According to the authors, between 10% and 13% of the world population suffer from chronic kidney disease, a gradual irreversible loss of renal function that is associated with high blood pressure and cardiovascular disorder.

The study, conducted at the Obesity and Comorbidities Research Center (OCRC), resulted from PhD research by first author Letícia de Barros Sene with a fellowship from FAPESP. 

OCRC is a Research, Innovation and Dissemination Center (RIDC) funded by FAPESP.

In the article, the researchers describe the molecular pathways involved in the proliferation and differentiation of embryonic and fetal kidney cells. They obtained this knowledge by sequencing microRNAs (often called miRNAs) from the offspring of rats fed a low-protein diet while gestating. MirRNAs are small non-coding RNAs that regulate gene expression.

“We know low-protein intake during pregnancy tends to lead to a 28% decrease in the number of the offspring’s nephrons, the structures that filter blood in the kidneys. The resulting overloading of nephrons has several consequences. In the case of rats, pups become hypertensive only ten weeks after birth, when they are still considered young,” Patrícia Aline Boer, a member of the OCRC team and last author of the article, told Agência FAPESP. A healthy kidney has about a million nephrons.

Fetal programming

There has been a great deal of research in recent decades on the links between maternal health during pregnancy and child development, especially focusing on a field known as developmental origins of health and disease (DOHaD).

“In humans, these links were first observed after World War Two as a result of what’s known as the ‘Dutch famine’ [Hongerwinter], when the Nazis blocked food supplies to the Netherlands. Scientific studies showed that babies born to women who starved while pregnant in this period were underweight and developed high blood pressure, alterations in response to stress, heart problems, propensity to diabetes, and increased insulin resistance,” said Boer, who is president of DOHaD Brazil

Since then, this epigenetic phenomenon has been studied in greater depth using animal experiment models. To understand at the molecular level what triggered the reduction in the number of nephrons, the OCRC researchers analyzed expression of miRNAs and target genes in fetal kidneys (metanephros) of rats at 17 days of gestation.

“We know the drop in the number of nephrons isn’t a genetic but an epigenetic effect,” Boer said. “It’s caused by something in the environment. In this case, gene expression is altered by the stress of hypoproteinemia. The DNA sequence doesn’t change. The expression of some genes in the offspring is altered, and the alteration can be heritable – it can be transmitted to future generations. We studied mirRNAs because they’re very important to genetic expression and alterations not associated with changes in DNA.”

Compared analysis between rats fed a regular protein diet (17% of daily calorie intake) and a second group fed a low-protein diet (6%) during pregnancy revealed alterations in 44 miRNAs – seven of which in genes associated with the proliferation and differentiation of cells essential to nephron development, researchers found. Genetic sequencing, immunohistochemistry and morphological analysis demonstrated that maternal protein restriction changed the expression of miRNAs and proteins involved in renal development as early as the 17th day of gestation.

“Previous research showed a 28% reduction in nephrogenesis, and in our study, there was a 28% decrease in the cells that give rise to nephrons. The proportion was the same, which means there must be some kind of signaling during the embryonic period that the organ has to adapt to a low-protein intake,” Boer said. 

Other examples of fetal adaptation to malnutrition leading to alterations in organ development can be found in nature, Boer explained. “In our study, we observed that stem cells [which will become nephrons] differentiate very rapidly and that there was more differentiation and less proliferation of the cells that form nephrons,” she said.

The article “Impact of gestational low-protein intake on embryonic kidney microRNA expression and in nephron progenitor cells of the male fetus” (doi: 10.1371/journal.pone.0246289) by Letícia de Barros Sene, Wellerson Rodrigo Scarano, Adriana Zapparoli, José Antônio Rocha Gontijo and Patrícia Aline Boer is at: journals.plos.org/plosone/article?id=10.1371/journal.pone.0246289.

Featured image: In an article published in PLOS ONE, scientists at a FAPESP-supported research center describe the impact of hypoproteinemia on the expression of microRNAs associated with kidney development in rat embryos (image: Wikimedia Commons)


Provided by FAPESP

A New Window to See Hidden Side of Magnetized Universe (Astronomy)

New observations and simulations show that jets of high-energy particles emitted from the central massive black hole in the brightest galaxy in galaxy clusters can be used to map the structure of invisible inter-cluster magnetic fields. These findings provide astronomers with a new tool for investigating previously unexplored aspects of clusters of galaxies.

