Worldwide, a majority of babies — approximately 75% — drink infant formula in their first six months of life, either as a sole source of nutrition or as a supplement to breastfeeding. But while formula provides essential food for growing babies, it currently does not replicate the full nutritional profile of breast milk.
That’s in part because human breast milk contains a unique blend of approximately 200 prebiotic sugar molecules that help prevent disease and support the growth of healthy gut bacteria. However, most of these sugars remain difficult, if not impossible, to manufacture.
New research led by scientists at the University of California, Berkeley, and the University of California, Davis, shows how genetically engineered plants may help close this gap.
In a new study published today in the journal Nature Food, the study team reprogrammed plants’ sugar-making machinery to produce a diverse array of these human milk sugars, also called human milk oligosaccharides. The findings could lead to healthier and more affordable formula for babies, or more nutritious non-dairy plant milk for adults.
“Plants are these phenomenal organisms that take sunlight and carbon dioxide from our atmosphere and use them to make sugars. And they don’t just make one sugar — they make a whole diversity of simple and complex sugars,” said study senior author Patrick Shih, an assistant professor of plant and microbial biology and an investigator at UC Berkeley’s Innovative Genomics Institute. “We thought, since plants already have this underlying sugar metabolism, why don’t we try rerouting it to make human milk oligosaccharides?”
All complex sugars — including human milk oligosaccharides — are made from building blocks of simple sugars, called monosaccharides, which can be linked together to form a vast array of chains and branched chains. What makes human milk oligosaccharides unique are the specific set of linkages, or rules, for connecting simple sugars together that are found in these molecules.
To convince plants to make human milk oligosaccharides, study first author Collin Barnum engineered the genes responsible for the enzymes that make these specific linkages. Working with Daniela Barile, David Mills and Carlito Lebrilla at UC Davis, he then introduced the genes into the Nicotiana benthamiana plant, a close relative of tobacco.

The genetically modified plants produced 11 known human milk oligosaccharides, along with a variety of other complex sugars with similar linkage patterns.
“We made all three major groups of human milk oligosaccharides,” Shih said. “To my knowledge, no one has ever demonstrated that you could make all three of these groups simultaneously in a single organism.”
Barnum then worked to create a stable line of N. benthamiana plants that were optimized to produce a single human milk oligosaccharide called LNFP1.
“LNFP1 is a five-monosaccharide-long human milk oligosaccharide that is supposed to be really beneficial, but so far cannot be made at scale using traditional methods of microbial fermentation,” said Barnum, who completed the work as a graduate student at UC Davis. “We thought that if we could start making these larger, more complex human milk oligosaccharides, we could solve a problem that that industry currently can’t solve.”
Currently, a small handful of human milk oligosaccharides can be manufactured using engineered E. coli bacteria. However, isolating the beneficial molecules from other toxic byproducts is a costly process, and only a limited number of baby formulas include these sugars in their mixtures.
As part of the study, Shih and Barnum worked with collaborator Minliang Yang at North Carolina State University to estimate the cost of producing human milk oligosaccharides from plants at an industrial scale and found that it would likely be cheaper than using microbial platforms.
“Imagine being able to make all the human milk oligosaccharides in a single plant. Then you could just grind up that plant, extract all the oligosaccharides simultaneously and add that directly into infant formula,” Shih said. “There would be a lot of challenges in implementation and commercialization, but this is the big goal that we’re trying to move toward.”
Additional authors include Bruna Paviani, Garret Couture, Chad Masarweh, Ye Chen, Yu-Ping Huang, David A. Mills, Carlito B. Lebrilla and Daniela Barile of UC Davis; Kasey Markel of UC Berkeley; and Minliang Yang of North Carolina State University.
This work was supported in part by the National Institutes of Health (NIGMS T32 Training Program), the U.S. Department of Energy and the National Center for Complementary and Integrative Health (R00AT009573)

An analysis of reviews of translational biomedical research reveals that just 5% of therapies tested in animals reach regulatory approval for human use. The study, an umbrella review, published June 13 in the open access journal PLOS Biology, summarizes other systematic reviews and provides high level evidence that while the rate of translation to human studies is 50%, there is steep drop off before final approval. The authors argue that improved robustness and generalizability of experimental approaches could help increase the chances of translation and final approval.
Animal studies are used in basic research to provide insight into aspects of human diseases. They have paved the way for certain therapeutic innovations, although there are several steps that follow before a treatment can be approved for human use. In debates about the ethics of animal research, clinical translation is one of the main justifications of such work, yet there is little evidence on how many studies make it through each step and are finally approved.
Benjamin Ineichen of the University of Zurich, Switzerland, and colleagues meta-analyzed 122 systematic reviews that evaluated the translation of therapies from animals to humans. They assessed how many advanced to any human study, to a randomized controlled trial and to regulatory approval as well as looking at consistency between animal and human study results. They found that of 367 therapeutic interventions tested in 54 human diseases, 50% progressed from human to animal studies, 40% to randomized controlled trials and only 5% to regulatory approval. There was a high rate — 86% — of alignment between animal and human studies, and the average time periods for reaching the different stages were five years to any human study, seven years to randomized controlled trials and 10 years to regulatory approval.
Although the number of studies crossing the first stage is higher than previous evidence has suggested, the low rate of final approval suggests there could be deficiencies to address in the design of both animal and early clinical studies.
The authors add, “To improve animal-to-human translation, we advocate for enhanced study design robustness of animal and human research which will not only benefit experimental animals but also affected patients.”

