Researchers from Children’s Hospital of Philadelphia (CHOP) found that young children between the ages of 5 and 12 were more likely to experience a concussion from recreation and other non-sport activities, yet those injuries were not seen by specialists until days later compared with sports-related concussions in the same age group.
This study suggests concussion research is needed for children outside of sports and that providing more resources and education to those providers diagnosing most concussions in this age group, particularly emergency departments and primary care, could reduce inequities in concussion care regardless of the mechanism of injury by which these patients experience concussions. The findings were recently published by the Journal of Pediatrics.
Adolescents experience high rates of sports- and recreation-related injuries, but the rate of injuries among children ages 5 through 12 is still high, at about 72.7 injuries per 1000 children. More than half of children in this age range participate in sports, as daily physical activity is recommended for optimal health and development, but with these activities comes a risk of pediatric concussion.
Most of the research into pediatric concussions has focused on adolescents and sports, which highlights a need to study concussions in younger children across all mechanisms of injury. Prior studies from nearly a decade ago reported the importance of non-sports and recreation-related concussions in elementary age children. Injuries sustained in these settings are marked by key differences in supervision at the time of injury that can influence how quickly a concussion is recognized, affecting access to and timing of care, which can lead to longer recovery times.
“In prior research, recreation-related injuries are not often differentiated from sports-related injuries, yet this study shows that these injuries can be just as serious and occur more frequently in this age group, suggesting that education and awareness about concussion needs to be emphasized to those who interact with children in these less structured settings,” said senior study author Kristy Arbogast, PhD, director of the Center for Injury Research and Prevention and co-director of the Minds Matter Concussion Program at CHOP. “Patients injured outside of sports and recreation experienced a higher burden of symptoms and more changes to daily life, and delays in appropriate care could exacerbate these negative effects.”
Using contemporary data from a pediatric concussion registry, researchers examined this age range and characterized concussions by their mechanisms of injury, distinguishing between injuries that occurred in organized sports and those that occurred outside of sports. They separated recreation, such as gym class, free play, or non-competitive sporting activities like biking, from other non-sports mechanisms, like motor vehicle crashes or falls, owing to the role of unstructured play in this age group. A total of 1,141 patients between the ages of 5 and 12 with concussions were evaluated within four weeks of injury and were included in this analysis. The researchers assessed whether the injury occurred during sports, recreation, or some other mechanism of injury (“non-sports-or-recreation-related”). Variations in demographics, point of healthcare entry, and clinical signs were evaluated across mechanisms.
The study found that recreation-related injuries were the most common in this age group at 37.3% of injuries, followed by non-sports-or-recreation-related concussions at 31.9%. These injuries were more likely to be seen first in the emergency department compared to sports-related concussions. Importantly, patients with recreation- or non-sports or recreation-related concussions were first evaluated by concussion specialists an average of 2 to 3 days later than sports-related concussions. Patients with concussions outside of sports and recreation also reported worse symptoms, including more visio-vestibular issues and more changes to sleep and other daily habits compared with the other patient groups.
“We see these findings as an opportunity to equip the clinical teams who may see these patients first with the latest tools for concussion diagnosis and management,” said study co-author Daniel Corwin, MD, Director of Research Operations in the Division of Emergency Medicine and Emergency Department Lead of the Minds Matter Concussion Program. “These findings could also serve as a basis for school-based resources, including engagement of school nurses, to help address disparities in care across these injuries, particularly in this less well understood elementary age population of patients who sustain their injuries outside of sports.”
This study was supported by the National Institute of Neurologic Disorders and Stroke of the National Institutes of Health under award numbers R01NS097549 and the Pennsylvania Department of Health.

Being near and having more exposure to urban green space and blue (water) space is linked to lower odds of having coronary artery calcification in middle age, which is an early marker of cardiovascular disease.
The associations were more pronounced among Black individuals and those living in neighborhoods with lower socioeconomic status, with the strongest effects observed in Black individuals in economically deprived neighborhoods.
Specifically, Black participants with the highest accessibility to a river had 32% lower odds of coronary artery calcification compared to those with the lowest accessibility. Black participants with greater access to green spaces had up to 35% lower odds of calcification. For each 10%-point increase in green space, the odds of having coronary artery calcification decreased by 15% on average.
The study was published today June 27 Circulation.
Coronary artery calcification (CAC) is when calcium builds up in the plaque found in the walls of the coronary arteries. It can be a sign of early coronary artery disease, which can cause a heart attack.
“The protective effect of having access to urban blue and green spaces with coronary artery calcification highlighted in our study underscore the potential benefits of such infrastructure, particularly for underserved populations at higher risk for cardiovascular disease,” said corresponding author Dr. Lifang Hou, a professor of preventive medicine at Northwestern University Feinberg School of Medicine. “Our findings provide quantitative evidence supporting environmental policies to enhance the accessibility and quality of residential blue and green spaces, which can promote public health benefit and address racial and neighborhood-related health disparities.”
Why do green and blue spaces improve health?
“Having more green and blue spaces may provide increased opportunities for physical activities, social interactions, stress relief and restoration, all of which have been linked to improved metabolic and cardiovascular health,” Hou said. “Additionally, exposure to green and blue spaces has been shown to boost people’s immune system, reduce chronic inflammation and slow down the biological aging process, all of which are biologically important in people’s overall health and cardiovascular health. More studies are needed to fully understand the role of urban natural environments in pathways related to human health.”

