“Most reactions involving free radicals take place at the site of the unpaired electron,” explained Brookhaven Lab chemist Matthew Bird, one of the co-corresponding authors on the paper. The Princeton team had become experts in using free radicals for a range of synthetic applications, such as polymer upcycling. But they’ve wondered whether free radicals might influence reactivity on other parts of the molecule as well, by pulling electrons away from those more distant locations.

“Our measurements show that these radicals can exert powerful ‘electron-withdrawing’ effects that make other parts of the molecule more reactive,” Bird said.

The Princeton team demonstrated how that long-distance pull can overcome energy barriers and bring together otherwise unreactive molecules, potentially leading to a new approach to organic molecule synthesis.

Combining capabilities

The research relied on the combined resources of a Princeton-led DOE Energy Frontier Research Center (EFRC) focused on Bio-Inspired Light Escalated Chemistry (BioLEC). The collaboration brings together leading synthetic chemists with groups having advanced spectroscopic techniques for studying reactions. Its funding was recently renewed for another four years.

Robert Knowles, who led Princeton’s role in this research, said, “This project is an example of how BioLEC’s combined expertise enabled the team to quantify an important physical property of these radical species, that in turn allowed us to design the resulting synthetic methodology.”

The Brookhaven team’s major contribution is a technique called pulse radiolysis — available only at Brookhaven and one other location in the U.S.

“We use the Laser Electron Accelerator Facility (LEAF) — part of the Accelerator Center for Energy Research (ACER) in Brookhaven’s Chemistry Division — to generate intense high-energy electron pulses,” Bird explained. “These pulses allow us to add or subtract electrons from molecules to make reactive species that might be difficult to make using other techniques, including short-lived reaction intermediates. With this technique, we can step into one part of a reaction and monitor what happens.”

For the current study, the team used pulse radiolysis to generate molecules with oxygen-centered radicals, and then measured the “electron-withdrawing” effects on the other side of the molecule. They measured the electron pull by tracking how much the oxygen at the opposite side attracts protons, positively charged ions sloshing around in solution. The stronger the pull from the radical, the more acidic the solution has to be for protons to bind to the molecule, Bird explained.

The Brookhaven scientists found the acidity had to be high to enable proton capture, meaning the oxygen radical was a very strong electron withdrawing group. That was good news for the Princeton team. They then demonstrated that it’s possible to exploit the “electron-withdrawing” effect of oxygen radicals by making parts of molecules that are generally inert more chemically reactive.

“The oxygen radical induces a transient ‘polarity reversal’ within the molecule — causing electrons that normally want to remain on that distant side to move toward the radical to make the ‘far’ side more reactive,” Bird explained.

These findings enabled a novel substitution reaction on phenol based starting materials to make more complex phenol products.

“This is a great example of how our technique of pulse radiolysis can be applied to cutting-edge science problems,” said Bird. “We were delighted to host an excellent graduate student, Nick Shin, from the Knowles group for this collaboration. We look forward to more collaborative projects in this second phase of BioLEC and seeing what new problems we can explore using pulse radiolysis.”

Brookhaven Lab’s role in this work and the EFRC at Princeton were funded by the DOE Office of Science (BES). Princeton received additional funding for the synthesis work from the National Institutes of Health.

Numerous prior studies conducted around the world have documented people’s beliefs in witchcraft — the idea that certain individuals have supernatural abilities to inflict harm. Understanding people’s witchcraft beliefs can be important for policymaking and other community engagement efforts. However, due to a lack of data, global-scale statistical analyses of witchcraft beliefs have been lacking.

To deepen understanding of witchcraft beliefs, Gershman compiled a new dataset that captures such beliefs among more than 140,000 people from 95 countries and territories. The data come from face-to-face and telephone surveys conducted by the Pew Research Center and professional survey organizations between 2008 and 2017, which included questions about religious beliefs and belief in witchcraft.

According to the dataset, over 40 percent of survey participants said they believe that “certain people can cast curses or spells that cause bad things to happen to someone.”Witchcraft beliefs appear to exist around the world but vary substantially between countries and within world regions. For instance, 9 percent of participants in Sweden reported belief in witchcraft, compared to 90 percent in Tunisia.