Observing anything and everything within the human brain, no matter how large or small while it is fully intact, has been an out-of-reach dream of neuroscience for decades, but in a new study in Science, an MIT-based team describes a technology pipeline that enabled them to finely process, richly label and sharply image full hemispheres of the brains of two donors — one with Alzheimer’s and one without — at high resolution and speed.
“We performed holistic imaging of human brain tissues at multiple resolutions from single synapses to whole brain hemispheres and we have made that data available,” said senior and corresponding author Kwanghun Chung, associate professor in The Picower Institute for Learning and Memory, the Departments of Chemical Engineering and Brain and Cognitive Sciences, and the Institute for Medical Engineering and Science at MIT. “This technology pipeline really enables us to analyze the human brain at multiple scales. Potentially this pipeline can be used for fully mapping human brains.”
The new study does not already present a comprehensive map or atlas of the entire brain, in which every cell, circuit and protein is identified and analyzed, but with full hemispheric imaging, it demonstrates an integrated suite of three technologies to enable that and other long-sought neuroscience investigations. The research provides a “proof of concept” by showing numerous examples of what the pipeline makes possible, including sweeping landscapes of thousands of neurons within whole brain regions, diverse forests of cells each in individual detail, and tufts of subcellular structures nestled among extracellular molecules. The researchers also present a rich variety of quantitative analytical comparisons focused on a chosen region within the Alzheimer’s and non-Alzheimer’s hemispheres.
The importance of being able to image whole hemispheres of human brains intact and down to the resolution of individual synapses (the teeny connections that neurons forge to make circuits) is two-fold for understanding the human brain in health and disease, Chung said.
On one hand, it will enable scientists to conduct integrated explorations of questions using the same brain, rather than having to, for example, observe different phenomena in different brains, which can vary significantly, and then trying to construct a composite picture of the whole system. A key feature of the new technology pipeline is that analysis doesn’t degrade the tissue. On the contrary, it makes the tissues extremely durable and repeatedly re-labelable to highlight different cells or molecules as needed for new studies for potentially years on end. In the paper Chung’s team demonstrates using 20 different antibody labels to highlight different cells and proteins but they are already expanding that to a hundred or more.
“We need to be able to see all these different functional components — cells, their morphology and their connectivity, subcellular architectures, and their individual synaptic connections — ideally within the same brain, considering the high individual variabilities in the human brain and considering the precious nature of human brain samples,” Chung said. “This technology pipeline really enables us to extract all these important features from the same brain in a fully integrated manner.”
On the other hand, the pipeline’s relatively high scalability and throughput (imaging a whole brain hemisphere once it is prepared takes 100 hours rather than many months) means that it is possible to create many samples to represent different sexes, ages, disease states and other factors that can enable robust comparisons with increased statistical power. Chung said he envisions creating a brain bank of fully imaged brains that researchers could analyze and re-label as needed for new studies to make more of the kinds of comparisons he and co-authors made with the Alzheimer’s and non-Alzheimer’s hemispheres in the new paper.

Three key innovations
Chung said the biggest challenge he faced in achieving the advances described in the paper was building a team at MIT that included three especially talented young scientists, each a co-lead author of the paper because of their key roles in producing the three major innovations. Ji Wang, a mechanical engineer and former postdoc, developed the “Megatome,” a device for slicing intact human brain hemispheres so finely that there is no damage to it. Juhyuk Park, a materials engineer and former postdoc, developed the chemistry that makes each brain slice clear, flexible, durable, expandable, and quickly, evenly and repeatedly labelable — a technology called “mELAST.” Webster Guan, a former MIT chemical engineering graduate student with a knack for software development, created a computational system called “UNSLICE” that can seamlessly reunify the slabs to reconstruct each hemisphere in full 3D down to the precise alignment of individual blood vessels and neural axons (the long strands they extend to forge connections with other neurons).
No technology allows for imaging whole human brain anatomy at subcellular resolution without first slicing it because it is very thick (it’s 3,000 times the volume of a mouse brain) and opaque. But in the Megatome, tissue remains undamaged because Wang, who is now at a company Chung founded called LifeCanvas Technologies, engineered its blade to vibrate side to side faster and yet sweep wider than previous vibratome slicers. Meanwhile she also crafted the instrument to stay perfectly within its plane, Chung said. The result are slices that don’t lose anatomical information at their separation or anywhere else. And because the vibratome cuts relatively quickly and can cut thicker (and therefore fewer) slabs of tissue, a whole hemisphere can be sliced in a day, rather than months.
A major reason why slabs in the pipeline can be thicker comes from mELAST. Park engineered the hydrogel that infuses the brain sample to make it optically clear, virtually indestructible and compressible and expandable. Combined with other chemical engineering technologies developed in recent years in Chung’s lab, the samples can then be evenly and quickly infused with the antibody labels that highlight cells and proteins of interest. Using a light sheet microscope the lab customized, a whole hemisphere can be imaged down to individual synapses in about 100 hours, the authors report in the study. Park is now an assistant professor at Seoul National University in South Korea. “This advanced polymeric network, which fine-tunes the physicochemical properties of tissues, enabled multiplexed multiscale imaging of the intact human brains,” Park said.
After each slab has been imaged, the task is then to restore an intact picture of the whole hemisphere computationally. Guan’s UNSLICE does this at multiple scales. For instance, at the middle, or “meso” scale, it algorithmically traces blood vessels coming into one layer from adjacent layers and matches them. But it also takes an even finer approach. To further register the slabs, the team purposely labeled neighboring neural axons in different colors (like the wires in an electrical fixture). That enabled UNSLICE to match layers up based on tracing the axons, Chung said. Guan is also now at LifeCanvas.
In the study the researchers present a litany of examples of what the pipeline can do. The very first figure demonstrates that the imaging allows one to richly label a whole hemisphere and then zoom in from the wide scale of brainwide structures to the level of circuits, then individual cells and then subcellular components such as synapses. Other images and videos demonstrate how diverse the labeling can be, revealing long axonal connections and the abundance and shape of different cell types including not only neurons but also astrocytes and microglia.