As clusters of galaxies grow through collisions with surrounding matter, they create bow shocks and wakes in their dilute plasma. The plasma motion induced by these activities can drape intra-cluster magnetic layers, forming virtual walls of magnetic force. These magnetic layers, however, can only be observed indirectly when something interacts with them. Because it is simply difficult to identify such interactions, the nature of intra-cluster magnetic fields remains poorly understood. A new approach to map/characterize magnetic layers is highly desired.

An international team of astronomers including Haruka Sakemi, a graduate student at Kyushu University (now a research fellow at the National Astronomical Observatory of Japan – NAOJ), used the MeerKAT radio telescope located in the Northern Karoo desert of South Africa to observe a bright galaxy in the merging galaxy cluster Abell 3376 known as MRC 0600-399. Located more than 600 million light-years away in the direction of the constellation Columba, MRC 0600-399 is known to have unusual jet structures bent to 90-degree angles. Previous X-ray observations revealed that MRC 0600-399 is the core of a sub-cluster penetrating the main cluster of galaxies, indicating the presence of strong magnetic layers at the boundary between the main and sub-clusters. These features make MRC 0600-399 an ideal laboratory to investigate interactions between jets and strong magnetic layers.

The MeerKAT observations revealed unprecedented details of the jets, most strikingly, faint “double-scythe” structure extending in the opposite direction from the bend points and creating a “T” shape. These new details show that, like a stream of water hitting a pane of glass, this is a very chaotic collision. Dedicated computer simulations are required to explain the observed jet morphology and possible magnetic field configurations.

Takumi Ohmura, a graduate student at Kyushu University (now a research fellow at the University of Tokyo’s Institute for Cosmic-Ray Research – ICRR), from the team performed simulations on NAOJ’s supercomputer ATERUI II, the most powerful computer in the world dedicated to astronomical calculations. The simulations assumed an arch-like strong magnetic field, neglecting messy details like turbulence and the motion of the galaxy. This simple model provides a good match to the observations, indicating that the magnetic pattern used in the simulation reflects the actual magnetic field intensity and structure around MRC 0600-399. More importantly, it demonstrates that the simulations can successfully represent the underlying physics so that they can be used on other objects to characterize more complex magnetic field structures in clusters of galaxies. This provides astronomers with a new way to understand the magnetized Universe and a tool to analyze the higher-quality data from future radio observatories like the SKA (the Square Kilometre Array).

These results appeared as Chibueze, Sakemi, Ohmura, et. al. “Jets from MRC 0600-399 bent by magnetic fields in the cluster Abell 3376” in Nature on May 6, 2021.

Featured image: The bent jet structures emitted from MRC 0600-399 as observed by the MeerKAT radio telescope (left) are well reproduced by the simulation conducted on ATERUI II (right). The nearby galaxy B visible in the left part of the MeerKAT image is not affecting the jet and has been excluded in the simulation. Credit: Chibueze, Sakemi, Ohmura et al. (MeerKAT image); Takumi Ohmura, Mami Machida, Hirotaka Nakayama, 4D2U Project, NAOJ (ATERUI II image)


Provided by National Institutes of Natural Sciences

Johns Hopkins Scientists Model Saturn’s Interior (Planetary Science)

Researchers simulate conditions necessary for planet’s unique magnetic field

New Johns Hopkins University simulations offer an intriguing look into Saturn’s interior, suggesting that a thick layer of helium rain influences the planet’s magnetic field.

The models, published this week in AGU Advances, also indicate that Saturn’s interior may feature higher temperatures at the equatorial region, with lower temperatures at the high latitudes at the top of the helium rain layer.

It is notoriously difficult to study the interior structures of large gaseous planets, and the findings advance the effort to map Saturn’s hidden regions.

“By studying how Saturn formed and how it evolved over time, we can learn a lot about the formation of other planets similar to Saturn within our own solar system, as well as beyond it,” said co-author Sabine Stanley, a Johns Hopkins planetary physicist.

Saturn stands out among the planets in our solar system because its magnetic field appears to be almost perfectly symmetrical around the rotation axis. Detailed measurements of the magnetic field gleaned from the last orbits of NASA’s Cassini mission provide an opportunity to better understand the planet’s deep interior, where the magnetic field is generated, said lead author Chi Yan, a Johns Hopkins PhD candidate.

By feeding data gathered by the Cassini mission into powerful computer simulations similar to those used to study weather and climate, Yan and Stanley explored what ingredients are necessary to produce the dynamo—the electromagnetic conversion mechanism—that could account for Saturn’s magnetic field.