Using this dataset, Gershman then conducted an investigation of various individual-level factors associated with witchcraft beliefs. This analysis suggests that, while beliefs cut across socio-demographic groups, people with higher levels of education and economic security are less likely to believe in witchcraft.

Gershman also combined this dataset with other country-level data, finding that witchcraft beliefs differ between countries according to various cultural, institutional, psychological, and socioeconomic factors. For instance, witchcraft beliefs are linked to weak institutions, low levels of social trust, and low innovation, as well as conformist culture and higher levels of in-group bias — the tendency for people to favor others who are similar to them”

These findings, as well as future research using the new dataset, could be applied to help optimize policies and development projects by accounting for local witchcraft beliefs.

The author adds: “The study documents that witchcraft beliefs are still widespread around the world. Moreover, their prevalence is systematically related to a number of cultural, institutional, psychological, and socioeconomic characteristics.”

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Now, a new animal study points to a gene that is important for the earliest development of basic social behaviors.

The work also suggests that exposure to certain drugs and environmental risk factors during embryonic development can cause changes to this gene, leading to alterations in social behavior that are similar to those found in individuals who have autism. Much to their surprise, the researchers also found they could reverse some of the effects using an experimental drug.

“This study helps us understand at the molecular level why sociability is disrupted during the very earliest stages of life,” says Randall T. Peterson, Ph.D., the corresponding author of the study and dean of the University of Utah College of Pharmacy. “It also gives us an opportunity to explore potential treatments that could restore sociability in these animals and, perhaps in time, eventually in humans as well.”

More broadly, their findings suggest that the gene — TOP2a — controls a large network of genes that are known to increase the risk of autism. It also may serve as a link between genetic and environmental factors that contribute to onset of disorder, Peterson adds.

The study, conducted by University of Utah Health researchers and colleagues nationwide, appears in the Nov. 23 issue of Science Advances.

Anti-social animals

Scientists suspect many social traits are determined before birth. But the precise mechanisms involved in this process remain murky. One promising area of research suggests that social behavior and other characteristics and traits are influenced not only by our genetic makeup but also how and where we live.

To test this model, the scientists evaluated whether environmental exposures during embryonic development could influence social behavior. Peterson and his colleagues exposed zebrafish embryos to more than 1,100 known drugs — one drug per 20 embryos — for 72 hours beginning three days after conception.

The researchers determined that four of the 1,120 tested drugs significantly reduced sociability among the zebrafish. Fish exposed to these drugs were less likely to interact with other fish. It turned out that the four medications all belonged to the same class of antibiotics, called fluoroquinolones. These drugs are used to treat upper and lower respiratory tract infections in people.

When the scientists gave a related drug to pregnant mice, the offspring behaved differently when they became adults. Even though they appeared normal, they communicated less with other mice and engaged in more repetitive acts — like repeatedly poking their head in the same hole — than other rodents.

A basis for sociability

Digging deeper, the researchers found that the drugs suppressed a gene called TOP2a, which, in turn, acted on a cluster of genes that are known to be involved in autism in humans.

They also found that the cluster of autism-associated genes shared another thing in common — a higher than usual tendency to bind a group of proteins called the PRC2. The researchers hypothesized that Top2a and the PRC2 work together to control the production of many autism-associated genes.

To determine whether the anti-social behaviors could be reversed, the research team gave embryonic and young zebrafish an experimental drug called UNC1999, which is known to inhibit the PRC2. After treatment with the drug, fish exposed to fluoroquinolones were more likely to swim closer to other fish, demonstrating that the drug helped restore sociability. They saw similar results with other drugs known to inhibit the same key gene, TOP2a.

“That really surprised me because I would’ve thought disrupting brain development when you’re an embryo would be irreversible,” Peterson says. “If you don’t develop sociality as an embryo, you’ve missed the window. But this study suggests that even in those individuals later in life, you can still come in and inhibit this pathway and restore sociality.”

Moving forward, the researchers plan to explore how and why this drug had this effect.

Although the scientists only found four compounds that are Top2a inhibitors, evidence suggests hundreds of other drugs and naturally occurring compounds in our environment can inhibit its activity.

