The study from researchers at the USC Dornsife College of Letters, Arts and Sciences was published in the journal Development on Dec. 22.

A little background

• All cells within the body begin as stem cells.
• In simplest terms, blood forms when stem cells in bone marrow develop along one of three paths to become either oxygen-carrying red cells, immune-system white cells, or platelets, which clot to stop bleeding.
• Scientists have long accepted that communication between cells can affect their fate, but they have largely found it too complex to study directly.
• Cells can communicate by sending growth factors, hormones or other molecules back and forth.

What’s new

• USC Dornsife’s Adam MacLean, assistant professor of quantitative and computational biology, and doctoral candidate Megan Rommelfanger, found a way to better understand how cell-to-cell communication affects the way blood stem cells develop.
• The scientists discovered that the communication process can change the formation of blood cell types dramatically.
• They also found that distance between cells matters.

“We discovered that the communication process can change the formation of blood cell types dramatically, and that cells that are closer to one another have a greater influence on each other’s fate,” MacLean said.

A controversy resolved

Researchers trying to determine what early factors nudge a cell down one developmental path or another have wondered if random fluctuations within the cell are enough to decide which path is taken. Many models have suggested they were, but recent breakthrough studies showed that random fluctuations were not enough, that something else drives cells toward their fate.

The model MacLean and Rommelfanger have developed appears to put an end to the controversy altogether. They show that cell-to-cell communication can, in fact, be the deciding factor that sets cells along a certain path.

• While focusing on understanding stem cells, the research can help scientists understand how cancer arises.
• Leukemias, for example, develop when certain white blood cells begin growing and accumulating out of control.
• Determining the factors that push cells down the path to cancer can open avenues for prevention and therapy.

“By understanding how blood cell fate decisions are made,” MacLean said, “we get closer to being able to identify leukemia cells of origin, and in theory we can design strategies to control or alter cell fate decision-making and stop the development of cancer.”

The research could help improve cancer therapies such as bone marrow transplant.

• Bone marrow transplant involves infusing marrow — and the stem cells within — from a healthy donor into leukemia and lymphoma patients whose cancer and marrow has been obliterated by chemotherapy and radiation.
• Despite its success, scientists and clinicians still aren’t fully sure how BMT works.

“Better understanding stem cell fate decisions, as our study provides, could provide new insight to improve clinical outcomes for these diseases,” MacLean said.

This new model has important implications beyond the blood system.

“Our model is broadly applicable, so researchers working on other cell types can apply it to find out for those other cells how important cell-to-cell communication may be,” said MacLean.

What’s next

The role of cell-to-cell communication in determining cell fate is in its nascent stages, says MacLean, but further experiments — and future technologies to integrate these new types of data with sophisticated models — should help expand understanding.

In addition, the team is developing methods to study the regulation of key genes involved in cell fate decisions, which should further advance their overall theoretical model.

About the study

This work was supported by National Science Foundation grant DMS 2045327 and a USC Women in Science and Engineering Top-up Fellowship.

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Evelien Bunnik, PhD, corresponding author of the paper, said the results hint of subtle differences in the quality of immune response based on COVID-19 severity. Dr. Bunnik is an assistant professor of microbiology, immunology and molecular genetics at the health science center, also referred to as UT Health San Antonio.

The study focused on memory B cells that react against the SARS-CoV-2 spike protein. Blood samples were analyzed one month after symptom onset and five months post-onset. After one month, a significant proportion of spike-specific B cells were active.

However, samples from eight individuals who recovered from less-severe disease showed increased expression of markers associated with durable B cell memory as compared to individuals who recovered from severe disease, the authors wrote. The markers include T-bet and FcRL5.

T-bet-positive, spike-specific B cells nearly disappeared from the blood samples five months post-symptom onset, the authors noted. Overall, a more dysfunctional B cell response is seen in severe disease cases, they wrote.

Non-severe cases were defined as not requiring supplemental oxygen or invasive ventilation, while severe cases needed invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO). “The definition of severe disease was made based on the need for mechanical ventilation or ECMO, because this distinguishes the most critical patients, who are the most likely to develop impaired immune responses,” said study senior author Thomas Patterson, MD, professor and chief of infectious diseases at UT Health San Antonio who leads COVID-19 care at clinical partner University Health.