Exploring Alzheimer’s
For years Chung has collaborated with co-author Matthew Frosch, an Alzheimer’s researcher and director of the brain bank at Massachusetts General Hospital, to image and understand Alzheimer’s disease brains. With the new pipeline established they began an open-ended exploration, first noticing where within a slab of tissue they saw the greatest loss of neurons in the disease sample compared to the control. From there, they followed their curiosity — as the technology allowed them to do — ultimately producing a series of detailed investigations described in the paper.
“We didn’t lay out all these experiments in advance,” Chung said. “We just started by saying, ‘OK, let’s image this slab and see what we see.’ We identified brain regions with substantial neuronal loss so let’s see what’s happening there. ‘Let’s dive deeper.’ So we used many different markers to characterize and see the relationships between pathogenic factors and different cell types.
“This pipeline allows us to have almost unlimited access to the tissue,” Chung said. “We can always go back and look at something new.”
They focused most of their analysis in the orbitofrontal cortex within each hemisphere. One of the many observations they made was that synapse loss was concentrated in areas where there was direct overlap with amyloid plaques. Outside of areas of plaques the synapse density was as high in the brain with Alzheimer’s as in the one without the disease.
With just two samples, Chung said, the team is not offering any conclusions about the nature of Alzheimer’s disease, of course, but the point of the study is that the capability now exists to fully image and deeply analyze whole human brain hemispheres to enable exactly that kind of research.
Notably, the technology applies equally well to many other tissues in the body, not just brains.
“We envision that this scalable technology platform will advance our understanding of the human organ functions and disease mechanisms to spur development of new therapies,” the authors conclude.
In addition to Park, Wang, Guan, Chung and Frosch, the paper’s other authors are Lars A. Gjesteby, Dylan Pollack, Lee Kamentsky, Nicholas B. Evans, Jeff Stirman, Xinyi Gu, Chuanxi Zhao, Slayton Marx, Minyoung E. Kim, Seo Woo Choi, Michael Snyder, David Chavez, Clover Su-Arcaro, Yuxuan Tian, Chang Sin Park, Qiangge Zhang, Dae Hee Yun, Mira Moukheiber, Guoping Feng, X. William Yang, C. Dirk Keene, Patrick R. Hof, Satrajit S. Ghosh, and Laura J. Brattain.
The main funding for the work came from the National Institutes of Health, The Picower Institute for Learning and Memory, The JPB Foundation, and the NCSOFT Cultural Foundation.

Bacteriophages, viruses that attack and destroy bacteria, are everywhere in the natural world where they play a vital role in regulating microbe populations in ways that are not yet well understood.
New research led by the University of Utah and University College London (UCL) has found that plant bacterial pathogens are able to repurpose elements of their own bacteriophages, or phages, to wipe out competing microbes. These surprise findings suggest such phage-derived elements could someday be harnessed as an alternative to antibiotics, according to Talia Karasov, an assistant professor in the U’s School of Biological Sciences.
This result was hardly what she expected to find when she embarked on this research with an international team of scientists.
Microbial pathogens are all around, but only a fraction of the time do they sicken humans, other animals or plants, according to Karasov, whose primary research interest is in interactions between plants and microbial pathogens. The Karasov lab is seeking to understand the factors that lead to sickness and epidemics versus keeping the pathogens in check.
For its prior research, the lab looked at how a particular bacterial pathogen, Pseudomonas viridiflava, manifests in agricultural and wild settings. On cultivated land, they found, one variant would spread broadly in a crop field and become the dominant microbe present. But that was not the case on uncultivated land, prompting Karasov to find out why.
“We see that no single lineage of bacteria can dominate. We wondered whether the phages, the pathogens of our bacterial pathogens, could prevent single lineages from spreading — maybe phages were killing some strains and not others. That’s where our study started, but that’s not where it ended up,” Karasov said. “We looked in the genomes of plant bacterial pathogens to see which phages were infecting them. But it wasn’t the phage we found that was interesting. The bacteria had taken a phage and repurposed it for warfare with other bacteria, now using it to kill competing bacteria.”
According to her study published this week in Science, the pathogen acquires elements of the phages in the form of non-self-replicating clusters of repurposed phage called tailocins, which penetrate the outer membranes of other pathogens and kill them. After discovering this ongoing warfare in the bacterial pathogen populations, the Karasov lab and lab of Hernán Burbano at UCL mined the genomes of modern and historical pathogens to determine how the bacteria evolve to target one another.

