A new study by the Centre for Addiction and Mental Health (CAMH), entitled “Mental Health Service Use Before First Diagnosis of a Psychotic Disorder” and published in JAMA Psychiatry, found that nearly 75 per cent of young Ontarians with a psychotic disorder had at least one mental health service visit within the three years prior to their first diagnosis of the disorder.
The retrospective cohort study — one of the largest of its kind — suggests that youth with a psychotic disorder are nearly four times as likely to have a previous mental health-related hospital admission, twice as likely to have a mental health-related emergency department visit, and more likely to have a past diagnosis of substance use disorder compared to youth diagnosed with a mood disorder.
“Our findings suggest that these factors — prior mental health-related hospital admissions and emergency department visits, and prior diagnosis of substance use disorder — may indicate increased risk for a psychotic disorder,” says Dr. Nicole Kozloff, Co-Director of the Slaight Family Centre for Youth in Transition at CAMH. “These results are remarkably consistent with other jurisdictions outside Canada, and should guide further research into detecting and intervening earlier in the course of psychotic illness.”
As part of the study, the researchers used information held by ICES on health service use and other linked data to examine previous mental health use in Ontarians aged 15-29 years who were later diagnosed with a psychotic disorder between April 1, 2012 and March 31, 2018. The team identified more than 10,000 individuals with a first diagnosis of psychotic disorder and matched them with individuals who were diagnosed with a mood disorder.
“Those at risk for psychosis are ‘hiding in plain sight,'” says Dr. Aristotle Voineskos, Vice President, Research at CAMH and Director of the Campbell Family Mental Health Research Institute. “These data provide a very different picture of who is at risk for psychosis, and also suggest the opportunity moving forward to examine whether effective treatment for prior conditions may change the risk for psychosis.”
The early findings from this research inspired the launch of the Toronto Adolescent & Youth (TAY) Cohort Study at CAMH. This five-year study is tracking 1,500 children and youth presenting for mental health services, examining their biology, education and cognition, social factors, and service use patterns. The goal is to increase understanding of who is at risk for psychosis and, most importantly, how to mitigate that risk via earlier intervention.
This research underpins a key pillar of CAMH’s new strategic plan, Get Upstream, which aims to position the hospital at the forefront of early mental illness identification, prevention strategies, and timely access to high-quality care.
CAMH is already a leader in both research and clinical care for youth experiencing psychosis. The Slaight Family Centre for Youth in Transition’s unique integrated approach translates the latest clinical and scientific evidence into better intervention and recovery strategies, making a real difference in the lives of young people. The Slaight Centre houses an outpatient early psychosis intervention program, clinical high risk program, and an inpatient early psychosis unit, which treat more than 425 patients on average each month between the ages of 14 to 29 years old.

Our bone marrow — the fatty, jelly-like substance inside our bones — is an unseen powerhouse quietly producing 500 billion new blood cells every day. That process is driven by hematopoietic stem cells that generate all of the various types of blood cells in our bodies and regenerating themselves to keep the entire assembly line of blood production operating smoothly.
As with any complex system, hematopoietic stem cells lose functionality as they age — and, in the process, contribute to the risk of serious diseases, including blood cancers. We know that the risk of developing aging-associated diseases is different among different individuals. Surprisingly, however, little is known about whether hematopoietic stem cells age differently between individuals.
“If you take a room full of 50-year-olds, some will be completely gray-haired, others will be salt-and-pepper, and a few will not have any gray hairs at all,” said Jennifer Trowbridge, Dattels Family Endowed Chair and professor at the Jackson Laboratory. “Logically, you’d expect to see the same kind of variation in the function of hematopoietic stem cells — but until now, nobody has studied that directly.”
For good reason: Because these hematopoietic stem cells are so rare, researchers typically pool all of these stem cells together, studying them in aggregate. In a paper published in Blood, Trowbridge and colleagues studied hematopoietic stem cells at the single cell level in nine individual, genetically identical middle-aged mice — offering the first close look at how subtle changes in the bone marrow microenvironment ages hematopoietic stem cells across individual mice.