Study participants were enrolled in the Adaptive COVID-19 Treatment Trial (ACTT)-1 or ACTT-2 clinical trials. Samples were from University Health patients co-enrolled in the UT Health San Antonio COVID-19 Repository.

“The increased percentage of B cells associated with long-lived immunity in non-severe COVID-19 patients may have consequences for long-term immunity against SARS-CoV-2 re-infection or severity of the resulting disease,” the authors wrote.

Acknowledgments

This work was supported by a COVID-19 pilot award from the UT Health San Antonio Joe R. and Teresa Lozano Long School of Medicine (10009547 to Dr. Evelien Bunnik). Raphael A. Reyes was supported by Translational Science Training award TL1 TR002647. Data were generated in the Flow Cytometry Shared Resource Facility, which is supported by UT Health San Antonio, NIH-NCI P30 CA054174-20 (Mays Cancer Center, home to UT Health San Antonio MD Anderson) and UL1 TR001120 (Clinical Translational Science Award grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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The study was led by David Ho, MD, director of the Aaron Diamond AIDS Research Center and the Clyde’56 and Helen Wu Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons. The findings were published in Nature.

A striking feature of the omicron variant is the alarming number of changes in the virus’s spike protein that could pose a threat to the effectiveness of current vaccines and therapeutic antibodies.

Large drop in omicron neutralization by antibodies from vaccines

The new study tested the ability of antibodies generated by vaccination to neutralize the omicron variant in laboratory assays that pitted antibodies against live viruses and against pseudoviruses constructed in the lab to mimic omicron.

Antibodies from people double-vaccinated with any of the four most widely used vaccines — Moderna, Pfizer, AstraZeneca, Johnson & Johnson — were significantly less effective at neutralizing the omicron variant compared to the ancestral virus. Antibodies from previously infected individuals were even less likely to neutralize omicron.

Individuals who received a booster shot of either of the two mRNA vaccines are likely to be better protected, although even their antibodies exhibited diminished neutralizing activity against omicron.

“The new results suggest that previously infected individuals and fully vaccinated individuals are at risk for infection with the omicron variant,” says Ho. “Even a third booster shot may not adequately protect against omicron infection, but of course it is advisable to get one, as you’ll still benefit from some immunity.”

The results are consistent with other neutralization studies, as well as early epidemiological data from South Africa and the U.K., which show efficacy of two doses of the vaccines against symptomatic disease is significantly reduced against the omicron variant.

Most monoclonal antibodies are unable to neutralize omicron

When administered early in the course of infection, monoclonal antibodies can prevent many individuals from developing severe COVID. But the new study suggests that all of the therapies currently in use and most in development are much less effective against omicron, if they work at all.

In neutralization studies with monoclonal antibodies, only one (Brii198 approved in China) maintained notable activity against omicron. A minor form of omicron is completely resistant to all antibodies in clinical use today. The authors note that omicron is now the most complete “escapee” from neutralization that scientists have seen.

In this study Ho’s lab also identified four new spike mutations in omicron that help the virus evade antibodies. This information should inform the design of new approaches to combat the new variant.

Future directions

Ho suggests that scientists will need to develop vaccines and treatments that can better anticipate how the virus is evolving.

It is not too far-fetched to think that SARS-CoV-2 is now only a mutation or two away from being completely resistant to current antibodies, either the monoclonal antibodies used as therapies or the antibodies generated by vaccination or infection with previous variants,” says Ho.

More information

The paper is titled “Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization.”

The full list of contributors is available in the online version of the paper.

David Ho and some of his colleagues are inventors of certain monoclonal antibodies described in the paper.

Periodontal disease affects nearly half of Americans over age 30, and 70% of those 65 and older. It is a bacterial infection of the tissues supporting the teeth. In its early stages, periodontal disease causes redness and swelling (inflammation) of the gums. In advanced stages, called periodontitis, the underlying bone becomes damaged, leading to tooth loss. While scientists have known that periodontitis is driven in part by an exaggerated immune cell response, until now, it was unclear what triggered the response, and how it caused tissue and bone damage.