“It’s possible that these four compounds are just the tip of the iceberg in terms of substances that could be problematic for embryonic exposure,” Peterson says.

However, Peterson notes that this study was conducted in animals, and more research needs to be done before any of its results can be confirmed in humans. Therefore, he cautions against drawing conclusions about real-world applications.

“We have no evidence that fluroquinolones or any other antibiotic causes autism in humans,” Peterson says. “So, there is no reason to stop using antibiotics. What this paper does identify is a new molecular pathway that appears to control social development and is worthy of further exploration.”

In addition to Dr. Peterson, U of U Health scientists Yijie Geng, Tejia Zhang, Ivy G. Alonzo, Sean C. Godar, Christopher Yates, Brock Plummer, and Marco Bortolato contributed to this study. Other participating institutions include the University of Chicago; Beth Israel Deaconess Medical Center in Boston; Massachusetts General Hospital and Harvard Medical School; the Broad Institute, Cambridge, Massachusetts; and MDI Biological Laboratory, Bar Harbor, Maine.

The study, “Top2a promotes the development of social behavior via PRC2 and H3K27me3,” appears in the Nov. 23, 2022, issue of Science Advances. This research was supported by the L. S. Skaggs Presidential Endowed Chair and the National Institute of Environmental Health Sciences at the National Institutes of Health.

In this new study, an international team, led by Bristol’s Professor Christiane Schaffitzel, scrutinised the spike glycoproteins decorating all coronaviruses. They reveal that a tailor-made pocket feature in the SARS-CoV-2 spike protein, first discovered in 2020, is present in all deadly coronaviruses, including MERS and Omicron. In striking contrast, the pocket feature is not present in coronaviruses which cause mild infection with cold-like symptoms.

The team say their findings suggest that the pocket, which binds a small molecule, linoleic acid—an essential fatty acid indispensable for many cellular functions including inflammation and maintaining cell membranes in the lungs so that we can breathe properly—could now be exploited to treat all deadly coronaviruses, at the same time rendering them vulnerable to a linoleic acid-based treatment targeting this pocket.   

COVID-19, caused by SARS-CoV-2, is the third deadliest coronavirus outbreak following SARS-CoV in 2002 and MERS-CoV in 2012. The much more infectious SARS-CoV-2 continues to infect people and damage communities and economies worldwide, with new variants of concern emerging successively, and Omicron evading vaccination and immune response.

Professor Schaffitzel from Bristol’s School of Biochemistry, explained: “In our earlier work we identified the presence of a small molecule, linoleic acid, buried in a tailor-made pocket within the SARS-Cov-2 glycoprotein, known as the ‘Spike protein’, which binds to the human cell surface, allowing the virus to penetrate the cells and start replicating, causing widespread damage.

“We showed that binding linoleic acid in the pocket could stop virus infectivity, suggesting an anti-viral treatment. This was in the original Wuhan strain that started the pandemic. Since then, a whole range of dangerous SARS-CoV-2 variants have emerged, including Omicron, the currently dominating variant of concern. We scrutinised every new variant of concern and asked whether the pocket function is still present.”

Omicron has undergone many mutations, enabling it to escape immune protection offered by vaccination or antibody treatments that lag behind this rapidly evolving virus.  Intriguingly, while everything else may have changed, the researchers found that the pocket remained virtually unaltered, also in Omicron.

Christine Toelzer, Research Associate in the School of Biochemistry and lead author of the study, added: “When we realised that the pocket we had discovered remained unchanged, we looked back and asked whether SARS-CoV and MERS-CoV, two other deadly coronaviruses causing previous outbreaks years ago, also contained this linoleic acid binding pocket feature.”  

The team applied high-resolution electron cryo-microscopy, cutting-edge computational approaches and cloud computing. Their results showed that SARS-CoV and MERS-CoV also had the pocket, and could bind the ligand, linoleic acid, by a virtually identical mechanism.  

Professor Schaffitzel concluded: “In our current study, we provide evidence that the pocket remained the same in all deadly coronaviruses, from the first SARS-CoV outbreak 20 years ago to Omicron today. We have shown previously that linoleic acid binding to this pocket induces a locked spike, abrogating viral infectivity. We also show now that linoleic acid supplementation suppresses virus replication inside cells. We anticipate that future variants will also contain the pocket, which we can exploit to defeat the virus.”