“You can imagine an arms race between the bacteria where they’re trying to kill each other and trying to evolve resistance to one another over time,” Burbano said. “The herbarium samples from the past 200 years that we analyzed, provided a window into this arms race, providing insight into how bacteria evade being killed by their competitors.”
Mining herbarium specimens for their microbial DNA
Burbano has pioneered the use of herbarium specimens to explore the evolution of plants and their microbial pathogens. His lab sequences the genomes of both host plants and those of the microbes associated with the plant at the time of collection more than a century ago.
For the phage research, Burbano analyzed historical specimens of Arabidopsis thaliana, a plant from the mustard family commonly called thale cress, collected in southwestern Germany, comparing them and the microbes they harbored to plants growing today in the same part of Germany.
“We discovered that all the historical tailocins were present in our present-day dataset, suggesting that evolution has maintained the diversity of tailocin variants over the century-scale,” he said. “This likely indicates a finite set of possible resistance/sensitivity mechanisms within our studied bacterial population.
Lead author Talia Backman wonders if tailocins could help solve the impending crisis in antibiotic resistance seen in harmful bacteria that infect humans.

“We as a society are in dire need of new antibiotics, and tailocins have potential as new antimicrobial treatments,” said Backman, a graduate student in the Karasov lab. “While tailocins have been found previously in other bacterial genomes, and have been studied in lab settings, their impact and evolution in wild bacterial populations was not known. The fact that we found that these wild plant pathogens all have tailocins and these tailocins are evolving to kill neighboring bacteria shows how significant they may be in nature.”
Like most pesticides, many of our antibiotics were developed decades ago to kill a broad array of harmful organisms, ones that are both harmful and beneficial to human and plant health. Tailocins on the other hand, have greater specificity than most modern antibiotics, killing only a select few strains of bacteria, suggesting they could be deployed without laying waste to entire biological communities.
“This is basic research at this point, not yet ready for application, but I think that there is good potential that this could be adapted for treating infection,” Karasov said. “We as a society have, in how we treat both pests in agriculture and bacterial pathogens in humans, used uniform and broad-spectrum treatments. The specificity of tailocin killing is a way that you could imagine doing more finely tailored treatments.”
Titled “A phage tail-like bacteriocin suppresses competitors in metapopulations of pathogenic bacteria,” the study was published in the June 14 edition of Science. The research was supported by the National Institutes of Health, University of Utah startup funds, the Leverhulme Trust and the Royal Society. Participating in the research with the U School of Biological Sciences were University College London, the Max Planck Institute for Biology, the Complex Carbohydrate Research Center Analytical Services and Training Lab at the University of Georgia, New York University, the U’s Department of Biochemistry and Lawrence Berkeley National Laboratory.

A new study by investigators from Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system, reveals that computer software that helps inform clinicians’ decisions about a patient’s care can prevent 95% of medication errors in the operating room. The findings are reported in Anesthesia & Analgesia, published by Wolters Kluwer.
“Medication errors in the operating room have high potential for patient harm,” said senior author Karen C. Nanji, MD, MPH, a physician investigator in the Department of Anesthesia, Critical Care, and Pain Medicine at Massachusetts General Hospital and an associate professor in the Department of Anesthesia at Harvard Medical School. “Clinical decision support involves comprehensive software algorithms that provide evidence-based information to clinicians at the point-of-care to enhance decision-making and prevent errors.”
“While clinical decision support improves both efficiency and quality of care in operating rooms, it is still in the early stages of adoption,” added first author Lynda Amici, DNP, CRNA, of Cooper University Hospital (who was at Massachusetts General Hospital at the time of this study).
For the study, Nanji, Amici, and their colleagues obtained all safety reports involving medication errors documented by anesthesia clinicians for surgical procedures from August 2020 to August 2022 at Massachusetts General Hospital. Two independent reviewers classified each error by its timing and type, whether it was associated with patient harm and the severity of that harm, and whether it was preventable by clinical decision support algorithms.
The reviewers assessed 127 safety reports involving 80 medication errors, and they found that 76 (95%) of the errors would have been prevented by clinical decision support. Certain error types, such as wrong medication and wrong dose, were more likely to be preventable by clinical decision support algorithms than other error types.
“Our results support emerging guidelines from the Institute for Safe Medication Practices and the Anesthesia Patient Safety Foundation that recommend the use of clinical decision support to prevent medication errors in the operating room,” said Nanji. “Massachusetts General Hospital researchers have designed and built a comprehensive intraoperative clinical decision support software platform, called GuidedOR, that improves both quality of care and workflow efficiency. GuidedOR is currently implemented at our hospital and is being adopted at additional Mass General Brigham sites to make surgery and anesthesia safer for patients.”
Nanji noted that future research should include large multi-center randomized controlled trials to more precisely measure the effect of clinical decision support on medication errors in the operating room.
Authorship: Lynda D. Amici DNP, CRNA; Maria van Pelt, PhD, CRNA, FAAN; Laura Mylott, RN, PhD, NEA-BC; Marin Langlieb, BA; and Karen C. Nanji, MD, MPH. Funding: Research support was provided from institutional and/or departmental sources from Massachusetts General Hospital’s Department of Anesthesia, Critical Care, and Pain Medicine. Dr. Nanji is additionally supported by a grant from the Doris Duke Foundation.

