The default mode network (DMN), which comprises the posterior medial cortex, medial prefrontal cortex, and lateral temporal-parietal regions, has been shown to be engaged in several task-related behaviors. Studies show that DMN activity increases during inward-directed thought and decreases during externally directed tasks requiring focused attention. Despite evidence for a role for the DMN in shaping behavior, little is known about how task-related changes in the DMN influence connectivity with other brain regions. For example, while some observations indicate an indirect relationship between the DMN and the striatum, how the DMN and striatum interact during tasks remains unclear.

To further explore the functions of the DMN, Drs. Dobryakova and Smith applied a novel analysis to the reward task, using behavioral and neuroimaging data from 495 randomly selected individuals in the Human Connectome Project, an open access database of healthy participants. The goals of this network-based psycho-physiological interaction analysis were twofold, according to Dr. Dobryakova, a senior research scientist in the Foundation’s Center for Traumatic Brain Injury Research. “First, to test the effects of reward on connectivity between the DMN and the striatum; and second, whether such connectivity is associated with behavioral and personality characteristics relevant to reward processing,” she explained.

In line with other studies, during the task, they observed decreased activation of the DMN and relative increased activation of other networks. “Most notably, we found that the experience of reward enhanced connectivity between the DMN and the ventral striatum,” Dr. Dobryakova reported, “an effect specific to the DMN. We were also surprised that the strength of this connectivity correlated with personality characteristics relating to openness,” she added.

Greater understanding of the workings of the healthy brain will influence future research and care for individuals with neuropsychiatric syndromes. “Improving our understanding of the interaction of the DMN with other brain networks has the potential to aid clinical research into better treatments for common syndromes such as depression, substance abuse, and schizophrenia,” Dr. Dobryakova concluded.

This research was supported by grants from the National Institutes of Health grants R21-MH113917 (DVS), R03-DA046733 (DVS), RF1-AG067011 (DVS), R01-NS121107 (ED).

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Published in the Cell Press journal iScience, Deep learning models fail to capture the configural nature of human shape perception is a collaborative study by Elder, who holds the York Research Chair in Human and Computer Vision and is Co-Director of York’s Centre for AI & Society, and Assistant Psychology Professor Nicholas Baker at Loyola College in Chicago, a former VISTA postdoctoral fellow at York.

The study employed novel visual stimuli called “Frankensteins” to explore how the human brain and DCNNs process holistic, configural object properties.

“Frankensteins are simply objects that have been taken apart and put back together the wrong way around,” says Elder. “As a result, they have all the right local features, but in the wrong places.”

The investigators found that while the human visual system is confused by Frankensteins, DCNNs are not — revealing an insensitivity to configural object properties.

“Our results explain why deep AI models fail under certain conditions and point to the need to consider tasks beyond object recognition in order to understand visual processing in the brain,” Elder says. “These deep models tend to take ‘shortcuts’ when solving complex recognition tasks. While these shortcuts may work in many cases, they can be dangerous in some of the real-world AI applications we are currently working on with our industry and government partners,” Elder points out.

One such application is traffic video safety systems: “The objects in a busy traffic scene — the vehicles, bicycles and pedestrians — obstruct each other and arrive at the eye of a driver as a jumble of disconnected fragments,” explains Elder. “The brain needs to correctly group those fragments to identify the correct categories and locations of the objects. An AI system for traffic safety monitoring that is only able to perceive the fragments individually will fail at this task, potentially misunderstanding risks to vulnerable road users.”

According to the researchers, modifications to training and architecture aimed at making networks more brain-like did not lead to configural processing, and none of the networks were able to accurately predict trial-by-trial human object judgements. “We speculate that to match human configural sensitivity, networks must be trained to solve broader range of object tasks beyond category recognition,” notes Elder.

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The approach proved more than 90% accurate at predicting outcomes among more than two dozen patients in the intensive care unit at UVA and 100 patients from publicly available data generated at Duke and Harvard. The test, called CovGENE, analyzes genes expressed in a person’s blood to determine whether they may experience a severe disease course with increased risk of death.