“One thing we discovered was how sensitive the model was to very specific things like temperature,” said Stanley, who is also a Bloomberg Distinguished Professor at Johns Hopkins in the Department of Earth & Planetary Sciences and the Space Exploration Sector of the Applied Physics Lab. “And that means we have a really interesting probe of Saturn’s deep interior as far as 20,000 kilometers down. It’s a kind of X-ray vision.”

Saturn’s interior with stably stratified Helium Insoluble Layer. Image: Yi Zheng (HEMI/MICA Extreme Arts Program)

Strikingly, Yan and Stanley’s simulations suggest that a slight degree of non-axisymmetry could actually exist near Saturn’s north and south poles.

“Even though the observations we have from Saturn look perfectly symmetrical, in our computer simulations we can fully interrogate the field,” said Stanley.

Direct observation at the poles would be necessary to confirm it, but the finding could have implications for understanding another problem that has vexed scientists for decades: how to measure the rate at which Saturn rotates, or, in other words, the length of a day on the planet.

This project was conducted using computational resources at the Maryland Advanced Research Computing Center (MARCC).

Featured image: The magnetic field of Saturn seen at the surface. Image: Ankit Barik/Johns Hopkins University


Reference: Yan, C., & Stanley, S. (2021). Recipe for a Saturn‐like dynamo. AGU Advances, 2, e2020AV000318. https://doi.org/10.1029/2020AV000318


Provided by Johns Hopkins University

COVID-19 Test Detects Antibodies in Hundreds of Tiny Blood Samples (Medicine)

Antibody testing can be a powerful tool for tracking the spread of SARS-CoV2 infections, the virus responsible for the COVID-19 pandemic. A group of scientists from EPFL, UNIGE and HUG have now developed a reliable and cheap antibody test that can analyze more than 1,000 samples at once and requires a small drop of blood, such as that from a finger prick.

After people get infected with the SARS-CoV-2 virus that causes COVID-19, they start to produce immune molecules called antibodies. COVID-19 antibody tests pick up on the presence of antibodies against SARS-CoV-2 in the blood. Because antibodies can take several days to weeks to develop, antibody tests can’t detect active infections, but they can help to find out what proportion of communities have been infected with the virus in the past. This knowledge is useful for epidemiological investigations, and informing public-health policies. Antibody tests are also a powerful tool to evaluate COVID-19 vaccine efficacy in clinical trials, when scientists look at the rise in antibodies after volunteers get a jab.

However, antibody tests rely on rather expensive reagents and typically require larger quantities of blood taken with a venous blood draw, which can only be performed by trained healthcare personnel. What’s more, some of the tests on the market are too inaccurate to deliver reliable results. Now, researchers from EPFL, UNIGE and HUG have developed a highly accurate test that can analyze hundreds of samples at the same time, using minute quantities of reagents and single drops of blood.

“The coolest thing about our approach is that you can do a lot of tests at once with minimal reagents, and you could even have people collect their own blood samples at home,” says study first author Zoe Swank, a former PhD student in the EPFL’s Laboratory of Biological Network Characterization led by Sebastian Maerkl.

In early 2020, Swank and Maerkl teamed up with Benjamin Meyer, a virologist at UNIGE Faculty of Medicine and scientific collaborator at HUG Division of Laboratory Medicine, and with Isabella Eckerle, a professor at UNIGE Faculty of Medicine and Medical Coordinator of the UNIGE-HUG Centre for Emerging Viral Diseases, and set out to repurpose a diagnostics platform that had been previously developed in Maerkl’s lab, so that it could be used to perform SARS-CoV-2 antibody tests.

The platform, which can analyze up to 1024 samples at once, consists of a complex network of tiny tubes carved into a plastic chip that is about the size of a USB stick. To perform the assay, the researchers feed individual blood samples and test reagents through the channels of this ‘microfluidic’ chip. If antibodies against SARS-CoV-2 are present in a blood sample, a molecule generates a signal that can be detected as a fluorescent glow under a microscope.

When the team tested blood samples from 155 individuals infected with SARS-CoV-2, the assay detected antibodies against the virus in 98% of cases. The assay is also extremely specific: it never detected antibodies against the virus in samples from people who had not been infected with SARS-CoV-2.

Because the microfluidic device is very small, the amounts of blood and reagents used are a fraction of those required for standard COVID-19 antibody tests. And running hundreds of assays on a single platform means that a person can perform more assays in less time, with potential cost savings on human labor, Maerkl says. “If you do a back-of-the-envelope calculation and take everything into consideration, including salary costs and the cost of reagents, it is about 0.5 Swiss francs per assay,” he says. “It’s almost negligible.”