Trowbridge and team found that despite the mice being all the same age, the hematopoietic stem cells in the bone marrow of these individual mice aged differently. But that’s not all. The team could predict the function of the hematopoietic stem cells based on the activity of two growth factors that are also present in humans.
The two growth factors — Kitl and Igf1 — are produced by mesenchymal stromal cells (MSC) that surround the stem cells in the bone marrow microenvironment. By profiling the RNA transcriptome in these MSCs across individual mice, Trowbridge found that the decline of these growth factors correlated with age-associated molecular programs in hematopoietic stem cells.
“The amount of the growth factors that are being produced directly correlates to the declining function of the stem cells — and we found markedly more variation in hematopoietic stem cells than in other cells in the bone marrow,” Trowbridge said. “This is really a snapshot of the aging process at work, at the cellular level.” ”
In humans, who are genetically diverse and have varying lifestyles, variations in hematopoietic stem cell aging are likely to be even greater than in carefully controlled animal models, explained Trowbridge. While the current study didn’t explore whether cellular aging of the stem cells directly triggers adverse health outcomes, it’s likely that such variations play a role in a wide range of health outcomes for both mice and humans.

Chronic pain affects millions worldwide, and current treatments often rely on opioids, which carry risks of addiction and overdose.
Non-addictive alternatives could revolutionize pain management, and new research targeting the human protein which regulates cold sensations, brings scientists closer to developing pain medications that don’t affect body temperature and don’t carry the risks of addiction.
Research published in Science Advances on June 21, led by Wade Van Horn, professor in Arizona State University’s School of Molecular Sciences and Biodesign Center for Personalized Diagnostics, has uncovered new insights into the main human cold and menthol sensor TRPM8 (transient receptor potential melastatin 8). Using techniques from many fields like biochemistry and biophysics, their study revealed that it was a chemical sensor before it became a cold temperature sensor.
“If we can start to understand how to decouple the chemical sensing of cold from actual cold sensing, in theory, we could make side-effect-free drugs,” said Van Horn whose research focuses on membrane proteins involved in human health and disease. “By understanding the evolutionary history of TRPM8, we hope to contribute to designing better drugs that offer relief without the dangerous side effects associated with current painkillers.”
When a person touches a metal desk and it feels cold, the human body activates TRPM8. For cancer patients who are on certain kinds of chemotherapeutics, touching a desk can hurt. TRPM8 is also involved in many other types of pain as well, including chronic neuropathic and inflammatory pain.
By further understanding this specificity of the chemical sensing of cold versus physically sensing cold, scientists can target relief without triggering the temperature regulation side effects often seen in TRPM8 clinical trials for pain treatments.
In the research, the team used ancestral sequence reconstruction, a time machine for proteins of sorts, compiling the family tree of TRPM8 that exists today and then used that information to determine what the proteins from long-extinct animals might have looked like.

Using computational methods to resurrect ancestral primate, mammalian, and vertebrate TRPM8, the researchers were able to understand how TRPM8 has changed over hundreds of millions of years by comparing the sequences of current proteins to predict the sequences of their ancient ancestors. Additionally, the combination of lab experiments and computational studies enable the researchers to identify critical places in TRPM8 that allow a more clear understanding of temperature sensing, which can be tested in subsequent experiments.
“Comparative dynamics analysis of ancestral and human TRPM8 also supports the experimental data and will allow us to identify critical sites in temperature sensing, which we will be testing soon,” said Banu Ozkan, professor in ASU’s Department of Physics, who was involved in the study.
The team then expressed these ancestral TRPM8s in human cells and characterized them using various cellular and electrophysiology techniques.
“Ancestral protein-based studies allow us to focus on the lineage of most interest, such as human TRPM8, to alleviate concerns arising in drug discovery from speciation differences, like in mice and humans,” said first author on the study Dustin Luu, an ASU School of Molecular Sciences doctoral alumnus, and current postdoctoral fellow in ASU’s Biodesign Center for Personalized Diagnostics.