“Severe periodontal disease can lead to tooth loss and remains a barrier to productivity and quality of life for far too many Americans, especially those lacking adequate access to dental care,” said NIDCR Director Rena D’Souza, D.D.S., Ph.D. “By providing the most comprehensive picture yet of the underlying mechanisms of periodontal disease, this study brings us closer to more effective methods for prevention and treatment.”

At sites of injury or inflammation, fibrin normally plays a protective role, helping to form blood clots and activating immune cells to fight infection. But too much fibrin has been linked with health problems, including a rare form of periodontitis due to a condition called plasminogen (PLG) deficiency. In affected people, mutations in the PLG gene lead to fibrin buildup and disease at various body sites, including the mouth.

To explore the connection between abnormal fibrin buildup and periodontitis, the scientists, led by NIDCR investigators Niki Moutsopoulos, D.D.S., Ph.D., and Thomas Bugge, Ph.D., studied PLG deficiency in mice and analyzed human genetic data.

Like humans with the condition, PLG-deficient mice developed periodontitis, including periodontal bone loss and elevated levels of fibrin in the gums. The mice’s gums were crowded with immune cells called neutrophils, which are also found at high levels in common forms of periodontitis.

Neutrophils typically defend the oral cavity from harmful microbes. But an excessive neutrophil response is thought to cause tissue damage.

To find out if fibrin was driving this overactive response, the researchers impaired its ability to interact with (bind to) protein receptors on neutrophils. The weakened binding between fibrin and neutrophils completely prevented periodontal bone loss in PLG-deficient mice. Strikingly, it also reduced bone loss in normal mice with a common, age-related form of periodontitis, suggesting that similar mechanisms were at play in both forms of the disease.

“This study suggests that fibrin can cause neutrophil immunity to shift from protective to damaging in certain circumstances,” said Moutsopoulos, who credited postdoctoral fellow and study first author Lakmali Silva, Ph.D., for her research that led to the findings. “This fibrin-neutrophil engagement may be a driver of periodontitis.”

A genetic analysis of over 1,000 people seemed to support the animal findings. Even in the absence of PLG deficiency, variations in the PLG gene were linked to an increased risk of severe periodontitis, consistent with the idea that similar processes contribute to rare and common forms of the disease.

Taken together, the study suggests that excessive buildup of fibrin in the gums — whether due to changes in genes like PLG, chronic inflammation from a bacterial infection, or some combination of the two — triggers an elevated and ultimately harmful neutrophil response that causes periodontal disease.

The results are also in line with findings from other research teams, which have found that elevated fibrin may contribute to other inflammatory and autoimmune diseases such as arthritis and multiple sclerosis, and that interfering with fibrin activity could help treat these conditions.

“Our data support the idea that targeting the fibrin-neutrophil interaction could be a promising treatment avenue to explore in both rare and common forms of periodontitis,” added Silva.

This research was supported by the NIDCR Division of Intramural Research. Support also came from the intramural programs of the National Institute on Deafness and Other Communication and the National Institute of Allergy and Infectious Diseases, the extramural programs of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Cancer Institute, the National Heart, Lung, and Blood Institute, and the National Fund for Scientific and Technological Development, Chile.

The researchers, from the University of Cambridge, used an organic molecule as a ‘template’ to guide perovskite films into the desired phase as they form. Their results are reported in the journal Science.

Perovskite materials offer a cheaper alternative to silicon for producing optoelectronic devices such as solar cells and LEDs.

There are many different perovskites, resulting from different combinations of elements, but one of the most promising to emerge in recent years is the formamidinium (FA)-based FAPbI₃ crystal.

The compound is thermally stable and its inherent ‘bandgap’ — the property most closely linked to the energy output of the device — is not far off ideal for photovoltaic applications.

For these reasons, it has been the focus of efforts to develop commercially available perovskite solar cells. However, the compound can exist in two slightly different phases, with one phase leading to excellent photovoltaic performance, and the other resulting in very little energy output.

“A big problem with FAPbI₃ is that the phase that you want is only stable at temperatures above 150 degrees Celsius,” said co-author Tiarnan Doherty from Cambridge’s Cavendish Laboratory. “At room temperature, it transitions into another phase, which is really bad for photovoltaics.”

Recent solutions to keep the material in its desired phase at lower temperatures have involved adding different positive and negative ions into the compound.