Loneliness may be harmful to our daily health, according to a new study led by researchers in the Penn State College of Health and Human Development and Center for Healthy Aging focused on understanding the subtleties of loneliness and how variations in daily feelings of loneliness effect short- and long-term well-being. The researchers said the work provides more evidence in support of the 2023 statement made by U.S. Surgeon General Vivek Murthy on the devastating impact of loneliness and isolation on physical health in the country, calling it a public health crisis.
The work, published in the journal Health Psychology, also brings more attention to different experiences of loneliness, a focus during June 10-16 for Loneliness Awareness Week.
The long-term health consequences of loneliness and insufficient social connection include a 29% increased risk of heart disease, a 32% increased risk of stroke and a 50% increased risk of developing dementia in older adults, according to the surgeon general. People who frequently feel lonely are also more likely to develop depression and other mental health challenges, compared to people who rarely or never feel lonely.
In the current study, the researchers found that loneliness can lead to negative health symptoms for people even if they do not generally identify as lonely or typically experience loneliness. People who experience more temporary feelings of loneliness or have a lot of variability in their feelings of loneliness are likely to have daily health issues related to loneliness, including general fatigue, headaches and nausea.
The data represents 1,538 participants in the National Study of Daily Experiences (NSDE), one of the studies in the MacArthur Foundation Survey of Midlife in the United States. NSDE is led by David Almeida, professor of human development and family studies at Penn State and senior author on the paper. The current study focuses on loneliness in midlife, using data from respondents between the ages of 35 and 65. Prior research on loneliness largely focuses on adolescents and older adults, the researchers said.
NSDE participants engaged in telephone interviews that assessed their daily stress and mood for eight consecutive days. Respondents were asked to describe any stressful and/or positive situations they encountered and their feelings for each day, including whether they felt lonely and how often. They were also asked if they had physical symptoms that day, including general fatigue or headaches. These assessments were performed twice, 10 years apart.
From this data, researchers found that when participants were less lonely on average, and on days when loneliness was lower than a person’s average, they had fewer and less severe physical health symptoms. Additionally, participants who were more stable in loneliness across the eight days had less severe physical health symptoms.

“These findings suggest that day-to-day dynamics of loneliness may be crucial in understanding and addressing the health effects of loneliness,” Almeida said. “Increasing feelings of social connection even for one day could result in fewer health symptoms on that day. Such a daily focus offers a manageable and hopeful micro-intervention for individuals living with loneliness.”
Dakota Witzel, a postdoctoral research fellow in the Center for Healthy Aging and the lead author on the paper, said the results suggest that closer attention should be paid to daily, more temporary feelings of loneliness. While sustained loneliness can contribute to the long-term health effects identified in the surgeon general’s advisory, these shorter, more variable instances of loneliness can produce shorter-term negative health symptoms.
“A lot of research is focused on loneliness being a binary trait — either you’re lonely or you’re not. But based on our own anecdotal lives, we know that’s not the case. Some days are worse than others — even some hours,” Witzel said. “If we can understand variations in daily loneliness, we can begin to understand how it affects our daily and long-term health.”
Karina Van Bogart, doctoral candidate in the Department of Biobehavioral Health at Penn State; Erin Harrington, assistant professor of cognition and cognitive development at the University of Wyoming; and Shelbie Turner, postdoctoral fellow in the Division of Geriatrics and Palliative Medicine at Weill Cornell Medicine, also contributed to this research.
The National Institutes of Health funded this research.