Luu continued: “We discovered that surprisingly menthol sensing appeared way before cold sensing. The difference in appearance and attenuation of these activation modes suggest they are separate and can be disentangled with further research enabling new pain therapies without the adverse side effect in thermal sensing and thermal regulation, which has plagued TRPM8-targeted clinical trials.”
As science continues to uncover the mysteries of our biological mechanisms, studies like this exemplify how evolutionary biology and modern pharmacology can collaborate to address pressing medical needs and improve the quality of life for those suffering from chronic pain.

An orange teeming with antioxidants and other health benefits may be a shot in the arm for consumers and citrus growers, if the fruit is stored at cool temperatures, a new University of Florida study shows.
But it’s too soon to know if the so-called “blood oranges” are a viable crop for the Florida citrus industry, says Ali Sarkhosh, a UF/IFAS associate professor of horticultural sciences. Sarkhosh’s post-doctoral associate Fariborz Habibi explains further.
“Although blood oranges typically command higher prices than other common varieties, such as navel or Valencia oranges, it is unclear if farmers could substantially increase their per-acre income by adding them to their crop selection and then storing them for internal color development,” said Habibi, lead author of the study. “Improved fruit quality from the storage method presents a promising opportunity for the Florida citrus industry. However, further study is needed before recommending anything to growers.”
The fruit is rich in anthocyanins, which have been linked to various health benefits, including anti-inflammatory and antioxidant properties. They also contain other beneficial phytochemicals such as vitamin C, flavonoids and dietary fiber.
“Fruit can also develop internal color under similar conditions at home. However, the fruit in the supermarket should have a good internal color and be ready for consumption,” Sarkhosh said.
For this research, scientists harvested fruit from a research plot at the UF/IFAS North Florida Research and Education Center in Quincy.
Scientists found that storing the blood oranges at 40 to 53 degrees enhances anthocyanin, phenolic content, and antioxidants. When they lowered the temperatures 43 to 46 degrees, they also preserved fruit firmness, weight loss and sugar content.
“Attributes such as firmness are crucial for maintaining the overall quality, texture and taste of the blood oranges during storage,” said Habibi.
Blood oranges get their name from their deep red flesh. Their skin contains a type of antioxidant pigment. The fruit is commonly grown in countries like Italy and Spain, which have the Mediterranean climate – cold, but above 32 degrees — that helps them grow. In the United States, blood oranges grow primarily in California, but are not grown commercially yet in Florida.
Anthocyanin develops when the fruit is exposed to cold temperatures between 46 and 59 degrees for at least 20 days. Such conditions are rare in Florida’s subtropical climate.

Researchers at the Pacific Northwest Research Institute (PNRI) and collaborating institutions have made a groundbreaking discovery that could significantly advance our understanding of genomic disorders. Their latest study, funded by the National Institutes of Health and published in the journal Cell Genomics, reveals how specific DNA rearrangements called inverted triplications contribute to the development of various genetic diseases.
Understanding the Study
Genomic disorders occur when there are changes or mutations in DNA that disrupt normal biological functions. These can lead to a range of health issues, including developmental delays and neurological problems. One type of complex DNA mutation involves a structure known as a duplication-triplication/inversion-duplication (DUP-TRP/INV-DUP). This study delves into how these complex rearrangements form and their impact on human health.
Key Findings
The research team, led by PNRI Assistant Investigator Cláudia Carvalho, Ph.D., collaborated with her lab colleagues, study lead author Christopher Grochowski, Ph.D., from the James R. Lupski Lab at Baylor College of Medicine, and other scientists to analyze the DNA of 24 individuals with inverted triplications.
They discovered that these rearrangements are caused by segments of DNA switching templates during the repair process. Normally, DNA repair mechanisms use the undamaged complementary strand as a template to accurately repair the damaged DNA. However, sometimes during repair, the repair machinery may inadvertently switch to a different but similar sequence elsewhere in the genome.