“That’s been successful and has led to record photovoltaic devices but there are still local power losses that occur,” said Doherty. “You end up with local regions in the film that aren’t in the right phase.”

Little was known about why the additions of these ions improved stability overall, or even what the resulting perovskite structure looked like.

“There was this common consensus that when people stabilise these materials, they’re an ideal cubic structure,” said Doherty. “But what we’ve shown is that by adding all these other things, they’re not cubic at all, they’re very slightly distorted. There’s a very subtle structural distortion that gives some inherent stability at room temperature.”

The distortion is so minor that it had previously gone undetected, until Doherty and colleagues used sensitive structural measurement techniques that have not been widely used on perovskite materials.

The team used scanning electron diffraction, nano-X-ray diffraction and nuclear magnetic resonance to see, for the first time, what this stable phase really looked like.

“Once we figured out that it was the slight structural distortion giving this stability, we looked for ways to achieve this in the film preparation without adding any other elements into the mix.”

Co-author Satyawan Nagane used an organic molecule called Ethylenediaminetetraacetic acid (EDTA) as an additive in the perovskite precursor solution, which acts as a templating agent, guiding the perovskite into the desired phase as it forms. The EDTA binds to the FAPbI₃ surface to give a structure-directing effect, but does not incorporate into the FAPbI₃ structure itself.

“With this method, we can achieve that desired band gap because we’re not adding anything extra into the material, it’s just a template to guide the formation of a film with the distorted structure — and the resulting film is extremely stable,” said Nagane.

“In this way, you can create this slightly distorted structure in just the pristine FAPbI₃ compound, without modifying the other electronic properties of what is essentially a near-perfect compound for perovskite photovoltaics,” said co-author Dominik Kubicki from the Cavendish Laboratory, who is now based at the University of Warwick.

The researchers hope this fundamental study will help improve perovskite stability and performance. Their own future work will involve integrating this approach into prototype devices to explore how this technique may help them achieve the perfect perovskite photovoltaic cells.

“These findings change our optimisation strategy and manufacturing guidelines for these materials,” said senior author Dr Sam Stranks from Cambridge’s Department of Chemical Engineering & Biotechnology. “Even small pockets that aren’t slightly distorted will lead to performance losses, and so manufacturing lines will need to have very precise control of how and where the different components and ‘distorting’ additives are deposited. This will ensure the small distortion is uniform everywhere — with no exceptions.”

The work was a collaboration with the Diamond Light Source and the electron Physical Science Imaging Centre (ePSIC), Imperial College London, Yonsei University, Wageningen University and Research, and the University of Leeds.

While dinosaurs ruled the land, ichthyosaurs and other aquatic reptiles (that were emphatically not dinosaurs) ruled the waves, reaching similarly gargantuan sizes and species diversity. Evolving fins and hydrodynamic body-shapes seen in both fish and whales, ichthyosaurs swam the ancient oceans for nearly the entirety of the Age of Dinosaurs.

“Ichthyosaurs derive from an as yet unknown group of land-living reptiles and were air-breathing themselves,” says lead author Dr. Martin Sander, paleontologist at the University of Bonn and Research Associate with the Dinosaur Institute at the Natural History Museum of Los Angeles County (NHM). “From the first skeleton discoveries in southern England and Germany over 250 years ago, these ‘fish-saurians’ were among the first large fossil reptiles known to science, long before the dinosaurs, and they have captured the popular imagination ever since.”

Excavated from a rock unit called the Fossil Hill Member in the Augusta Mountains of Nevada, the well-preserved skull, along with part of the backbone, shoulder, and forefin, date back to the Middle Triassic (247.2-237 million years ago), representing the earliest case of an ichthyosaur reaching epic proportions. As big as a large sperm whale at more than 17 meters (55.78 feet) long, the newly named Cymbospondylus youngorum is the largest animal yet discovered from that time period, on land or in the sea. In fact, it was the first giant creature to ever inhabit the Earth that we know of.

“The importance of the find was not immediately apparent,” notes Dr. Sander, “because only a few vertebrae were exposed on the side of the canyon. However, the anatomy of the vertebrae suggested that the front end of the animal might still be hidden in the rocks. Then, one cold September day in 2011, the crew needed a warm-up and tested this suggestion by excavation, finding the skull, forelimbs, and chest region.”