Researchers at the University of Michigan Health Rogel Cancer Center are one step closer to understanding how pediatric DIPG tumors work.
Diffuse intrinsic pontine glioma, or DIPG, is the most aggressive pediatric brain tumor and incredibly difficult to treat since surgery isn’t feasible and recurrence is likely after radiation.
These tumors are often defined by the H3K27M driver histone mutation. Rogel researchers, led by Daniel Wahl, M.D., Ph.D., wanted to understand how this mutation affects DIPG tumor metabolism and influences radiation resistance. “These questions pointed us straight to purine metabolism,” said Wahl, associate professor of radiation oncology and neurosurgery.
The findings were published in Cancer & Metabolism.
Wahl’s team has previously explored how purines are metabolized in adult glioblastoma, including a clinical trial to see how blocking purine metabolism improves treatment success.
Here, the team tried a similar method of inhibiting purine synthesis. While it worked well in DIPG cells, it was less impressive in animal models.
Wahl explains that, unlike many adult glioblastomas, DIPG tumors seem to rely on two different routes to make purines. He likens it to a road with two on-ramps. “In adult GBMs, one of these on-ramps seems to be blocked, almost like it’s under construction. If you block the second on-ramp with a drug, it’s a real problem for the tumor. But in these pediatric brain tumors, both on-ramps appear to be wide open. So a drug that just blocks one of them doesn’t really slow down the DIPGs.”
Although there isn’t a drug available to block this “second” on-ramp, Wahl was able, through genetic silencing, to stop purines from being made inside the cell. “When we did that, radiation worked great,” Wahl said.

Erik Peterson, lead author and cancer biology graduate student agrees: “A better understanding of how these tumors evade treatment means that we’re better equipped to develop new strategies to beat them at their own game and improve the outlook for kids with this disease.”
Next, the researchers want to build on these findings to better understand why pediatric DIPG tumors rely on a different route from adult tumors, and how they can develop therapies to block it. With this additional work, the research team is hopeful that they could make a dent in this disease for patients in the future.
Additional authors: Peter Sajjakulnukit, PhD, Andrew J. Scott, PhD, Caleb Heaslip, Anthony Andren, Kari Wilder-Romans, Weihua Zhou, PhD, Sravya Palavalasa, MBBS, PhD, Navyateja Korimerla, PhD, Angelica Lin, Alexandra O’Brien, Ayesha Kothari, Zitong Zhao, Li Zhang, PhD, Meredith A. Morgan, PhD, Sriram Venneti, MD, PhD, Carl Koschmann, MD, Nada Jabado, MD, PhD, Costas A. Lyssiotis, PhD, Maria G. Castro, PhD
Funding: ChadTough Defeat DIPG Foundation, Alex’s Lemonade Stand, Rogel Cancer Center,

In a world where external and internal stimuli can throw our entire body system off balance, how does our brain prevent itself from becoming overly stimulated?
The answer lies in our brain’s ability to maintain the balance of neural excitation (E) and inhibition (I), known as the E/I ratio. By regulating the E/I ratio, the brain prevents over-stimulation and under-stimulation.
The E/I ratio of children decreases with healthy development. Children with a lower E/I ratio were observed to have better performance than their peers in cognitive tests such as memory and intelligence, according to studies by researchers from the Centre for Sleep and Cognition at the Yong Loo Lin School of Medicine (NUS Medicine).
With the aim of drawing meaningful connections between E/I ratio and brain maturation, the study team, led by fourth-year PhD student Zhang Shaoshi, Associate Professor Thomas Yeo from the Centre for Sleep and Cognition at NUS Medicine, Assistant Professor Bart Larsen from the University of Minnesota and Associate Professor Theodore Satterthwaite from the University of Pennsylvania, looked at how E/I ratio changes in youths, by studying the MRI brain scans of 885 children, adolescents and young adults from the United States of America and 154 children from Singapore. E/I ratio is an aspect that is continually changing and developing throughout childhood and adolescence. The Singaporean data cohort were obtained from GUSTO, Singapore’s largest and most comprehensive birth cohort study that seeks to help the next generation become healthier.
Described as the Yin and Yang of the brain, researchers have found that too much excitation or excessive inhibition can be harmful, leading to a higher risk of developing brain disorders, such as autism, Alzheimer’s disease and schizophrenia. In less severe situations, someone with too much excitation might overthink in social situations, resulting in anxiety. Indeed, a common drug for reducing anxiety symptoms is Xanax, which increases neural inhibition, thus reducing neural excitation. In more severe scenarios, over-excitation can cause an epileptic seizure.
On the opposite end of the spectrum, too much inhibition indicates an absence of brain activity, effectively putting the person in a vegetative state. Therefore, inhibition is needed to balance excitation. Overall, a balanced E/I ratio is important for a well-functioning brain.
Despite E/I’s importance for brain health, it is hard to measure its ratio in the human brain without using invasive techniques. Therefore, the team developed a technique, combining artificial intelligence and biophysical modeling to infer E/I ratios from non-invasive, non-radioactive MRI scans. The team demonstrated the validity of their estimated E/I ratios through an experiment, during which participants ingested anti-anxiety medication (Xanax) or a placebo.