Conversely, the study also showed shorter distances to parks were associated with higher odds of CAC in these neighborhoods, with individuals having the highest park accessibility showing 29% higher odds of CAC compared to those with the lowest accessibility.
“The poor condition of parks and/or safety concerns in underserved urban neighborhoods might deter park use and prevent residents from fully benefiting from these spaces,” said study first author Kyeezu Kim, adjunct assistant professor of preventive medicine at Feinberg and assistant professor at Sungkyunkwan University School of Medicine in South Korea. “From a public health perspective, the results suggest the need for quality control and management of the surrounding environment in neighborhoods with disadvantaged social determinants of health. More data is warranted to fully explain this observation.”
How the study was conducted
The study included 2,960 Black and white men and women (average age of 50 years) from Birmingham, Ala., Chicago, Ill., Minneapolis, Minn., and Oakland, Calif., who were followed for 25 years (from 1985-1986 to 2010-2011). While proximity to urban blue and green spaces has been linked to better cardiovascular health, few studies have examined the role of social determinants of health, such as race and neighborhoods with lower socioeconomic status in these associations, particularly with long-term observational data.
Data for this study were drawn from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a multi-center prospective cohort study across four urban cities in the U.S. The CARDIA study began in 1985-1986 with 5,115 self-reported Black and white individuals in early adulthood (mean age 24.8). For blue and green spaces, researchers included percent blue space cover, distance to the nearest river, percent green space cover and distance to the nearest major park within 5 km of the participants’ residential addresses. The presence of CAC was measured using a CT (computed tomography) scan when participants were about 50 years old. Researchers examined the associations between each blue and green space and CAC by race and neighborhood socioeconomic status.
The CARDIA study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham grants HHSN268201800005I and HHSN268201800007I, Northwestern University grant HHSN268201800003I, University of Minnesota grant HHSN268201800006I and Kaiser Foundation Research Institute grant HHSN268201800004I. The research is also supported by NHLBI grant R01HL114091 and National Institute on Aging grant R01AG081244, all of the National Institutes of Health. It is also supported by the American Heart Association.

The protein Foxp3 is vital to the function of immune cells called regulatory T cells, which control immune system activation. Despite its importance, how Foxp3 regulates the immune system using environmental cues has remained unclear. St. Jude Children’s Research Hospital scientists have discovered that Foxp3 does not work alone, rather it hijacks DNA-binding proteins that are activated based on the immunological context sensed by regulatory T cells. Through this cooperative interaction, Foxp3 prevents unwanted immune responses, and determines to what extent it needs to suppress the response. The findings, which have implications for future T-cell engineering, were published today in the Journal of Experimental Medicine.
The ability of the human body to differentiate its own cells from external attacks is a fundamental process in immune regulation. “Since the 1950s, the topic of how we distinguish self from non-self has been the key topic in our field,” said corresponding author Yongqiang Feng, PhD, Department of Immunology. This concept of discriminating between self vs. non-self is controlled by regulatory T cells. The protein Foxp3 is at the center of this discriminatory practice, functioning like a gate keeper in deciding what to hide from immune attack. Loss of this protein leads to a breakdown in this coordination, and lethal systemic inflammation.
Transcription factor or cofactor?
A protein which coordinates expression of genes is called a transcription factor. The tunable nature and broad swath of responses that Foxp3 controls led Feng to question the biochemical nature of how this transcription factor was, itself, regulated. How did Foxp3 know whether or not to coordinate a suppressive immune response?
The researchers studied the relationship between Foxp3’s protein-binding partners and its function, making a surprising discovery. “We found that when the [environmental] conditions changed, the ability of Foxp3 to interact with DNA also changed,” Feng said. “We found the Foxp3 does not directly interact very much with the DNA, but rather binds to other DNA-binding proteins. In this sense, it is a transcriptional cofactor.”
It had been speculated for decades that Foxp3 was a transcription factor, with immune suppression coordinated through its expression. However, these findings imply that the environmental trigger which activates regulatory T cells drives the expression of Foxp3’s binding partners, which then coordinate with Foxp3 to establish the appropriate immune response. It “swaps out” these binding partners depending on the environmental cue.
“Better protein, better cells, better treatments”
Regulatory T cells are vital to overcoming disease. These cells can be isolated from patients, expanded and engineered to express receptors that allow them to specifically target diseased tissues. “With regulatory T cells we hope to treat autoimmune diseases such as type 1 diabetes. But we never fully considered how this protein works,” said Feng. “As immunologists, we don’t just want to understand the protein, we want to know how we can take advantage of this knowledge to engineer better therapies.”
Feng aspires to do just that, ultimately utilizing these findings in the design of regulatory T cells with better suppressive function. “With this knowledge, by modifying the different domains within FOXP3, we hope to design a better protein, leading to better regulatory T cells, meaning better treatments.”