These switches occur within pairs of inverted repeats — sections of DNA that are mirror images of each other. Inverted repeats can confuse the repair machinery, leading to the use of the wrong template, which can disrupt normal gene function and contribute to genetic disorders. Structural Diversity: The study found that these inverted triplications generate a surprising variety of structural variations in the genome, which can lead to different health outcomes. Gene Dosage Impact: These rearrangements can alter the number of copies of certain genes, known as gene dosage. The correct number of gene copies is crucial for normal human development and function. Changes in gene dosage can cause diseases like MECP2 duplication syndrome, a rare neurodevelopmental disorder. Mapping Breakpoints: By using advanced DNA sequencing techniques, the researchers identified the precise locations where these DNA segments switch templates leading to an altered number of genes including MECP2.

Dr. Carvalho and Baylor scientists first observed this pathogenic genomic structure in 2011 while studying MECP2duplication syndrome. Only recently, with the advent of long-read sequencing technology, has it become possible to investigate in detail how it forms in the genome.
Implications for Rare Disease Research and Treatment
“This study sheds light on the intricate mechanisms driving genetic rearrangements and their profound impact on rare diseases,” said Dr. Cláudia Carvalho, PNRI’s lead scientist on the study. “By unraveling these complex DNA structures, we open new avenues for understanding the genetic causes of rare diseases and developing targeted treatments to improve patient outcomes.”
These findings are being applied in a follow-up study led by Baylor’s Davut Pehlivan, M.D., investigating how complex genomic structures influence the clinical features of MECP2 duplication syndrome and their impact on targeted therapeutic approaches.

A new UCLA Health study has found that resilient people exhibit neural activity in the brain regions associated with improved cognition and regulating of emotions, and were more mindful and better at describing their feelings. The same group also exhibited gut microbiome activity linked to a healthy gut, with reduced inflammation and gut barrier.
For the study, rather than examine microbiome activity and composition linked to disease conditions — like anxiety and depression — the researchers wanted to flip the script and study the gut microbiome and brain in healthy, resilient people who effectively cope with different types of stress, including discrimination and social isolation.
“If we can identify what a healthy resilient brain and microbiome look like, then we can develop targeted interventions to those areas to reduce stress,” said Arpana Gupta, PhD, senior author and co-director of the UCLA Goodman-Luskin Microbiome Center. This is believed to be the first study to explore the intersection of resiliency, the brain, and the gut microbiome.
Gupta and her team focused on methods to cope with stress because research has shown that untreated stress can increase the risk of heart disease, stroke, obesity, and diabetes. While stress is an inevitable part of life, studying how to handle stress can help prevent developing diseases.
To conduct the study, published in Nature Mental Health, the researchers surveyed 116 people about their resiliency — like trust in one’s instincts and positive acceptance of change — and separated them into two groups. One group ranked high on the resiliency scale and the other group ranked low. The participants also underwent MRI imaging and gave stool samples two or three days before their scans.
The researchers found that people in the high resiliency group were less anxious and depressed, less prone to judge, and had activity in regions of the brain associated with emotional regulation and better cognition compared to the group with low resiliency. “When a stressor happens, often we go to this aroused fight or flight response, and this impairs the breaks in your brain,” Gupta said. “But the highly resilient individuals in the study were found to be better at regulating their emotions, less likely to catastrophize, and keep a level head,” added Desiree Delgadillo, postdoctoral researcher and one of the first authors.
The high resiliency group also had different microbiome activity than the low resiliency group. Namely, the high resiliency group’s microbiomes excreted metabolites and exhibited gene activity associated with low inflammation and a strong and healthy gut barrier. A weak gut barrier, otherwise known as a leaky gut, is caused by inflammation and impairs the gut barrier’s ability to absorb essential nutrients needed by the body while blocking toxins from entering the gut.

The researchers were surprised to find these microbiome signatures associated with the high resiliency group.