To eliminate the need for collecting blood from people’s veins, Swank and her colleagues assessed whether they could use blood samples obtained from a finger prick — a simple procedure in which a finger is pierced with a tiny needle to obtain a small quantity of blood. The researchers tested three commercially available devices to perform finger-prick blood tests, including glucose test strips used by people with diabetes to measure their sugar blood levels.

The microfluidics-based antibody test could be successfully run on blood samples collected with all three methods, even when the blood was left to dry and stored for about one week at room temperature, or when samples were shipped by regular mail from Geneva to Lausanne. The study was published in PNAS.

“The approach of collecting blood in a decentralized way by a simple finger prick that can be even done at home, and a sophisticated laboratory-based assay with high diagnostic accuracy makes this test very attractive for large-scale epidemiological studies, explains Isabella Eckerle. It could even be used for remote geographic regions that lack sufficient laboratory capacity, for example to conduct seroprevalence studies in Sub-Saharan Africa.” She adds that “the small amount of blood and the collection by a finger prick, which is quick and almost painless, also makes this method very attractive for the use in children and offers a unique opportunity to assess seroprevalence rates in daycare centers or kindergartens.”

Maerkl and his collaborators are now using the test to determine the prevalence of antibodies against SARS-CoV-2 among kindergarteners in Geneva, in collaboration with Silvia Stringhini and Idris Guessous of the Population Epidemiology Unit at HUG. In the future, Maerkl says, this technology could make it possible for people to buy a blood sampling kit at a pharmacy or a supermarket, collect their own blood with a simple finger prick, and mail it to a central laboratory that analyzes the blood sample and returns the test results via email or a smart-phone app.

There’s no obvious limit on how many molecular assays can be done using the microfluidic diagnostics platform, Maerkl adds. “We’re interested in expanding this platform to other types of assays that would detect other biomarkers that people might want to measure — for example, blood ferritin levels in people with anemia,” he says.

Featured image: A MITOMI microfluidic device © Sebastian Maerkl / 2021 EPFL


References: Zoe Swank, Grégoire Michielin, Hon Ming Yip, Patrick Cohen, Diego O. Andrey, Nicolas Vuilleumier, Laurent Kaiser, Isabella Eckerle, Benjamin Meyer, Sebastian J. Maerkl, “A high-throughput microfluidic nanoimmunoassay for detecting anti–SARS-CoV-2 antibodies in serum or ultralow-volume blood samples”, Proceedings of the National Academy of Sciences May 2021, 118 (18) e2025289118; DOI: 10.1073/pnas.2025289118


Provided by EPFL

Targeted Methods to Control the Spread of COVID-19 (Medicine)

New research analyzes more palatable alternatives to pandemic mandates

At the beginning of the COVID-19 pandemic, intense social distancing and lockdown measures were the primary weapon in the fight against the spread of SARS-CoV-2, but they came with a monumental societal burden. New research from the Center for the Ecology of Infectious Diseases and the College of Public Health at the University of Georgia explores if there could have been a better way.

Published in the journal Proceedings of the Royal Society B, the research analyzes more palatable alternatives to the kind of social distancing mandates that threw a wrench at how businesses, schools and even family gatherings work. The alternatives—widespread testing, contact tracing, quarantines, certification for non-infected people and other public health policy measures—can slow the spread when combined together, but only with significant investments and broad public compliance.

“I understand why government leaders quickly enacted strict social distancing mandates as the COVID-19 pandemic was rapidly spreading in 2020,” said lead author John Drake, director of the Center for the Ecology of Infectious Diseases and Distinguished Research Professor in the Odum School of Ecology. “This was the best that we could do at the time. However, school and workplace closures, gathering limits and shelter-in-place orders have had extreme economic consequences. These are harsh, and we really need to find alternative solutions.”

Drake worked with other researchers to develop two models. One targeted how to find infected people to limit transmission through active case finding (through testing of at-risk individuals), thorough contact tracing when cases arise, and quarantines for people infected and their traced contacts.

The second model focused on a strategy of limiting exposure by certifying healthy individuals.

“Each model was tested independently and in combination with general non-pharmaceutical interventions (NPIs),” said co-author Kyle Dahlin, a postdoctoral associate with the center.

Kyle Dahlin

For this study, those interventions were defined as behavioral or generalized interventions that can be broadly adopted, such as wearing a face mask, hand washing, enhanced sick leave, micro distancing and contactless transactions.