Harnessing nanoparticles to deliver drugs precisely to a surgically repaired tendon is a promising new approach that reduced scar tissue formation and improved mechanical function in a study appearing in Science Advances. Researchers’ success in pinpointing a drug therapy inside the body, at the cellular level, proved to be a highly efficient delivery method that could be used to treat other injuries.
Whether it’s a season-ending Achilles rupture by pro footballer Aaron Rodgers or an everyday workplace accident, tendon injuries are common and can be life-changing. They require 300,000 surgeries per year and often result in lost work time and permanent impaired physical function.
Typically, traumatic tendon injuries are surgically repaired with sutures, but optimal healing is often impaired by the tendon’s propensity to heal with scar tissue that restricts tendon movement and function.
Researchers at the University of Rochester and University of Oregon combined their expertise in tendon cell biology and drug delivery systems to find a better way to deliver therapies that can reduce scar tissue and facilitate improved healing.
“There are very few effective drug regimens to assist the tendon healing process, despite the high number of these injuries and the poor outcomes that often result,” said Alayna Loiselle, PhD, associate professor at the University of Rochester’s Center for Musculoskeletal Research. “Systemic drug treatments delivered orally or via injection show poor tendon homing; in some cases, less than 1 percent of a systemically delivered medication reaches the healing tendon. Local administration of drugs directly to the tendon has disadvantages as well, including potential tissue damage from the injection and poor control over drug concentrations at the point of injury.”
“We want to pivot from using suturing alone to incorporating therapeutics,” said Emmanuela Adjei-Sowah, a Biomedical Engineering PhD student at the University of Rochester, who has spent the past several years working with co-authors Loiselle, Danielle S.W. Benoit, PhD, and others to develop the nanoparticle delivery system to improve healing in tendon injuries. “Advances in multiomics and drug delivery using nanoparticles open up new possibilities in treatment.”
The challenge for researchers was to identify which substances could assist tendon healing.

Molecular ‘map’ of healing process charts a new therapeutic path
“The fundamental cellular and molecular mechanisms that drive scar-mediated tendon healing are really only just beginning to be well-defined,” Loiselle said. “Our prior work used spatial transcriptomic profiling to define a molecular map of the healing tendon. In subsequent analysis of this data, we found that the area right at the injury site had high levels of Acp5 gene expression, which was both surprising and exciting.”
The Acp5 gene produces a protein called Tartrate Resistant Acid Phosphatase (TRAP); both are known to occur as injured bones recover and rebuild. High TRAP activity within the healing tendon allowed researchers to employ a peptide that binds with TRAP to deliver medication directly to the healing tendon site.
“While Benoit’s lab has previously used TRAP-binding peptide nanoparticles (TBP-NP) for targeted drug delivery to bone, high TRAP activity in the healing tendon opened up an entirely new research direction,” Loiselle said.
Prior to initiating studies with therapeutic agents, the team completed a series of dose and timing studies, using a mouse model of complete transection and surgical repair of the flexor tendon, to define the window in which their drug delivery system could most effectively target the healing tendon.
“Defining an optimal treatment window is critical to successfully developing an innovative and effective drug delivery system that improves tendon healing by encouraging a more regenerative, rather than fibrotic, healing cascade,” said Benoit, the Lorry Lokey Department Chair and Professor in the Department of Bioengineering at the University of Oregon. “In addition, by defining the optimal therapeutic window for this drug delivery system, we can mitigate the unwanted side effects that typically accompany the high doses or multiple doses required to achieve sufficient drug accumulation in the tissue.”
As a therapeutic, the team chose Niclosamide, which inhibits S100a4, a protein that Loiselle’s lab already identified as contributing to scar formation. Previous work from Loiselle’s lab demonstrated that genetic knockdown of S100a4 improved mechanical and functional outcomes in this mouse tendon healing model. S100a4 has been implicated in scar formation in many tissues, including the liver, heart, lung, and oral submucosa; Loiselle’s discovery that it complicates tendon healing gave them a therapeutic target for this study, where they used their TRAP-binding peptide nanoparticle drug delivery system to precisely affect the injured tendon.

As a comparison, they delivered Niclosamide systemically; it did slightly reduce the amount of S100a4 in the healing tendon but it had no beneficial impact on the healing process. In contrast, delivery of the same dose of Niclosamide using the nanoparticle system resulted in robust inhibition of S100a4 mRNA and protein levels in the healing tendon.
This targeted drug delivery method also significantly benefited the tendon healing process. TBP-NP delivery of Niclosamide improved both functional range of motion recovery and increased the mechanical integrity of the healing tendon across both short- and longer-term timepoints. Importantly, these sustained effects occurred with just a single treatment.
Researchers will continue their work to define how broadly the system can be used for other tendon injuries and disease, as well as other types of tissue injury that result in scar formation.
“The beauty of this system is that it can be loaded with different kinds of drugs to target different molecular processes or pathways,” said Adjei-Sowah.