“Resilience truly is a whole-body phenomenon that not only affects your brain but also your microbiome and what metabolites that it is producing,” Gupta said. “We have this whole community of microbes in our gut that exudes these therapeutic properties and biochemicals, so I’m looking forward to building upon this research,” Delgadillo said.
The team’s future research will study whether an intervention to increase resilience will change brain and gut microbiome activity. “We could have treatments that target both the brain and the gut that can maybe one day prevent disease,” Gupta said.
A new UCLA Health study has found that resilient people exhibit neural activity in the brain regions associated with improved cognition and regulating of emotions, and were more mindful and better at describing their feelings. The same group also exhibited gut microbiome activity linked to a healthy gut, with reduced inflammation and gut barrier.
For the study, rather than examine microbiome activity and composition linked to disease conditions — like anxiety and depression — the researchers wanted to flip the script and study the gut microbiome and brain in healthy, resilient people who effectively cope with different types of stress, including discrimination and social isolation.
“If we can identify what a healthy resilient brain and microbiome look like, then we can develop targeted interventions to those areas to reduce stress,” said Arpana Gupta, PhD, senior author and co-director of the UCLA Goodman-Luskin Microbiome Center. This is believed to be the first study to explore the intersection of resiliency, the brain, and the gut microbiome.
Gupta and her team focused on methods to cope with stress because research has shown that untreated stress can increase the risk of heart disease, stroke, obesity, and diabetes. While stress is an inevitable part of life, studying how to handle stress can help prevent developing diseases.
To conduct the study, published in Nature Mental Health, the researchers surveyed 116 people about their resiliency — like trust in one’s instincts and positive acceptance of change — and separated them into two groups. One group ranked high on the resiliency scale and the other group ranked low. The participants also underwent MRI imaging and gave stool samples two or three days before their scans.
The researchers found that people in the h

Gupta and her team focused on methods to cope with stress because research has shown that untreated stress can increase the risk of heart disease, stroke, obesity, and diabetes. While stress is an inevitable part of life, studying how to handle stress can help prevent developing diseases.
To conduct the study, published in Nature Mental Health, the researchers surveyed 116 people about their resiliency — like trust in one’s instincts and positive acceptance of change — and separated them into two groups. One group ranked high on the resiliency scale and the other group ranked low. The participants also underwent MRI imaging and gave stool samples two or three days before their scans.
The researchers found that people in the high resiliency group were less anxious and depressed, less prone to judge, and had activity in regions of the brain associated with emotional regulation and better cognition compared to the group with low resiliency. “When a stressor happens, often we go to this aroused fight or flight response, and this impairs the breaks in your brain,” Gupta said. “But the highly resilient individuals in the study were found to be better at regulating their emotions, less likely to catastrophize, and keep a level head,” added Desiree Delgadillo, postdoctoral researcher and one of the first authors.
The high resiliency group also had different microbiome activity than the low resiliency group. Namely, the high resiliency group’s microbiomes excreted metabolites and exhibited gene activity associated with low inflammation and a strong and healthy gut barrier. A weak gut barrier, otherwise known as a leaky gut, is caused by inflammation and impairs the gut barrier’s ability to absorb essential nutrients needed by the body while blocking toxins from entering the gut.
The researchers were surprised to find these microbiome signatures associated with the high resiliency group.
“Resilience truly is a whole-body phenomenon that not only affects your brain but also your microbiome and what metabolites that it is producing,” Gupta said. “We have this whole community of microbes in our gut that exudes these therapeutic properties and biochemicals, so I’m looking forward to building upon this research,” Delgadillo said.
The team’s future research will study whether an intervention to increase resilience will change brain and gut microbiome activity. “We could have treatments that target both the brain and the gut that can maybe one day prevent disease,” Gupta said.
A new UCLA Health study has found that resilient people exhibit neural activity in the brain regions associated with improved cognition and regulating of emotions, and were more mindful and better at describing their feelings. The same group also exhibited gut microbiome activity linked to a healthy gut, with reduced inflammation and gut barrier.