The team’s hypothesis is that once Xanax is ingested, inhibition will increase, so the overall E/I ratio decreases. To test this hypothesis, the research team scanned healthy individuals on two separate occasions. A participant is given Xanax before one MRI session and placebo in another MRI session. For some participants, Xanax might be administered in the first session, while for others Xanax might be administered in the second session. All parties involved in this experiment were not privy to whether an MRI session involved the placebo or the anti-anxiety drug. The team found that estimated E/I ratio markers were indeed lower after participants had ingested Xanax, compared with the placebo, and thus validating their technique. The study team then proceeded to use MRI brain scans to study brain development in a large sample of more than 1000 children, adolescents and young adults from Singapore and the United States of America. They discover that E/I ratios decrease with healthy development. Next, to establish the link between E/I ratios and cognitive function, the team divided participants, ranging from age 7 to 23, into high and low-performance groups based on their scores on certain cognitive tests. They found that the high performing groups had lower E/I ratios than their peers of the same age, suggesting that cognitive abilities improve as the E/I ratio matures during development.
Beyond their study on neurodevelopment, the team is keen on applying their approach to gain mechanistic insights into various brain disorders, by studying how the E/I ratio differs between healthy participants and patients battling mental disorders. The team also aims to study how the E/I ratio changes as people age, to gain insights into neurodegenerative disorders, such as Alzheimer’s Disease.
Assoc Prof Thomas Yeo, who is also from the NUS College of Design and Engineering and Principal Investigator of this study, adds, “Our findings enhance our understanding of brain development and highlight potential avenues for understanding the emergence of psychopathology in youth. Hopefully, these findings will lead us to figure out which brain circuits get over-excited or over-inhibited easily, or pinpoint certain abnormal brain regions specific to an individual patient. This could shed more light on how medication or brain stimulation can be customised according to individuals, that would shape the course of treatment of brain disorders in the long run.”
This study is published in Proceedings of the National Academy of Sciences of the United States of America, titled ‘In vivo whole-cortex marker of excitation-inhibition ratio indexes cortical maturation and cognitive ability in youth’.

New University of Pittsburgh research points to a potential approach to reducing the risk of diabetes associated with widely prescribed antipsychotic medications.
The study presents early evidence in support of co-administering antipsychotic medications that block dopamine receptors in the brain alongside drugs that stop antipsychotics from blocking those same receptors in the pancreas. This approach, published today in Diabetes, could limit metabolic side effects, including impaired control over blood sugar, or dysglycemia.
This research may also explain why weight control medications, including new neuropeptide drugs Wegovy and Ozempic, may not be as effective as hoped in controlling dysglycemia caused by antipsychotic drugs. Patients who are experiencing the weight gain associated with antipsychotic medications might be tempted to take these new drugs to control satiety — but they may miss an important underlying cause of the drug-induced deglycation.
“Antipsychotic medications don’t just stop working below the neck,” said senior author Zachary Freyberg, M.D., Ph.D., associate professor of psychiatry and cell biology at Pitt’s School of Medicine. “Maintaining glucose metabolism requires the brain to be in constant communication with the rest of the body, and vice versa. Next-generation antipsychotic drugs can be modified as a new strategy to control dysglycemia and diabetes.”
Most prescription antipsychotic medications work by blocking the class of brain receptors that respond to a neurotransmitter called dopamine — a cornerstone molecule of the brain’s reward system and brain-directed movement control. However, the subtype of dopamine receptors that respond to antipsychotic medications, called dopamine D2 receptors, are not exclusive to the brain. As Freyberg’s earlier research has shown, antipsychotic medications also block D2 receptors in the pancreas.
Freyberg’s dogma-breaking discovery highlighted that pancreatic dopamine plays a key role in controlling blood sugar by interacting with D2 receptors on the surface of pancreatic cells that control production and secretion of hormones insulin and glucagon. When the fragile balance between glucose-raising and -lowering hormones is destabilized by antipsychotic medications, dysglycemia and diabetes may follow.
However, peripheral dopamine signaling can be harnessed for therapeutic good. In collaboration with researchers at the National Institutes of Health’s National Institute on Drug Abuse (NIH NIDA), the team created a molecule that can limit antipsychotic drugs from blocking D2 receptors in organs like the pancreas, but not in the brain. This molecule, called bromocriptine methiodide, or BrMel, is structurally similar to bromocriptine — an FDA-approved drug to treat type 2 diabetes — but has a modification that makes it less likely to pass through the brain-blood barrier if administered systemically, therefore limiting its activity to the periphery.