The hypothalamus is a small region of the human brain typically associated with regulating body temperature, hunger, thirst, fatigue, and sleep. But it also has another important role: helping the brain and body switch between different and opposing survival behaviors such as hunting prey and escaping predators. That’s the conclusion of a new study publishing June 27th in the open-access journal PLOS Biology by Jaejoong Kim and Dean Mobbs of California Institute of Technology, US, and colleagues.
Previous studies in animals have suggested that the hypothalamus is critical in switching between behaviors, but it has been unclear if this is the case in humans. Studying the brain region in humans is challenging because of the tiny size of the hypothalamus; several of its subregions are below the resolution of typical functional magnetic resonance imaging (fMRI) scans.
In the new study, the researchers developed artificial-intelligence-based approaches to optimize and analyze fMRI scans of the brains of 21 healthy individuals, taken over four-hour periods while people were engaged in a hunting and escaping survival game within the fMRI scanner. Participants had to control an avatar, switching between hunting prey and escaping a predator.
The researchers built a computational model to explain the differences in movement patterns that characterized hunting behavior compared to escaping behavior. Then, they analyzed how changes in movements were linked with subtle changes in hypothalamus activity. Using this approach, the team discovered that patterns of neural activity in the hypothalamus, as well as nearby regions of the brain that are directly connected to the hypothalamus, are associated with behavior switching — at least for survival behaviors. Moreover, the strength of this hypothalamus signaling could predict how well someone would perform in their next survival task. While the association was seen for switching between hunting and escaping behaviors, it was not observed for switching between other behaviors.
The authors conclude that the hypothalamus plays a key role in how the human brain switches between and coordinates survival behaviors — a function that is important and evolutionarily advantageous.
The authors add, “New research demonstrates the vital role of the human hypothalamus in switching between survival behaviors such as hunting and escaping, employing advanced imaging and computational modeling methods. This research also reveals how the hypothalamus interacts with other brain regions to coordinate these survival strategies.”

What happens when measles virus meets a human cell? The viral machinery unfolds in just the right way to reveal key pieces that let it fuse itself into the host cell membrane.
Once the fusion process is complete, the host cell is a goner. It belongs to the virus now.
Scientists in the La Jolla Institute for Immunology (LJI) Center for Vaccine Innovation are working to develop new measles vaccines and therapeutics that stop this fusion process. The researchers recently harnessed an imaging technique called cryo-electron microscopy to show — in unprecedented detail — how a powerful antibody can neutralize the virus before it completes the fusion process.
“What’s exciting about this study is that we’ve captured snapshots of the fusion process in action,” explains LJI Professor, President and CEO Erica Ollmann Saphire, Ph.D., who co-led the Science study with Matteo Porotto, Ph.D., Professor of Viral Molecular Pathogenesis (in Pediatrics) at Columbia University. “The series of images is like a flip book where we see snapshots along the way of the fusion protein unfolding, but then we see the antibody locking it together before it can complete the last stage in the fusion process. We think other antibodies against other viruses will do the same thing but have not been imaged like this before.”
Indeed this work may prove important beyond measles. Measles virus is just one member of the larger paramyxovirus family, which also includes the deadly Nipah virus. Nipah virus is known for being less contagious but causing a much higher mortality rate than measles.
“What we learn about the fusion process can be medically relevant for Nipah, parainfluenza viruses, and Hendra virus,” says study first author and LJI Postdoctoral Researcher Dawid Zyla, Ph.D. “These are all viruses with pandemic potential.”
The urgent need for measles treatments
Measles is a highly contagious, airborne disease that tends to strike children the hardest. Despite extensive vaccine efforts, the virus remains a major health threat. According to the World Health Organization and the U.S. Centers for Disease Control, measles caused around 136,000 deaths globally in 2022, with recent outbreaks in over a dozen U.S. states. The victims were mostly children under age five who were unvaccinated or undervaccinated.

“Measles causes more childhood deaths than any other vaccine-preventable disease, and it’s also one of the most infectious viruses known,” says Saphire.
It’s not just young children at risk, explains Zyla. “The current vaccine works well, but it cannot be taken by pregnant people or people with compromised immune systems,” Zyla says.
There is no specific treatment for measles, so researchers are looking for antibodies to use as an emergency treatment to prevent severe disease.
To better understand how the measles virus fuses with cells, the LJI team turned to an antibody called mAb 77. Researchers have found that mAb 77 targets the measles fusion glycoprotein, the piece of viral machinery measles uses to enter human cells via a specialized process called fusion.
Could mAb 77 work as a therapeutic antibody against measles? To find out, the LJI scientists investigated exactly how the antibody combats the virus.
Membrane fusion, interrupted
The LJI team needed to engineer a version of the measles fusion glycoprotein — a harmless fragment of the virus — stable enough to image with a cryo-electron microscope. To do this, Zyla worked closely with scientists in Porotto’s laboratory at Columbia University.

Porotto’s group had uncovered some strange mutations in a measles variant that attacked peoples’ central nervous systems. This mutated variant had some weak points in its fusion glycoprotein structure. To compensate, the virus had evolved special stabilizing mutations. “The virus has to mutate to go into the brain, but then it needs these stabilizing mutations to compensate,” says Porotto.
Thanks to these discoveries at Columbia, Zyla had a handy blueprint for engineering a fusion glycoprotein with these same stabilizing mutations. This new fusion glycoprotein could be mass produced in cell culture, and it was sturdy enough for structural investigations.
“We got extremely good yields for the glycoprotein, which also enabled us to do structural biology and biochemical and biophysical studies,” says Zyla.
Next, the researchers started capturing images with the help of the LJI Cryoelectron Microscopy Core. The new images showed the fusion glycoprotein together “in complex” with mAb 77.
The researchers found mAb 77 arrests the virus in the middle of the fusion process — when fusion glycoprotein is already part way done “folding” into the right conformation to complete membrane fusion. At last, the researchers could see exactly how mAb 77 locks together pieces of the fusion glycoprotein to prevent viral infection.
“It was striking to see what this intermediate step in the fusion process actually looks like,” says Zyla.
Next steps for stopping measles
Now that they know how mAb 77 works, the researchers hope the antibody could be used as part of a treatment cocktail to protect people against measles or to treat people with active measles infection.
In a follow-up experiment, the researchers showed that mAb 77 provided significant protection against measles in cotton rat models of measles virus infection. Cotton rats pretreated with mAb 77 prior to measles virus exposure showed either no infection or reduced signs of infection in their lung tissue.
Going forward, Saphire and Zyla are interested in studying different antibodies against measles. “We’d like to stop fusion at different points in the process and investigate other therapeutic opportunities,” Zyla says.
Zyla also plans to continue working closely with measles researchers at Columbia University. “The combination of structural biology expertise from LJI and cell biology and virology expertise from Columbia was key to pushing this project forward,” says Zyla.
This research was supported by the National Institutes of Health (NS105699, NS091263, and AI176833), Swiss National Science Foundation Postdoc Mobility fellowships (P2EZP3_195680 and P500PB_210992), the Measles Virus Biobank, the Dutch Research Council NWO Gravitation 2013 BOO, Institute for Chemical Immunology (ICI 024.002.009), and institutional funds of La Jolla Institute for Immunology (EOS)