Halo Therapeutics, a recent University of Bristol spin-out Professor Schaffitzel co-founded, is using these findings to develop pocket-binding pan-coronavirus antivirals.

The team included experts from the Bristol UNCOVER Group, Max Planck Bristol Centre for Minimal Biology, Bristol University spin-out Halo Therapeutics Ltd, and collaborators in Sweden and France. The studies have been supported by funds from Max Planck Gesellschaft, Wellcome Trust and European Research Council, with additional support from Oracle for Research for high-performance cloud computing resources.

The coin, housed at The Hunterian collection at the University of Glasgow, was among a handful of coins of the same design unearthed in Transylvania, in present-day Romania, in 1713. They have been regarded as fakes since the mid-19^th-century, due to their crude, strange design features and jumbled inscriptions.

In the new study, published in PLOS ONE, researchers compared the Sponsion coin with other Roman coins kept at The Hunterian, including two that are known to be genuine.

They found minerals on the coin’s surface that were consistent with it being buried in soil over a long period of time, and then exposed to air. These minerals were cemented in place by silica — cementing that would naturally occur over a long time in soil. The team also found a pattern of wear and tear that suggested the coin had been in active circulation.

Lead author Professor Paul N. Pearson (UCL Earth Sciences) said: “Scientific analysis of these ultra-rare coins rescues the emperor Sponsian from obscurity. Our evidence suggests he ruled Roman Dacia, an isolated gold mining outpost, at a time when the empire was beset by civil wars and the borderlands were overrun by plundering invaders.”

The Roman province of Dacia, a territory overlapping with modern-day Romania, was a region prized for its gold mines. Archaeological studies have established that the area was cut off from the rest of the Roman empire in around 260 CE. Surrounded by enemies, Sponsian may have been a local army officer forced to assume supreme command during a period of chaos and civil war, protecting the military and civilian population of Dacia until order was restored, and the province evacuated between 271 and 275 CE.

Coinage has always been an important symbol of power and authority. Recognising this and unable to receive official issues from the mint in Rome, Sponsian seems to have authorised the creation of locally produced coins, some featuring an image of his face, to support a functioning economy in his isolated frontier territory.

When the coins were discovered in the early 18th century, they were thought to be genuine and classed alongside other imitations of Roman coins made beyond the fringes of the empire. However, from the mid-19th century, attitudes changed. Coins from the hoard were dismissed as fakes because of the way they looked. This has been the accepted view until now.

The new study is the first time scientific analysis has been undertaken on any of the Sponsian coins. The research team used powerful microscopes in visible and ultraviolet light, as well as scanning electron microscopy and spectroscopy — studying how light at different wavelengths is absorbed or reflected — to study the coins’ surface.

Only four coins featuring Sponsian are known to have survived to the present day, all apparently originally from the 1713 hoard. Another is in Brukenthal National Museum in Sibiu, Romania. High magnification microscopic analysis performed there, following the research on the coin at The Hunterian, has revealed similar evidence of authenticity.

Curator of Numismatics at The Hunterian, Jesper Ericsson, said: “This has been a really exciting project for The Hunterian and we’re delighted that our findings have inspired collaborative research with museum colleagues in Romania. Not only do we hope that this encourages further debate about Sponsian as a historical figure, but also the investigation of coins relating to him held in other museums across Europe.”

The interim manager of the Brukenthal National Museum, Alexandru Constantin Chituță, said: “For the history of Transylvania and Romania in particular, but also for the history of Europe in general, if these results are accepted by the scientific community they will mean the addition of another important historical figure in our history.

“It is a wonderful thing for the Brukenthal National Museum, because the museum in Sibiu, Romania, is the holder of the only known coin belonging to Sponsian from the territory of Romania. I would like to express my gratitude to the colleagues from the Brukenthal Național Museum — History Museum Altemberger House and especially to the leader of the scientific team, Professor Paul N. Pearson from UCL, for their commitment, hard work and their impressive result.”