“We have come far in the prevention and treatment of COVID-19 in the past two years. Regardless, we still struggle to identify patients at highest risk for severe disease. Our study uses a gene-analysis approach to identify an immune cell signature, distinct from other respiratory illnesses, that correlates with worse outcomes,” said researcher Alexandra Kadl, MD, of UVA Health’s Division of Pulmonary and Critical Care Medicine. “This knowledge has the potential to help evaluate patients’ immune profile with commonly, readily available assays to identify patients at risk for bad outcomes who would benefit from closer monitoring and advanced therapies to aid their recovery.”

Predicting COVID-19 Severity

Based on the promising results of the UVA research, CovGENE’s developer, AMPEL Biosolutions, is seeking to partner with a diagnostic testing company or pharmaceutical company to bring the approach to market as a simple PCR-based blood test.

“This unique collaboration with our colleagues from the University of Virginia has provided an easy and novel means to assess an individual patient’s response to the SARS-CoV-2 virus and predict the clinical outcome,” said Peter Lipsky, MD, AMPEL’s CEO, chief medical officer and co-founder. “Now that this unique approach has been validated, we look forward to its rapid development as a precision-medicine tool that can improve the outcome of patients with COVID-19 and reduce the number of hospitalizations, especially the most vulnerable.”

AMPEL Biosolutions aims to use genomic data to improve healthcare for patients. The company develops gene expression tests for blood or tissue samples to assist doctors in clinical decision-making.

Company co-founder Amrie Grammer, PhD, is an alumna of UVA, having received both her bachelor’s and master’s degree there.

Findings Published

The researchers have published their findings in the journal Frontiers in Immunology. The team consisted of Andrea R. Daamen, Prathyusha Bachali, Catherine A. Bonham, Lindsay Somerville, Jeffrey M. Sturek, Amrie Grammer, Alexandra Kadl and Peter Lipsky. Daamen, Bachali, Grammer and Lipsky are employed by AMPEL BioSolutions.

The work was supported by the National Institutes of Health’s National Heart Lung Blood Institute, grant K23 HL143135; the National Institute of Allergy and Infectious Diseases, grant 1R21AI160334; the COVID-19 Rapid Response Initiative by UVA’s Global Infectious Disease Institute; and The RILITE Foundation.

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Both infection and vaccination against SARS-CoV-2 contribute to building a population’s immunity to the virus — an important factor for deciding when and to whom booster shots should be offered. Although immunity against a pathogen is more than antibodies, the easiest strategy for assessing population immunity is to perform seroepidemiological studies (i.e., quantifying virus-specific antibodies in a given population group).

“Most of the serological studies performed after COVID-19 vaccination focused on specific groups such as healthcare workers, did not distinguish between people with or without previous infection, or did not have clinical and immunological data of the infection,” explains Manolis Kogevinas, ISGlobal researcher and senior co-author of the study together with Carlota Dobaño, also researcher at ISGlobal.

In this study, the research team performed a second measurement in a population-based cohort from Catalonia (COVICAT study — GCAT cohort) six months after the start of the vaccination campaign (the first one was just after the first confinement), to monitor the level and type of antibodies against five viral antigens (the whole Spike (S) protein, the RBD receptor binding domain, the S2 fragment, the full nucleocaspid (N) protein, or the N-terminal fragment). They also used information from a questionnaire and health records to identify potential factors that determine the magnitude and duration of the antibody response in unvaccinated, vaccinated, or vaccinated and infected persons. A total of 1,076 people, aged 43 to 72 years, were included in the analysis.

The results yielded three main conclusions: First, that in 36% of infected but unvaccinated persons, antibodies were no longer detectable almost a year after the infection, particularly in those older than 60 years and smokers.

Second, that vaccination induced significantly higher antibody levels in people who had a prior infection, as compared to those without prior infection; and that these levels were strongly associated with the magnitude of the response during the infection. “Our data underscore the importance of vaccinating people even if they have been previously infected, and confirm that hybrid immunity is superior and more durable. This means that people who have been vaccinated but have not been infected would need a booster earlier than those who have,” points out Marianna Karachaliou, first author of the study together with Gemma Moncunill.