Researchers from MIT and the University of Michigan have discovered a new way to drive chemical reactions that could generate a wide variety of compounds with desirable pharmaceutical properties.
These compounds, known as azetidines, are characterized by four-membered rings that include nitrogen. Azetidines have traditionally been much more difficult to synthesize than five-membered nitrogen-containing rings, which are found in many FDA-approved drugs.
The reaction that the researchers used to create azetidines is driven by a photocatalyst that excites the molecules from their ground energy state. Using computational models that they developed, the researchers were able to predict compounds that can react with each other to form azetidines using this kind of catalysis.
“Going forward, rather than using a trial-and-error process, people can prescreen compounds and know beforehand which substrates will work and which ones won’t,” says Heather Kulik, an associate professor of chemistry and chemical engineering at MIT.
Kulik and Corinna Schindler, a professor of chemistry at the University of Michigan, are the senior authors of the study, which appears today in Science. Emily Wearing, recently a graduate student at the University of Michigan, is the lead author of the paper. Other authors include University of Michigan postdoc Yu-Cheng Yeh, MIT graduate student Gianmarco Terrones, University of Michigan graduate student Seren Parikh, and MIT postdoc Ilia Kevlishvili.
Light-driven synthesis
Many naturally occurring molecules, including vitamins, nucleic acids, enzymes and hormones, contain five-membered nitrogen-containing rings, also known as nitrogen heterocycles. These rings are also found in more than half of all FDA-approved small-molecule drugs, including many antibiotics and cancer drugs.

Four-membered nitrogen heterocycles, which are rarely found in nature, also hold potential as drug compounds. However, only a handful of existing drugs, including penicillin, contain four-membered heterocycles, in part because these four-membered rings are much more difficult to synthesize than five-membered heterocycles.
In recent years, Schindler’s lab has been working on synthesizing azetidines using light to drive a reaction that combines two precursors, an alkene and an oxime. These reactions require a photocatalyst, which absorbs light and passes the energy to the reactants, making it possible for them to react with each other.
“The catalyst can transfer that energy to another molecule, which moves the molecules into excited states and makes them more reactive. This is a tool that people are starting to use to make it possible to make certain reactions occur that wouldn’t normally occur,” Kulik says.
Schindler’s lab found that while this reaction sometimes worked well, other times it did not, depending on which reactants were used. They enlisted Kulik, an expert in developing computational approaches to modeling chemical reactions, to help them figure out how to predict when these reactions will occur.
The two labs hypothesized that whether a particular alkene and oxime will react together in a photocatalyzed reaction depends on a property known as the frontier orbital energy match. Electrons that surround the nucleus of an atom exist in orbitals, and quantum mechanics can be used to predict the shape and energies of these orbitals. For chemical reactions, the most important electrons are those in the outermost, highest energy (“frontier”) orbitals, which are available to react with other molecules.
Kulik and her students used density functional theory, which uses the Schrödinger equation to predict where electrons could be and how much energy they have, to calculate the orbital energy of these outermost electrons.

These energy levels are also affected by other groups of atoms attached to the molecule, which can change the properties of the electrons in the outermost orbitals.
Once those energy levels are calculated, the researchers can identify reactants that have similar energy levels when the photocatalyst boosts them into an excited state. When the excited states of an alkene and an oxime are closely matched, less energy is required to boost the reaction to its transition state — the point at which the reaction has enough energy to go forward to form products.
Accurate predictions
After calculating the frontier orbital energies for 16 different alkenes and nine oximes, the researchers used their computational model to predict whether 18 different alkene-oxime pairs would react together to form an azetidine. With the calculations in hand, these predictions can be made in a matter of seconds.
The researchers also modeled a factor that influences the overall yield of the reaction: a measure of how available the carbon atoms in the oxime are to participate in chemical reactions.
The model’s predictions suggested that some of these 18 reactions won’t occur or won’t give a high enough yield. However, the study also showed that a significant number of reactions are correctly predicted to work.
“Based on our model, there’s a much wider range of substrates for this azetidine synthesis than people thought before. People didn’t really think that all of this was accessible,” Kulik says.
Of the 27 combinations that they studied computationally, the researchers tested 18 reactions experimentally, and they found that most of their predictions were accurate. Among the compounds they synthesized were derivatives of two drug compounds that are currently FDA-approved: amoxapine, an antidepressant, and indomethacin, a pain reliever used to treat arthritis.
This computational approach could help pharmaceutical companies predict molecules that will react together to form potentially useful compounds, before spending a lot of money to develop a synthesis that might not work, Kulik says. She and Schindler are continuing to work together on other kinds of novel syntheses, including the formation of compounds with three-membered rings.
“Using photocatalysts to excite substrates is a very active and hot area of development, because people have exhausted what you can do on the ground state or with radical chemistry,” Kulik says. “I think this approach is going to have a lot more applications to make molecules that are normally thought of as really challenging to make.”