Four gold coins analysed by researchers, including the Sponsian coin and other Roman coins previously dismissed as forgeries, are on display in The Hunterian at the University of Glasgow, while the Sponsian coin in the Brukenthal National Museum is also on public display.

However, using real image data can raise practical and ethical concerns: The images could run afoul of copyright laws, violate people’s privacy, or be biased against a certain racial or ethnic group. To avoid these pitfalls, researchers can use image generation programs to create synthetic data for model training. But these techniques are limited because expert knowledge is often needed to hand-design an image generation program that can create effective training data.

Researchers from MIT, the MIT-IBM Watson AI Lab, and elsewhere took a different approach. Instead of designing customized image generation programs for a particular training task, they gathered a dataset of 21,000 publicly available programs from the internet. Then they used this large collection of basic image generation programs to train a computer vision model.

These programs produce diverse images that display simple colors and textures. The researchers didn’t curate or alter the programs, which each comprised just a few lines of code.

The models they trained with this large dataset of programs classified images more accurately than other synthetically trained models. And, while their models underperformed those trained with real data, the researchers showed that increasing the number of image programs in the dataset also increased model performance, revealing a path to attaining higher accuracy.

“It turns out that using lots of programs that are uncurated is actually better than using a small set of programs that people need to manipulate. Data are important, but we have shown that you can go pretty far without real data,” says Manel Baradad, an electrical engineering and computer science (EECS) graduate student working in the Computer Science and Artificial Intelligence Laboratory (CSAIL) and lead author of the paper describing this technique.

Co-authors include Tongzhou Wang, an EECS grad student in CSAIL; Rogerio Feris, principal scientist and manager at the MIT-IBM Watson AI Lab; Antonio Torralba, the Delta Electronics Professor of Electrical Engineering and Computer Science and a member of CSAIL; and senior author Phillip Isola, an associate professor in EECS and CSAIL; along with others at JPMorgan Chase Bank and Xyla, Inc. The research will be presented at the Conference on Neural Information Processing Systems.

Rethinking pretraining

Machine-learning models are typically pretrained, which means they are trained on one dataset first to help them build parameters that can be used to tackle a different task. A model for classifying X-rays might be pretrained using a huge dataset of synthetically generated images before it is trained for its actual task using a much smaller dataset of real X-rays.

These researchers previously showed that they could use a handful of image generation programs to create synthetic data for model pretraining, but the programs needed to be carefully designed so the synthetic images matched up with certain properties of real images. This made the technique difficult to scale up.

In the new work, they used an enormous dataset of uncurated image generation programs instead.

They began by gathering a collection of 21,000 images generation programs from the internet. All the programs are written in a simple programming language and comprise just a few snippets of code, so they generate images rapidly.

“These programs have been designed by developers all over the world to produce images that have some of the properties we are interested in. They produce images that look kind of like abstract art,” Baradad explains.

These simple programs can run so quickly that the researchers didn’t need to produce images in advance to train the model. The researchers found they could generate images and train the model simultaneously, which streamlines the process.

They used their massive dataset of image generation programs to pretrain computer vision models for both supervised and unsupervised image classification tasks. In supervised learning, the image data are labeled, while in unsupervised learning the model learns to categorize images without labels.

Improving accuracy

When they compared their pretrained models to state-of-the-art computer vision models that had been pretrained using synthetic data, their models were more accurate, meaning they put images into the correct categories more often. While the accuracy levels were still less than models trained on real data, their technique narrowed the performance gap between models trained on real data and those trained on synthetic data by 38 percent.

“Importantly, we show that for the number of programs you collect, performance scales logarithmically. We do not saturate performance, so if we collect more programs, the model would perform even better. So, there is a way to extend our approach,” Manel says.

The researchers also used each individual image generation program for pretraining, in an effort to uncover factors that contribute to model accuracy. They found that when a program generates a more diverse set of images, the model performs better. They also found that colorful images with scenes that fill the entire canvas tend to improve model performance the most.

Now that they have demonstrated the success of this pretraining approach, the researchers want to extend their technique to other types of data, such as multimodal data that include text and images. They also want to continue exploring ways to improve image classification performance.

“There is still a gap to close with models trained on real data. This gives our research a direction that we hope others will follow,” he says.