“When we ran the model to evaluate the effectiveness of only using social distancing measures, like workplace closures, after the onset of the first wave, approximately half of the population eventually became infected,” said study co-author Andreas Handel, associate professor of biostatistics and epidemiology in UGA’s College of Public Health who helped design the models.  “When we combined social distancing with general interventions, SARS-CoV-2 transmission was slowed, but not enough for complete suppression.”

When they tested the model that actively looked for infection, they found that active case-finding had to identify approximately 95% of infected persons to stop viral spread. When combined with NPIs, like face masks, the fraction of active cases that needed to be located dropped to 80%. Considering that during the first wave of the pandemic in 2020, only 1% to 10% of positive cases were found, such an approach by itself wouldn’t work.

The researchers also determined that adding contact tracing and quarantine to active case finding and general NPIs did not drastically change the model’s success.

The model that targeted healthy people to limit exposure determined that to successfully control viral spread, SARS-CoV-2 test validity had to occur within a very narrow window of seven to 10 days with a waiting time of three days or less, and NPIs had to be strictly adopted. Otherwise, a large outbreak would occur.

Pej Rohani, Regents’ and Georgia Athletic Association Professor of Ecology and Infectious Diseases in the Odum School and College of Veterinary Medicine, said that the models’ conclusions indicated the need for continued research.

“These models are important because infectious disease ecologists and epidemiologists need to understand how SARS-CoV-2 transmission can be reduced using measures that do not have extreme societal consequences,” he said.

The CEID’s research highlighted the importance of a robust and widespread testing program, the general adoption of NPIs like face masks, and targeted measures to globally control the ongoing pandemic. These approaches are still extremely important as vaccines continue to be distributed.

This research was funded by the National Institutes of Health under Award Numbers U01GM110744 and R01GM123007 and R01 GM 12480-03S1.

Featured image: John Drake in the Ecology Auditorium at UGA. (Photo by Andrew Davis Tucker)


Reference: John M. Drake, Kyle Dahlin et al., “Five approaches to the suppression of SARS-CoV-2 without intensive social distancing”, Proceedings of the Royal Society B, 2021. https://doi.org/10.1098/rspb.2020.3074


Provided by UGA Today

Africa’s Oldest Human Burial Site Uncovered (Paleontology)

The discovery of the earliest human burial site yet found in Africa, by an international team including several CNRS researchers1, has just been announced in the journal Nature. At Panga ya Saidi, in Kenya, north of Mombasa, the body of a three-year-old, dubbed Mtoto (Swahili for ‘child’) by the researchers, was deposited and buried in an excavated pit approximately 78,000 years ago. Through analysis of sediments and the arrangement of the bones, the research team showed that the body had been protected by being wrapped in a shroud made of perishable material, and that the head had likely rested on an object also of perishable material. Though there are no signs of offerings or ochre, both common at more recent burial sites, the funerary treatment given Mtoto suggests a complex ritual that likely required the active participation of many members of the child’s community. Though Mtoto was a Homo sapiens, the child’s dental morphology, in contrast with that observed in human remains of the same period, preserves certain archaic traits connecting it to distant African ancestors. This apparently confirms that, as has often been posited in recent years, our species has extremely old and regionally diverse roots in the African continent where it arose.

For more information :

A documentary on the work of the French team at Panga ya Saidi in English, French, and Italian can be viewed at: https://youtu.be/_lYQ3P9X8tU (English version)

The Université de Bordeaux organizing a digital film debate on Friday, May 7.

Featured Photo by Panga Ya Saidi. Karst system located 50 kilometers north of Mombasa in Kenya (top); 3D reconstruction of the arrangement of the child’s remains (center), artistic reconstruction of the burial (down).
© Mohammad Javad Shoaee / Jorge González / Elena Santos / F. Fuego / MaxPlanck Institute / CENIEH.


Bibliography

Earliest human burial in Africa. María Martinón-Torres, Francesco d’Errico, Elena Santos, Ana Álvaro Gallo, Noel Amano, William Archer, Simon J. Armitage, Juan Luis Arsuaga, José María Bermúdez de Castro, James Blinkhorn, Alison Crowther, Katerina Douka, Stéphan Dubernet, Patrick Faulkner, Pilar Fernández-Colón, Nikos Kourampas, Jorge González García, David Larreina, François-Xavier Le Bourdonnec, George MacLeod, Laura Martín-Francés, Diyendo Massilani, Julio Mercader, Jennifer M. Miller, Emmanuel Ndiema, Belén Notario, Africa Pitarch Martí, Mary E. Prendergast, Alain Queffelec, Solange Rigaud, Patrick Roberts, Mohammad Javad Shoaee, Ceri Shipton, Ian Simpson, Nicole Boivin and Michael D. Petraglia. Nature, may 5 2021. DOI : 10.1038/s41586-021-03457-8.