Early studies in mice suggest that dopamine’s effects on glucose metabolism require communication between the brain and the peripheral organs including the pancreas. Experiments have shown that, unlike systemically administered bromocriptine that improves the glucose profile of insulin-resistant mice, peripherally-limited BrMeI, or bromocriptine delivered directly to the brain, failed to show improvements. Drugs like BrMeI that can stop antipsychotic medications from acting on peripheral targets may therefore be useful in preventing, or even reversing, dysglycemia.
Freyberg and his collaborators at Pitt are in the early stages of a safety clinical trial to ensure that the therapeutic effects of antipsychotic drugs are preserved when these psychiatric medications are administered in tandem with bromocriptine since it is already FDA approved. They hope to launch a bigger trial to test the efficacy of BrMel and similar molecules for limiting dysglycemia in the next several years.
“The fact that both the brain and the body are required to maintain stable glycemic control provides a novel dimension in understanding neuropsychiatry and begins to integrate disparate pieces of knowledge about different organ systems into a coherent whole,” said Freyberg.
“The majority of psychiatric medications are prescribed by general practitioners and not psychiatrists,” he added. “We hope that our research builds awareness about the importance of communication between the brain and the rest of the body in maintaining physiological functions and reminds clinicians that they should also consider that drugs designed to act on targets in the brain, like psychiatric medications, may also have significant actions outside of the brain when making prescription recommendations.”
Other authors of this research are Zachary Farino, M.S., Despoina Aslanoglou, Ph.D., and José Mantilla-Rivas, M.D., all of Pitt; Alessandro Bonifazi, Ph.D., Michael Ellenberger, J.D., Comfort Boateng, Ph.D., and Amy Hauck Newman, Ph.D., all of NIDA; Rana Rais, Ph.D., and Barbara Slusher, Ph.D., both of Johns Hopkins University; Sandra Pereira, Ph.D., and Margaret Hahn, M.D., Ph.D., both of the University of Toronto; Amy Eshleman, Ph.D., and Aaron Janowsky, Ph.D., both of the Oregon Health & Science University; and Gary Schwartz, Ph.D., of Albert Einstein College of Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

A new study led by UCLA Health and the U.S. Veterans Affairs Office found chronic pain among older adults could be significantly reduced through a newly developed psychotherapy that works by confronting past trauma and stress-related emotions that can exacerbate pain symptoms.
Published in JAMA Network Open on June 13, the study compared the newer therapy, known as emotional awareness and expression therapy, or EAET, to traditional cognitive behavioral therapy, or CBT, in treating chronic pain as well as mental health symptoms such as depression, anxiety and post-traumatic stress disorder symptoms among older veterans.
The study found that 63% of veterans who underwent EAET reported at least a 30% reduction in pain — a clinically significant reduction — after treatment compared to only 17% of veterans who underwent cognitive behavioral therapy. Pain reduction was sustained among 41% of EAET participants six months after treatment compared to 14% of CBT patients. Additionally, EAET patients reported greater benefits for addressing anxiety, depression, PTSD and life satisfaction.
“Most people with chronic pain don’t consider psychotherapy at all. They’re thinking along the lines of medications, injections, sometimes surgery or bodily treatments like physical therapy,” said lead author Brandon Yarns, an assistant professor at UCLA Health’s Department of Psychiatry and Biobehavioral Sciences and psychiatrist at the Veteran’s Affairs Greater Los Angeles. “Psychotherapy is an evidence-based treatment for chronic pain. What this study adds is that the type of psychotherapy matters.”
Cognitive behavioral therapy has long been the “gold standard” for psychotherapeutic treatment of chronic pain among veterans, Yarns said. However, studies so far have shown CBT produces modest benefits for relieving pain. For chronic pain, patients undergo a treatment package with some similar exercises to those used to treat depression or anxiety such as guided imagery, muscle relaxation, cognitive restructuring and activity pacing. The end goal is for patients to improve their ability to tolerate their pain, Yarns said.
“The goal in CBT is not necessarily to cure pain but to learn to cope and live well despite chronic pain,” Yarns said.
By comparison, EAET has one primary intervention: experiencing, expressing and releasing emotions.

Developed in the 2010s, the therapy aims to show patients that the brain’s perception of pain is strongly influenced by stress-related emotions. Patients are asked to focus on a stressful interaction, from anything as mundane as being cut off by a driver to severe traumas such as sexual assault. Yarns said the purpose is to have patients experience these emotions both in mind and in body. The patients then work to confront these emotions, express their reactions and ultimately to let go.
“If there is a hurt or stressor people have a series of normal, natural emotional reactions. There might be anger, guilt and sadness. Because these feelings are painful, people often avoid them, but EAET helps people face difficult feelings with honesty and self-compassion,” Yarns said. “In therapy, they can release anger, pain and guilt that they’ve been carrying and are left with self-compassion in the end.”
In the study, researchers recruited 126 veterans — predominantly men — ages 60 to 95 with at least three months of musculoskeletal pain. More than two-thirds of participants had a psychiatric diagnosis, with about one-third having post-traumatic stress disorder. The study was the first full-scale clinical trial of EAET among older adults, older men and veterans, with past studies being largely made up of younger, female participants, Yarns said.
Half of the participants underwent in-person cognitive behavioral therapy while the other half concurrently underwent in-person emotional awareness and expression therapy over nine sessions, which included one personal session and eight small group sessions.
Patients were asked to rate their pain levels using a 0 to 10 scale in the Brief Pain Inventory before starting treatment, at the end of the nine sessions and six months after the sessions ended. At posttreatment, 63% of EAET participants reported at least a 30% reduction in pain compared to 17% of CBT patients.
Yarns said he is now studying whether similar positive results could be replicated using virtual group sessions, which will compare EAET, CBT and also include a mindfulness therapy cohort. Additionally, Yarns said that neuroimaging studies will be pursued to understand the brain changes among participants in EAET versus CBT therapies.