Academics from the Universities of Cambridge and Manchester analysed the well-being and self-esteem of more than 11,000 young people from across the UK, using data collected when they were 11, and again when they were 14. The adolescents’ overall ‘subjective well-being’ — their satisfaction with different aspects of life (such as friends, school and family) — dropped significantly during the intervening years.

It is widely accepted that young people’s well-being and mental health are influenced by factors such as economic circumstances and family life. The research shows that notwithstanding this, well-being tends to fall steeply and across the board during early adolescence.

That decline is probably linked to the transition to secondary school at age 11. The study identified that the particular aspects of well-being which changed in early adolescence were typically related to school and peer relationships, suggesting a close connection with shifts in these young people’s academic and social lives.

In addition, students with higher self-esteem at age 11 experienced a less significant drop in well-being at age 14. This indicates that structured efforts to strengthen adolescents’ self-esteem, particularly during the first years of secondary school, could mitigate the likely downturn in well-being and life satisfaction.

Ioannis Katsantonis, a doctoral researcher at the Faculty of Education, University of Cambridge, who led the study said: “Even though this was a large, diverse group of adolescents, we saw a consistent fall in well-being. One of the most striking aspects was the clear association with changes at school. It suggests we urgently need to do more to support students’ well-being at secondary schools across the UK.”

Ros McLellan, Associate Professor at the University of Cambridge, specialist in student well-being, and co-author, said: “The link between self-esteem and well-being seems especially important. Supporting students’ capacity to feel positive about themselves during early adolescence is not a fix-all solution, but it could be highly beneficial, given that we know their well-being is vulnerable.”

Globally, adolescent well-being is in decline. In the UK, the Children’s Society has shown that 12% of young people aged 10 to 17 have poor well-being. Dr Jose Marquez, a Research Associate at the Institute of Education, University of Manchester, and co-author, said: “Until now, we haven’t fully understood how universally poor well-being is experienced. The relationship between well-being and self-esteem has also been unclear.”

The researchers used data from the Millennium Cohort Study, which involves a nationally representative sample of people born between 2000 and 2002 and incorporates standard questionnaires about well-being and self-esteem. They then calculated a well-being ‘score’ for each student, balanced to control for other factors that influence well-being — such as economic advantage, bullying, and general feelings of safety.

While most adolescents were satisfied with life at age 11, the majority were extremely dissatisfied by age 14. By that age, the well-being scores of 79% of the participants fell below what had been the average score for the entire group three years earlier. “This is a statistically significant drop,” Katsantonis said. “It goes far beyond anything we would classify as moderate.”

The study also captured information about the adolescents’ satisfaction with specific aspects of their lives, such as schoolwork, personal appearance, family and friends. This suggested that the most dramatic downturns between 11 and 14 were probably related to school and relationships with peers.

Despite the overall fall, students with better well-being at age 14 tended to be those who had higher self-esteem at age 11. The pattern did not apply in reverse, however: better well-being at age 11 did not predict better self-esteem later. This implies a causal link in which self-esteem seems to protect adolescents from what would otherwise be sharper declines in well-being.

“Supporting self-esteem is not the only thing we need to do to improve young people’s well-being,” Katsantonis said. “It should never, for example, become an excuse not to tackle poverty or address bullying — but it can be used to improve young people’s life satisfaction at this critical stage.”

The researchers identify various ways in which schools could support this. At a basic level, Katsantonis suggested that celebrating students’ achievements, underlining the value of things they had done well, and avoiding negative comparisons with other students, could all help.

More strategically, the study suggests incorporating more features that promote self-esteem into England’s well-being curriculum, and stresses the need to ensure that similar efforts are made across the UK. Recent studies have, for example, highlighted the potential benefits of mindfulness training in schools, and of ‘positive psychology’ initiatives which teach adolescents to set achievable personal goals, and to acknowledge and reflect on their own character strengths.

McLellan added: “It’s really important that this is sustained — it can’t just be a case of doing something once when students start secondary school, or implementing the odd practice here and there. A concerted effort to improve students’ sense of self-worth could have really positive results. Many good teachers are doing this already, but it is perhaps even more important than we thought.”