Drug development is typically slow: the pipeline from basic research discoveries that provide the basis for a new drug to clinical trials to production of a widely available medicine can take decades. But decades can feel impossibly far off to someone who currently has a fatal disease. Broad Institute Senior Group Leader Sonia Vallabh is acutely aware of that race against time, because the topic of her research is a neurodegenerative and ultimately fatal disease-fatal familial insomnia, a type of prion disease-that she will almost certainly develop as she ages. Vallabh and her husband, Eric Minikel, switched careers and became researchers after they learned that Vallabh carries a disease-causing version of the prion protein gene and that there is no effective therapy for fatal prion diseases. The two now run a lab at Broad Institute where they are working to develop drugs that can prevent and treat these diseases, and their deadline for success is not based on grant cycles or academic expectations but on the ticking time bomb in Vallabh’s genetic code.
That is why Vallabh was excited to discover, when she entered into a collaboration with Whitehead Institute Member Jonathan Weissman, that Weissman’s group likes to work at full throttle. In less than two years, Weissman, Vallabh, and their collaborators have developed a set of molecular tools called CHARMs that can turn off disease-causing genes such as the prion protein gene — as well as, potentially, genes coding for many other proteins implicated in neurodegenerative and other diseases — and they are refining those tools to be good candidates for use in human patients. Although the tools still have many hurdles to pass before the researchers will know if they work as therapeutics, the team is encouraged by the speed with which they have developed the technology thus far.
“The spirit of the collaboration since the beginning has been that there was no waiting on formality,” Vallabh says. “As soon as we realized our mutual excitement to do this, everything was off to the races.”
Co-corresponding authors Weissman and Vallabh and co-first authors Edwin Neumann, a graduate student in Weissman’s lab, and Tessa Bertozzi, a postdoc in Weissman’s lab, describe CHARM — which stand for Coupled Histone tail for Autoinhibition Release of Methyltransferase — in a paper published in the journal Science on June 27.
“With the Whitehead and Broad Institutes right next door to each other, I don’t think there’s any better place than this for a group of motivated people to move quickly and flexibly in the pursuit of academic science and medical technology,” says Weissman, who is also a professor of biology at the Massachusetts Institute of Technology and an HHMI Investigator. “CHARMs are an elegant solution to the problem of silencing disease genes, and they have the potential to have an important position in the future of genetic medicines.”
To treat a genetic disease, target the gene
Prion disease, which leads to swift neurodegeneration and death, is caused by the presence of misshapen versions of the prion protein. These cause a cascade effect in the brain: the faulty prion proteins deform other proteins, and together these proteins not only stop functioning properly but also form toxic aggregates that kill neurons. The most famous type of prion disease, known colloquially as mad cow disease, is infectious, but other forms of prion disease can occur spontaneously or be caused by faulty prion protein genes.

Most conventional drugs work by targeting a protein. CHARMs, however, work further upstream, turning off the gene that codes for the faulty protein so that the protein never gets made in the first place. CHARMs do this by epigenetic editing, in which a chemical tag gets added to DNA in order to turn off or silence a target gene. Unlike gene editing, epigenetic editing does not modify the underlying DNA — the gene itself remains intact. However, like gene editing, epigenetic editing is stable, meaning that a gene switched off by CHARM should remain off. This would mean patients would only have to take CHARM once, as opposed to protein-targeting medications that must be taken regularly as the cells’ protein levels replenish.
Research in animals suggests that the prion protein isn’t necessary in a healthy adult, and that in cases of disease, removing the protein improves or even eliminates disease symptoms. In a person who hasn’t yet developed symptoms, removing the protein should prevent disease altogether. In other words, epigenetic editing could be an effective approach for treating genetic diseases such as inherited prion diseases. The challenge is creating a new type of therapy.
Fortunately, the team had a good template for CHARM: a research tool called CRISPRoff that Weissman’s group previously developed for silencing genes. CRISPRoff uses building blocks from CRISPR gene editing technology, including the guide protein Cas9 that directs the tool to the target gene. CRISPRoff silences the targeted gene by adding methyl groups, chemical tags that prevent the gene from being transcribed or read into RNA and so from being expressed as protein. When the researchers tested CRISPRoff’s ability to silence the prion protein gene, they found that it was effective and stable.
Several of its properties, though, prevented CRISPRoff from being a good candidate for a therapy. The researchers’ goal was to create a tool based on CRISPRoff that was just as potent but also safe for use in humans, small enough to deliver to the brain, and designed to minimize the risk of silencing the wrong genes or causing side effects.
From research tool to drug candidate
Led by Neumann and Bertozzi, the researchers began engineering and applying their new epigenome editor. The first problem that they had to tackle was size, because the editor needs to be small enough to be packaged and delivered to specific cells in the body. Delivering genes into the human brain is challenging; many clinical trials have used adeno-associated viruses (AAVs) as gene-delivery vehicles, but these are small and can only contain a small amount of genetic code. CRISPRoff is way too big; the code for Cas9 alone takes up most of the available space.