Third, the factor most strongly associated with the level of antibodies is the type of vaccine — Moderna’s Spikevax generated the highest levels of antibodies. Other factors also appear to play a role: people older than 60 or with mental illness had lower antibody levels post-vaccination. “The association between mental health and antibody responses requires further investigation, but it is known that people with disorders such as depression, chronic stress or schizophrenia have a lower response to vaccination in general,” explains Dobaño.

Among those vaccinated, only 2.1% had no antibodies at the time of testing and approximately 1% had a breakthrough infection. “However, it should be noted that this study was done before the Omicron variant became dominant,” warns Kogevinas.

They have just published the results of their study in the journal Frontiers in Bioengineering and Biotechnology. During normal breathing, the diaphragm descends below the lungs with each breath. This causes the lungs to expand inside the chest, creating a negative pressure, or vacuum, in the lungs. To compensate for this negative pressure, air automatically flows into the lungs and the person breathes in. Mechanical ventilation involves pumping air into the lungs through a tube. The lungs then expand due to this positive pressure. “We assume that this positive pressure causes a slight compression of the lung tissue, whereas during normal breathing the lung is ‘pulled’ from the outside in order to create the expansion,” explains physicist Professor Mareike Zink, who conducted the interdisciplinary study on the physics of the premature lung together with her colleague Dr Mandy Laube from the neonatology research laboratory at the Faculty of Medicine.

“In our experiments, we studied foetal lung tissue under tensile and compressive stress to explore differences in tissue mechanics in the premature lung,” Mareike Zink reports. The experiments showed that the lung tissue deformed completely elastically under tension, as occurs during normal breathing. When subjected to pressure, however — as occurs with mechanical ventilation — viscoelastic deformation of the lungs was observed. This means that although the tissue returns to its original state after deformation, at the molecular level, there are already structural changes that indicate irreversible tissue damage.

“Furthermore, our results show that lung cell function is impaired under pressure. Even low pressure, as is common in mechanical ventilation, can result in structural units on the cell surface, which are important in the transport of molecules and water, for example, no longer being able to perform their function,” explains Mandy Laube.

The two scientists draw the following conclusion: for some premature infants, mechanical ventilation is the only treatment to ensure survival. Nevertheless, there is a risk of complications due to the altered mechanical properties of premature lungs compared to adults. Future therapeutic strategies should therefore consider the influence of physical forces on tissues and cells, and limit pressure increases in the lungs so as to minimise the risk of damage. “Since it has also been observed in ventilated Covid-19 patients that mechanical ventilation may result in further lung damage, we postulate that here, too, the damaged lung can be more easily overstretched by the positive pressure and that lung cell function stops or changes more quickly under increased pressure,” Mareike Zink concludes.

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The research team, led by Emory University and funded by the National Institute of Health’s (NIH) Rapid Acceleration of Diagnostics (RADx) Tech program, developed a novel method for evaluating how mutations to SARS-CoV-2 can affect recognition by antibodies used in rapid antigen tests. Because most rapid antigen tests detect the SARS-CoV-2 nucleocapsid protein (N protein), the team directly measured how mutations to the N protein impacted diagnostic antibodies’ ability to recognize their target.

“Based on our findings, none of the major past and present SARS-CoV-2 variants of concern contain mutations that would affect the capability of current rapid antigen tests to detect antibodies,” says first study author Filipp Frank, Ph.D., an assistant professor in the department of biochemistry at Emory University. “Further, these data allow us to look one step ahead and predict test performance against almost any variant that may arise.”

The study used a method called deep mutational scanning to evaluate all possible mutations in the N protein in a single, high-throughput experiment. Researchers then measured the impact of the mutations on their interaction with antibodies used in 11 commercially available rapid antigen tests and identified mutations that may allow for antibody escape.