The new name for the species, C. youngorum, honors a happy coincidence, the sponsoring of the fieldwork by Great Basin Brewery of Reno, owned and operated by Tom and Bonda Young, the inventors of the locally famous Icky beer which features an ichthyosaur on its label.

In other mountain ranges of Nevada, paleontologists have been recovering fossils from the Fossil Hill Member’s limestone, shale, and siltstone since 1902, opening a window into the Triassic. The mountains connect our present to ancient oceans and have produced many species of ammonites, shelled ancestors of modern cephalopods like cuttlefish and octopuses, as well as marine reptiles. All these animal specimens are collectively known as the Fossil Hill Fauna, representing many of C. youngorum‘s prey and competitors.

C. youngorum stalked the oceans some 246 million years ago, or only about three million years after the first ichthyosaurs got their fins wet, an amazingly short time to get this big. The elongated snout and conical teeth suggest that C. youngorum preyed on squid and fish, but its size meant that it could have hunted smaller and juvenile marine reptiles as well.

The giant predator probably had some hefty competition. Through sophisticated computational modeling, the authors examined the likely energy running through the Fossil Hill Fauna’s food web, recreating the ancient environment through data, finding that marine food webs were able to support a few more colossal meat-eating ichthyosaurs. Ichthyosaurs of different sizes and survival strategies proliferated, comparable to modern cetaceans’ — from relatively small dolphins to massive filter-feeding baleen whales, and giant squid-hunting sperm whales.

Co-author and ecological modeler Dr. Eva Maria Griebeler from the University of Mainz in Germany notes, “due to their large size and resulting energy demands, the densities of the largest ichthyosaurs from the Fossil Hill Fauna including C. youngourum must have been substantially lower than suggested by our field census. The ecological functioning of this food web from ecological modeling was very exciting as modern highly productive primary producers were absent in Mesozoic food webs and were an important driver in the size evolution of whales.”

Whales and ichthyosaurs share more than a size range. They have similar body plans, and both initially arose after mass extinctions. These similarities make them scientifically valuable for comparative study. The authors combined computer modeling and traditional paleontology to study how these marine animals reached record-setting sizes independently.

“One rather unique aspect of this project is the integrative nature of our approach. We first had to describe the anatomy of the giant skull in detail and determine how this animal is related to other ichthyosaurs,” says senior author Dr. Lars Schmitz, Associate Professor of Biology at Scripps College and Dinosaur Institute Research Associate. “We did not stop there, as we wanted to understand the significance of the new discovery in the context of the large-scale evolutionary pattern of ichthyosaur and whale body sizes, and how the fossil ecosystem of the Fossil Hill Fauna may have functioned. Both the evolutionary and ecological analyses required a substantial amount of computation, ultimately leading to a confluence of modeling with traditional paleontology.”

They found that while both cetaceans and ichthyosaurs evolved very large body sizes, their respective evolutionary trajectories toward gigantism were different. Ichthyosaurs had an initial boom in size, becoming giants early on in their evolutionary history, while whales took much longer to reach the outer limits of huge. They found a connection between large size and raptorial hunting — think of a sperm whale diving down to hunt giant squid — and a connection between large size and a loss of teeth — think of the giant filter-feeding whales that are the largest animals ever to live on Earth.

Ichthyosaurs’ initial foray into gigantism was likely thanks to the boom in ammonites and jawless eel-like conodonts filling the ecological void following the end-Permian mass extinction. While their evolutionary routes were different, both whales and ichthyosaurs relied on exploiting niches in the food chain to make it really big.

“As researchers, we often talk about similarities between ichthyosaurs and cetaceans, but rarely dive into the details. That’s one way this study stands out, as it allowed us to explore and gain some additional insight into body size evolution within these groups of marine tetrapods,” says NHM’s Associate Curator of Mammalogy (Marine Mammals), Dr. Jorge Velez-Juarbe. “Another interesting aspect is that Cymbospondylus youngorum and the rest of the Fossil Hill Fauna are a testament to the resilience of life in the oceans after the worst mass extinction in Earth’s history. You can say this is the first big splash for tetrapods in the oceans.”

C. youngorum will be permanently housed at the Natural History Museum of Los Angeles County, where it is currently on view.