The Weissman lab researchers decided to replace Cas9 with a much smaller zinc finger protein (ZFP). Like Cas9, ZFPs can serve as guide proteins to direct the tool to a target site in DNA. ZFPs are also common in human cells, meaning they are less likely to trigger an immune response against themselves than the bacterial Cas9.
Next, the researchers had to design the part of the tool that would silence the prion protein gene. At first, they used part of a methyltransferase, a molecule that adds methyl groups to DNA, called DNMT3A. However, in the particular configuration needed for the tool, the molecule was toxic to the cell. The researchers focused on a different solution: instead of delivering outside DNMT3A as part of the therapy, the tool is able to recruit the cell’s own DNMT3A to the prion protein gene. This freed up precious space inside of the AAV vector and prevented toxicity.
The researchers also needed to activate DNMT3A. In the cell, DNMT3A is usually inactive until it interacts with certain partner molecules. This default inactivity prevents accidental methylation of genes that need to remain turned on. Neumann came up with an ingenious way around this by combining sections of DNMT3A’s partner molecules and connecting these to ZFPs that bring them to the prion protein gene. When the cell’s DNMT3A comes across this combination of parts, it activates, silencing the gene.
“From the perspectives of both toxicity and size, it made sense to recruit the machinery that the cell already has; it was a much simpler, more elegant solution,” Neumann says. “Cells are already using methyltransferases all of the time, and we’re essentially just tricking them into turning off a gene that they would normally leave turned on.”
Testing in mice showed that ZFP-guided CHARMs could eliminate more than 80% of the prion protein in the brain, while previous research has shown that as little as 21% elimination can improve symptoms.
Once the researchers knew that they had a potent gene silencer, they turned to the problem of off-target effects. The genetic code for a CHARM that gets delivered to a cell will keep producing copies of the CHARM indefinitely. However, after the prion protein gene is switched off, there is no benefit to this, only more time for side effects to develop, so they tweaked the tool so that after it turns off the prion protein gene, it then turns itself off.
Meanwhile, a complementary project from Broad Institute scientist and collaborator Benjamin Deverman’s lab, focused on brain-wide gene delivery and published in Science on May 17, has brought the CHARM technology one step closer to being ready for clinical trials. Although naturally occurring types of AAV have been used for gene therapy in humans before, they do not enter the adult brain efficiently, making it impossible to treat a whole-brain disease like prion disease. Tackling the delivery problem, Deverman’s group has designed an AAV vector that can get into the brain more efficiently by leveraging a pathway that naturally shuttles iron into the brain. Engineered vectors like this one make a therapy like CHARM one step closer to reality.
Thanks to these creative solutions, the researchers now have a highly effective epigenetic editor that is small enough to deliver to the brain, and that appears in cell culture and animal testing to have low toxicity and limited off-target effects.
“It’s been a privilege to be part of this; it’s pretty rare to go from basic research to therapeutic application in such a short amount of time,” Bertozzi says. “I think the key was forming a collaboration that took advantage of the Weissman lab’s tool building experience, the Vallabh and Minikel lab’s deep knowledge of the disease, and the Deverman lab’s expertise in gene delivery.”
Looking ahead
With the major elements of the CHARM technology solved, the team is now fine-tuning their tool to make it more effective, safer, and easier to produce at scale as will be necessary for clinical trials. They have already made the tool modular, so that its various pieces can be swapped out and future CHARMs won’t have to be programmed from scratch. CHARMs are also currently being tested as therapeutics in mice.
The path from basic research to clinical trials is a long and winding one, and the researchers know that CHARMs still have a way to go before they might become a viable medical option for people with prion diseases, including Vallabh, or other diseases with similar genetic components. However, with a strong therapy design and promising laboratory results in hand, the researchers have good reason to be hopeful. They continue to work at full throttle, intent on developing their technology so that it can save patients’ lives not someday, but as soon as possible.

For a broad range of industries, separating gases is an important part of both process and product — from separating nitrogen and oxygen from air for medical purposes to separating carbon dioxide from other gases in the process of carbon capture or removing impurities from natural gas.
Separating gases, however, can be both energy-intensive and expensive. “For example, when separating oxygen and nitrogen, you need to cool the air to very low temperatures until they liquefy. Then, by slowly increasing the temperature, the gases will evaporate at different points, allowing one to become a gas again and separate out,” explains Wei Zhang, a University of Colorado Boulder professor of chemistry and chair of the Department of Chemistry. “It’s very energy intensive and costly.”
Much gas separation relies on porous materials through which gases pass and are separated. This, too, has long presented a problem, because these porous materials generally are specific to the types of gases being separated. Try sending any other types of gas through them and they don’t work.
However, in research published today in the journal Science, Zhang and his co-researchers detail a new type of porous material that can accommodate and separate many different gases and is made from common, readily available materials. Further, it combines rigidity and flexibility in a way that allows size-based gas separation to happen at a greatly decreased energy cost. “We are trying to make technology better,” Zhang says, “and improve it in a way that’s scalable and sustainable.”
Adding flexibility
For a long time, the porous materials used in gas separation have been rigid and affinity-based — specific to the types of gases being separated. The rigidity allows the pores to be well-defined and helps direct the gases in separating, but also limits the number of gases that can pass through because of varying molecule sizes.
For several years, Zhang and his research group worked to develop a porous material that introduces an element of flexibility to a linking node in otherwise rigid porous material. That flexibility allows the molecular linkers to oscillate, or move back and forth at a regular speed, changing the accessible pore size in the material and allowing it to be adapted to multiple gases.