Provided by CNRS

CHOP Researchers Discover New Disease That Prevents Formation Of Antibodies (Medicine)

CHOP team treated patient with the condition, known as PU.MA, thanks to a bone marrow donation from the patient’s older brother

When Luke Terrio was about seven months old, his mother began to realize something was off. He had constant ear infections, developed red spots on his face, and was tired all the time. His development stagnated, and the antibiotics given to treat his frequent infections stopped working. His primary care doctor at Children’s Hospital of Philadelphia (CHOP) ordered a series of blood tests and quickly realized something was wrong: Luke had no antibodies.

At first, the CHOP specialists treating Luke thought he might have X-linked agammaglobulinemia (XLA), a rare immunodeficiency syndrome seen in children. However, as the CHOP research team continued investigating Luke’s case, they realized Luke’s condition was unlike any disease described before.

Using whole exome sequencing to scan Luke’s DNA, CHOP researchers discovered the genetic mutation responsible for his condition, which prevents Luke and patients like him from making B cells and antibodies to fight infections. The study describing Luke’s condition, which CHOP researchers named PU.1 Mutated agammaglobulinemia (PU.MA), was published today in the Journal of Experimental Medicine.

“It can be pretty scary for a family whose child has a mysterious illness” said Neil D. Romberg, MD, an attending physician with the Division of Allergy and Immunology at CHOP and senior author of the paper. “In this case, science provided an explanation, thanks to numerous departments at CHOP, including the Roberts Individualized Medical Genetics Center, the Center for Spatial and Functional Genomics, and the Cancer Center. Understanding the cause of Luke’s condition absolutely helped us know what direction to take his therapy.”

“I was so impressed with how all of the specialists at CHOP worked together as a team, even though they specialized in different areas,” said Luke’s mother, Michelle. “They knew something was wrong with Luke, and they didn’t stop digging until they figured it out.”

Figuring Out the “Why”

To pinpoint the gene at fault, CHOP researchers compared whole exome sequences from 30 patients across the globe who were born without B lymphocytes, the cells which produce antibodies. From the larger group, they identified six patients, including Luke, who had a mutation in a gene called SPI1, which encodes the PU.1 protein. PU.1 helps B lymphocytes developing in bone marrow to open up “doors” in their chromatin, a type of tightly packed DNA. Without PU.1, those door remains shut, and the B cells never form. The six PU.MA patients, who ranged in age from 15 months to 37 years, each had different SPI1 mutations but shared insufficient levels of PU.1, absent B cells and, consequently, zero antibodies.

To validate the roles of SPI1 and PU.1, the researchers used CRISPR to reconstitute the condition in vitro. Using donated cord blood of patients who lacked SPI1 mutations, the researchers employed CRISPR to edit the patients’ SPI1 mutations into the donated cord blood genes. After culturing the cells for six weeks and sequencing the cells that survived, they found B cells were specifically intolerant of PU.1 changes.

Treatment Without a Playbook

Because Luke’s condition was entirely new, there was no playbook for his family or his medical team to follow. After consulting with the research team, the family decided to proceed with a bone marrow transplant in the hope that the procedure would help him make his own B cells and antibodies. Soon they discovered they had a perfect match living under their own roof: Luke’s older brother, Jack.

At three and a half years of age, Jack, who has high-functioning autism, donated his bone marrow to Luke. The transplant was successful at getting Luke to produce his own B cells. Until those B cells are able to create enough protective antibodies by themselves, Luke continues to receive infection protection from the antibody infusions he receives every two weeks.

“We call them his ninjas,” said Michelle describing antibodies. “We tell him that he doesn’t make his own ninjas, so he needs these ninja infusions to fight the germs and keep him safe.”

Thanks to those “ninjas” and his brother’s gift of bone marrow, Luke is now an energetic 4-year-old boy who loves Transformers, fire trucks, and his balance bike. Before his bone marrow transplant and the infusions, he needed naproxen twice a day for his joint pain, required leg braces to straighten his legs, and would lie on the floor exhausted tire after 10 minutes of activity. Now, he always seems to be running, often with his dog Charlie chasing behind him.