“Accurate and efficient identification of infected individuals remains a critically important strategy for COVID-19 mitigation, and our study provides information about future SARS-CoV-2 mutations that may interfere with detection,” says senior study author Eric Ortlund, Ph.D., a professor in the department of biochemistry at Emory University. “The results outlined here can allow us to quickly adapt to the virus as new variants continue to emerge, representing an immediate clinical and public health impact.”

Findings show that it’s relatively rare for variants to have mutations to the N protein that allow them to evade diagnostic tests, but there are a small proportion of sequences that could impact detection. Researchers, public health officials, and test manufacturers can use these data to determine if a diagnostic test needs to be evaluated for its ability to detect these mutations or to inform future test design.

“Considering the endless cycle of new variants, the data from this study will be useful for years to come,” says Bruce J. Tromberg, Ph.D., director of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and lead for the RADx® Tech program at NIH.

While many variants of concern contain multiple mutations to the N protein, the study authors note that their method does not evaluate how multiple mutations could affect diagnostic antibody recognition, representing a limitation of the study.

The project was supported by NIBIB under award numbers 75N92019P00328, U54EB015408, and U54EB027690 as part of the RADx initiative, launched to speed innovation in the development, commercialization and implementation of technologies for COVID-19 testing.

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“This is essential, because inflammation releases free radicals against which nerve fibers cannot protect themselves. Therefore, the inflammation must be cleared quickly, which is precisely what Schwann cells do,” explains Dr. Sabine Taschner-Mandl, who designed the study and heads a research group at St. Anna CCRI. The new results, in which the Medical University of Vienna is also significantly involved, were published in the journal Glia.

Do Schwann cells protect against malignancy?

How are these results related to tumor growth? After nerve injury, Schwann cells adopt a “repair” mode that is also found in benign infantile nerve tumors. There, it causes the tumor cells to mature and thus reach a stage where they lose their aggressive properties and no longer divide unchecked (Weiss T., Taschner-Mandl S., et al., Nat Commun 2021).

“Based on the current results, we now suspect that the immune cell functions of Schwann cells also become effective in childhood nerve tumors. This is because in cancer, there is always a kind of inflammation bubbling away that never comes to a halt. In benign nerve tumors, ganglioneuromas, the accompanying chronic inflammation could be stopped by Schwann cells similar to nerve healing, because unlike malignancies, benign nerve tumors have many Schwann cells in their microenvironment. We also see that a lot of immune cells migrate into these tumors, for which the Schwann cells could also be responsible,” says Sabine Taschner-Mandl.

Healthy Inflammation: First Activate, Then Shut Down

In particular, the current study shows that Schwann cells can influence certain immune cells, so-called T cells, which play an important role in the defense against cancer. Schwann cells — both those in nerve regeneration and those in benign tumors — carry MHC-I and MHC-II molecules on their surface that are important for T-cell regulation. Via these molecules, Schwann cells present recognition features of material they have previously taken up from their environment.

We mimicked an inflammatory response in the laboratory and detected a whole range of additional stimulatory and inhibitory surface molecules that are also necessary for T cell activation,” explains Jakob Berner, MSc, co-first author of the study and interim PhD student in Kaan Boztug’s group at St. Anna CCRI. “Our experiments show that Schwann cells are able to take up large amounts of material via phagocytosis.”

As the first immune response to a nerve cut, Schwann cells secrete substances that attract T cells, macrophages and other immune cells. Now it turned out that not only a reaction between the classical immune cells takes place, but also between Schwann cells and T cells.

While Schwann cells initially fuel the inflammatory response by releasing interferon-gamma, they can later shut it down by up-regulating the T-cell inhibitory PD-L1 molecule.

“First activate, then shut down — that’s the normal process of an inflammatory response. If this were also the case in cancer, then it could curb cancer growth,” comments Sabine Taschner-Mandl. Whether and how these findings can be used for potential cancer therapies is now being researched.