“We found that at room temperature, the pore is relatively the largest and the flexible linker barely moves, so most gases can get in,” Zhang says. “When we increase the temperature from room temperature to about 50 degrees (Celsius), oscillation of the linker becomes larger, causing effective pore size to shrink, so larger gases can’t get in. If we keep increasing the temperature, more gases are turned away due to increased oscillation and further reduced pore size. Finally, at 100 degrees, only the smallest gas, hydrogen, can pass through.”
The material that Zhang and his colleagues developed is made of small organic molecules and is most analogous to zeolite, a family of porous, crystalline materials mostly comprised of silicon, aluminum and oxygen. “It’s a porous material that has a lot of highly ordered pores,” he says. “You can picture it like a honeycomb. The bulk of it is solid organic material with these regular-sized pores that line up and form channels.”
The researchers used a fairly new type of dynamic covalent chemistry that focuses on the boron-oxygen bond. Using a boron atom with four oxygen atoms around it, they took advantage of the reversibility of the bond between the boron and oxygen, which can break and reform again and again, thus enabling self-correcting, error-proof behavior and leading to the formation of structurally ordered frameworks.
“We wanted to build something with tunability, with responsiveness, with adaptability, and we thought the boron-oxygen bond could be a good component to integrate into the framework we were developing, because of its reversibility and flexibility,” Zhang says.
Sustainable solutions
Developing this new porous material did take time, Zhang says: “Making the material is easy and simple. The difficulty was at the very beginning, when we first obtained the material and needed to understand or elucidate its structure — how the bonds form, how angles form within this material, is it two-dimensional or three-dimensional. We had some challenges because the data looked promising, we just didn’t know how to explain it. It showed certain peaks (x-ray diffraction), but we could not immediately figure out what kind of structure those peaks corresponded to.”
So, he and his research colleagues took a step back, which can be an important but little-discussed part of the scientific process. They focused on the small-molecule model system containing the same reactive sites as those in their material to understand how molecular building blocks packed in a solid state, and that helped explain the data.

Zhang adds that he and his co-researchers considered scalability in developing this material, since its potential industrial uses would require large amounts, “and we believe this method is highly scalable. The building blocks are commercially available and not expensive, so it could be adopted by industry when the time is right.”
They have applied for a patent on the material and are continuing the research with other building block materials to learn the substrate scope of this approach. Zhang also says he sees potential to partner with engineering researchers to integrate the material into membrane-based applications.
“Membrane separations generally require much less energy, so in the long term they could be more sustainable solutions,” Zhang says. “Our goal is to improve technology to meet industry needs in sustainable ways.”

Dementia risk factors associated with cardiovascular health may have increased over time compared to factors such as smoking and having less education, finds a new study led by UCL researchers.
The study, published in The Lancet Public Health, explored how the prevalence of dementia risk factors had changed over time and how this could impact rates of dementia in the future.
It is estimated that there are currently 944,000 people living with dementia in the UK and 52% of the UK public — 34.5 million — know someone who has been diagnosed with a form of the disease. It is one of the nation’s biggest killers and has been the leading cause of death in women in the UK since 2011.
There has been increasing interest in potentially modifiable risk factors, as eliminating these could theoretically prevent around 40% of dementia cases, according to research led by UCL academics.
For the new study, the researchers analysed 27 papers, involving people with dementia across the globe with data collected between 1947 and 2015, and the latest paper published in 2020. They extracted data from each paper about dementia risk factors and calculated what proportion of dementia cases were attributable to each one, over time.
Dementia usually develops because of a combination of genetic and environmental factors, including hypertension, obesity, diabetes, education and smoking.
The team found that having less education and smoking had become less common over time and was associated with a decline in rates of dementia. Rates of obesity and diabetes have increased over time, as has their contribution to dementia risk.

The greatest dementia risk factor remained as hypertension in most of the studies that were reviewed although it is worth noting proactive management of hypertension has also increased over time.
Lead author, Dr Naaheed Mukadam (UCL Psychiatry), said: “Cardiovascular risk factors may have contributed more to dementia risk over time, so these deserve more targeted action for future dementia prevention efforts.
“Our results show that levels of education have increased over time in many higher income countries, meaning that this has become a less important dementia risk factor. Meanwhile, smoking levels have also declined in Europe and the USA as it has become less socially acceptable and more expensive.
“These patterns suggest that population-level interventions could significantly impact the occurrence of dementia risk factors, and governments should consider implementing schemes such as worldwide policies of education, and restrictions on smoking.”
This study was funded by the National Institute for Health and Care Research (NIHR) Three Schools’ Dementia Research Programme.
Study limitations
While reported levels of cardiovascular risk factors, in particular, may have increased over time, the proactive management of these conditions has also increased over time in many countries so the effect on dementia may be neutral or may contribute less risk to dementia over time.
Additionally, all studies analysed in the new research were from 2015 and earlier so may not reflect how trends may have changed since that time.