“Knowing the source of the problem removed the boogeyman for the Terrios and allowed them to move their lives forward,” Romberg said. “Figuring out Luke’s case not only helped guide his therapy and gave answers to others suffering with this rare condition – in some cases for years – but also opens the door to learning more about the effects of PU.1 on a variety of more common human diseases and conditions.”

Featured image: Luke at 15 months with Dr. Neil Romberg © CHOP


Reference: Le Coz et al. “Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients,” Journal of Experimental Medicine, online May 5, 2021, DOI: 10.1084/jem.20201750


Provided by CHOP

Tracking Down the Tiniest of Forces: How T Cells Detect Invaders (Medicine)

T cells use their antigen receptors like sticky fingers – a team from TU Wien and MedUni Vienna was able to observe them doing so.

T-cells play a central role in our immune system: by means of their so-called T-cell receptors (TCR) they make out dangerous invaders or cancer cells in the body and then trigger an immune reaction. On a molecular level, this recognition process is still not sufficiently understood.

Intriguing observations have now been made by an interdisciplinary Viennese team of immunologists, biochemists and biophysicists. In a joint project funded by the Vienna Science and Technology Fund and the FWF, they investigated which mechanical processes take place when an antigen is recognized: As T cells move their TCRs pull on the antigen with a tiny force – about five pico-newtons (5 x 10-12 or 0.0000000005 newtons). This is not only sufficient to break the bonds between the TCRs and the antigen, it also helps T cells to find out whether they are interacting indeed with the antigen they are looking for. These results have now been published in the scientific journal “Nature Communications”.

Tailor-made for a specific antigen

“Each T cell recognizes one specific antigen particularly well,” explains Johannes Huppa, biochemist and immunology professor at MedUni Vienna. “To do so, it features around 100,000 TCRs of the same kind on its surface.”

When viruses attack our body, infected cells present various fragments of viral proteins on their surface. T cells examine such cells for the presence of such antigens. “This works according to the lock-and-key principle,” explains Johannes Huppa. “For each antigen, the body must produce T cells with matching TCRs. Put simply, each T-cell recognizes only one specific antigen to then subsequently trigger an immune response.”

That particular antigen, or more precisely, any antigenic protein fragment presented that exactly matches the T cell’s TCR, can form a somewhat stable bond. The question that needs to be answered by the T cell is: how stable is the binding between antigen and receptor?

Like a finger on the sticky surface

“Let’s say we wish to find out whether a surface is sticky – we then test how stable the bond is between the surface and our finger,” says Gerhard Schütz, Professor of Biophysics at TU Wien. “We touch the surface and pull the finger away until it comes off. That’s a good strategy because this pull-away behavior quickly and easily provides us information about the attractive force between the finger and the surface.”

In principle, T-cells do exactly the same. T cells are not static, they deform continuously and their cell membrane is in constant motion. When a TCR binds to an antigen, the cell exerts a steadily increasing pulling force until the binding eventually breaks. This can provide information about whether it is the antigen that the cell is looking for.

A nano-spring for force measurement

“This process can actually be measured, even at the level of individual molecules,” says Dr. Janett Göhring, who was active as coordinator and first author of the study at both MedUni Vienna and TU Vienna. “A special protein was used for this, which behaves almost like a perfect nano-spring, explain the two other first authors Florian Kellner and Dr. Lukas Schrangl from MedUni Vienna and TU Vienna respectively: “The more traction is exerted on the protein, the longer it becomes. With special fluorescent marker molecules, you can measure how much the length of the protein has changed, and that provides information about the forces that occur”. In this way, the group was able to show that T cells typically exert a force of up to 5 pico-newtons – a tiny force that can nevertheless separate the receptor from the antigen. By comparison, one would have to pull on more than 100 million such springs simultaneously to feel stickiness with a finger.

“Understanding the behavior of T cells at the molecular level would be a huge leap forward for medicine. We are still leagues away from that goal,” says Johannes Huppa. “But”, adds Gerhard Schütz, “we were able to show that not only chemical but also mechanical effects play a role. They have to be considered together.”

Featured image: The T cell (yellow) touches the antigen-presenting cell. Tiny forces are applied on the surface, eventually the connection breaks. © Tu Wein


Original publication

J. Göhring et al., Temporal analysis of T-cell receptor-imposed forces via quantitative single molecule FRET measurements, Nature Communications 12, 2502 (2021)


Provided by Tu Wein

Mysterious Hydrogen-free Supernova Sheds Light On Stars Violent Death Throes (Planetary Science)

A curiously yellow pre-supernova star has caused astrophysicists to re-evaluate what’s possible at the deaths of our Universe’s most massive stars. The team describe the peculiar star and its resulting supernova in a new study published today in Monthly Notices of the Royal Astronomical Society.