“What’s important about the tuatara is that it represents this enormous evolutionary story that we are lucky enough to catch in what is likely its closing act,” Carrano said. “Even though it looks like a relatively simple lizard, it embodies an entire evolutionary epic going back more than 200 million years.”

The discovery comes from a handful of specimens including an extraordinarily complete and well-preserved fossil skeleton excavated from a site centered around an Allosaurus nest in northern Wyoming’s Morrison Formation. Further study of the find could help reveal why this animal’s ancient order of reptiles were winnowed down from being diverse and numerous in the Jurassic to just New Zealand’s tuatara surviving today.

The tuatara looks a bit like a particularly stout iguana, but the tuatara and its newly discovered relative are in fact not lizards at all. They are actually rhynchocephalians, an order that diverged from lizards at least 230 million years ago, Carrano said.

In their Jurassic heyday, rhynchocephalians were found nearly worldwide, came in sizes large and small, and filled ecological roles ranging from aquatic fish hunters to bulky plant munchers. But for reasons that still are not fully understood, rhynchocephalians all but disappeared as lizards and snakes grew to be the more common and more diverse reptiles across the globe.

This evolutionary chasm between lizards and rhynchocephalians helps explain the tuatara’s odd features such as teeth fused to the jaw bone, a unique chewing motion that slides the lower jaw back and forth like a saw blade, a 100-year-plus lifespan and a tolerance for colder climates.

Following O. gregori‘s formal description, Carrano said the fossil has been added to the museum’s collections where it will remain available for future study, perhaps one day helping researchers figure out why the tuatara is all that remains of the rhynchocephalians, while lizards are now found across the globe.

“These animals may have disappeared partly because of competition from lizards but perhaps also due to global shifts in climate and changing habitats,” Carrano said. “It’s fascinating when you have the dominance of one group giving way to another group over evolutionary time, and we still need more evidence to explain exactly what happened, but fossils like this one are how we will put it together.”

The researchers named the new species after museum volunteer Joseph Gregor who spent hundreds of hours meticulously scraping and chiseling the bones from a block of stone that first caught museum fossil preparator Pete Kroehler’s eye back in 2010.

“Pete is one of those people who has a kind of X-ray vision for this sort of thing,” Carrano said. “He noticed two tiny specks of bone on the side of this block and marked it to be brought back with no real idea what was in it. As it turns out, he hit the jackpot.”

The fossil is almost entirely complete, with the exception of the tail and parts of the hind legs. Carrano said that such a complete skeleton is rare for small prehistoric creatures like this because their frail bones were often destroyed either before they fossilized or as they emerge from an eroding rock formation in the present day. As a result, rhynchocephalians are mostly known to paleontologists from small fragments of their jaws and teeth.

After Kroehler, Gregor and others had freed as much of the tiny fossil from the rock as was practical given its fragility, the team, led by DeMar, set about scanning the fossil with high-resolution computerized tomography (CT), a method that uses multiple X-ray images from different angles to create a 3D representation of the specimen. The team used three separate CT scanning facilities, including one housed at the National Museum of Natural History, to capture everything they possibly could about the fossil.

Once the fossil’s bones had been digitally rendered with accuracy smaller than a millimeter, DeMar set about reassembling the digitized bones of the skull, some of which were crushed, out of place or missing on one side, using software to eventually create a nearly complete 3D reconstruction. The reconstructed 3D skull now provides researchers an unprecedented look at this Jurassic-age reptile’s head.

Given Opisthiamimus‘s diminutive size, tooth shape and rigid skull, it likely ate insects, said DeMar, adding that prey with harder shells such as beetles or water bugs might have also been on the menu. Broadly speaking, the new species looks quite a bit like a miniaturized version of its only surviving relative (tuataras are about five times longer).

“Such a complete specimen has huge potential for making comparisons with fossils collected in the future and for identifying or reclassifying specimens already sitting in a museum drawer somewhere,” DeMar said. “With the 3D models we have, at some point we could also do studies that use software to look at this critter’s jaw mechanics.”

Funding and support for this research were provided by the Smithsonian and the Australian Research Council.