At the end of their lives, cool, yellow stars are typically shrouded in hydrogen, which conceals the star’s hot, blue interior. But this yellow star, located 35 million light years from Earth in the Virgo galaxy cluster, was mysteriously lacking this crucial hydrogen layer at the time of its explosion.

“We haven’t seen this scenario before,” said Charles Kilpatrick, postdoctoral fellow at Northwestern University’s Center for Interdisciplinary Exploration and Research in Astrophysics (CIERA), who led the study. “If a star explodes without hydrogen, it should be extremely blue — really, really hot. It’s almost impossible for a star to be this cool without having hydrogen in its outer layer. We looked at every single stellar model that could explain a star like this, and every single model requires that the star had hydrogen, which, from its supernova, we know it did not. It stretches what’s physically possible.”

Kilpatrick is also a member of the Young Supernova Experiment, which uses the Pan-STARRS telescope at Haleakalā, Hawaii to catch supernovae right after they explode. After the Young Supernova Experiment spotted supernova 2019yvr in the relatively nearby spiral galaxy NGC 4666, the team used deep space images captured by NASA’s Hubble Space Telescope, which fortunately already observed this section of the sky two and a half years before the star exploded.

“What massive stars do right before they explode is a big unsolved mystery,” Kilpatrick said. “It’s rare to see this kind of star right before it explodes into a supernova.”

The Hubble images show the source of the supernova, a massive star imaged just a couple of years before the explosion. Several months after the explosion however, Kilpatrick and his team discovered that the material ejected in the star’s final explosion seemed to collide with a large mass of hydrogen. This led the team to hypothesize that the progenitor star might have expelled the hydrogen within a few years before its death.

Hubble Space Telescope (HST) imaging showing the explosion site of 2019yvr from 2.5 years before its explosion. Upper left: the supernova itself is seen in an image from the Gemini-South telescope 72 days after it exploded. Lower left: a zoom in to the same site in the pre-explosion HST image, showing a single source that appears to be the progenitor star of 2019yvr. Charles Kilpatrick / Northwestern University

“Astronomers have suspected that stars undergo violent eruptions or death throes in the years before we see supernovae,” Kilpatrick said. “This star’s discovery provides some of the most direct evidence ever found that stars experience catastrophic eruptions, which cause them to lose mass before an explosion. If the star was having these eruptions, then it likely expelled its hydrogen several decades before it exploded.”

In the new study, Kilpatrick’s team also presents another possibility: a less massive companion star might have stripped away hydrogen from the supernova’s progenitor star. However, the team will not be able to search for the companion star until after the supernova’s brightness fades, which could take up to a decade.

“Unlike its normal behaviour right after it exploded, the hydrogen interaction revealed it’s kind of this oddball supernova,” Kilpatrick said. “But it’s exceptional that we were able to find its progenitor star in Hubble data. In four or five years, I think we will be able to learn more about what happened.”

The study was supported by NASA (award numbers GO-15691 and AR-16136), the National Science Foundation (award numbers AST-1909796, AST-1944985), the Canadian Institute for Advanced Research, the VILLUM Foundation, and the Australian Research Council Centre of Excellence. In addition to the Hubble Space Telescope, the researchers used instruments at the Gemini Observatory, Keck Observatory, Las Cumbres Observatory, Spitzer Space Telescope and the Swope Telescope.

Featured image: Artist’s impression of a yellow supergiant in a close binary with a blue, main sequence companion star.CreditKavli IPMU / Aya Tsuboi


Reference: Charles D Kilpatrick, Maria R Drout, Katie Auchettl, Georgios Dimitriadis, Ryan J Foley, David O Jones, Lindsay DeMarchi, K Decker French, Christa Gall, Jens Hjorth, Wynn V Jacobson-Galán, Raffaella Margutti, Anthony L Piro, Enrico Ramirez-Ruiz, Armin Rest, César Rojas-Bravo, A cool and inflated progenitor candidate for the Type Ib supernova 2019yvr at 2.6 yr before explosion, Monthly Notices of the Royal Astronomical Society, Volume 504, Issue 2, June 2021, Pages 2073–2093, https://doi.org/10.1093/mnras/stab838


Provided by Royal Astronomical Society