For the study, rather than examine microbiome activity and composition linked to disease conditions — like anxiety and depression — the researchers wanted to flip the script and study the gut microbiome and brain in healthy, resilient people who effectively cope with different types of stress, including discrimination and social isolation.
“If we can identify what a healthy resilient brain and microbiome look like, then we can develop targeted interventions to those areas to reduce stress,” said Arpana Gupta, PhD, senior author and co-director of the UCLA Goodman-Luskin Microbiome Center. This is believed to be the first study to explore the intersection of resiliency, the brain, and the gut microbiome.
Gupta and her team focused on methods to cope with stress because research has shown that untreated stress can increase the risk of heart disease, stroke, obesity, and diabetes. While stress is an inevitable part of life, studying how to handle stress can help prevent developing diseases.
To conduct the study, published in Nature Mental Health, the researchers surveyed 116 people about their resiliency — like trust in one’s instincts and positive acceptance of change — and separated them into two groups. One group ranked high on the resiliency scale and the other group ranked low. The participants also underwent MRI imaging and gave stool samples two or three days before their scans.
The researchers found that people in the high resiliency group were less anxious and depressed, less prone to judge, and had activity in regions of the brain associated with emotional regulation and better cognition compared to the group with low resiliency. “When a stressor happens, often we go to this aroused fight or flight response, and this impairs the breaks in your brain,” Gupta said. “But the highly resilient individuals in the study were found to be better at regulating their emotions, less likely to catastrophize, and keep a level head,” added Desiree Delgadillo, postdoctoral researcher and one of the first authors.
The high resiliency group also had different microbiome activity than the low resiliency group. Namely, the high resiliency group’s microbiomes excreted metabolites and exhibited gene activity associated with low inflammation and a strong and healthy gut barrier. A weak gut barrier, otherwise known as a leaky gut, is caused by inflammation and impairs the gut barrier’s ability to absorb essential nutrients needed by the body while blocking toxins from entering the gut.
The researchers were surprised to find these microbiome signatures associated with the high resiliency group.
“Resilience truly is a whole-body phenomenon that not only affects your brain but also your microbiome and what metabolites that it is producing,” Gupta said. “We have this whole community of microbes in our gut that exudes these therapeutic properties and biochemicals, so I’m looking forward to building upon this research,” Delgadillo said.
The team’s future research will study whether an intervention to increase resilience will change brain and gut microbiome activity. “We could have treatments that target both the brain and the gut that can maybe one day prevent disease,” Gupta said.

Many drug and antibody discovery pathways focus on intricately folded cell membrane proteins: when molecules of a drug candidate bind to these proteins, like a key going into a lock, they trigger chemical cascades that alter cellular behavior. But because these proteins are embedded in the lipid-containing outer layer of cells, they are tricky to access and insoluble in water-based solutions (hydrophobic), making them difficult to study.
“We wanted to get these proteins out of the cell membrane, so we redesigned them as hyperstable, soluble analogues, which look like membrane proteins but are much easier to work with,” explains Casper Goverde, a PhD student in the Laboratory of Protein Design and Immunoengineering (LPDI) in the School of Engineering.
In a nutshell, Goverde and a research team in the LPDI, led by Bruno Correia, used deep learning to design synthetic soluble versions of cell membrane proteins commonly used in pharmaceutical research. Whereas traditional screening methods rely on indirectly observing cellular reactions to drug and antibody candidates, or painstakingly extracting small quantities of membrane proteins from mammalian cells, the researchers’ computational approach allows them to remove cells from the equation. After designing a soluble protein analogue using their deep learning pipeline, they can use bacteria to produce the modified protein in bulk. These proteins can then bind directly in solution with molecular candidates of interest.
“We estimate that producing a batch of soluble protein analogues using E. coli is around 10 times less expensive than using mammalian cells,” adds PhD student Nicolas Goldbach.
The team’s research has recently been published in the journal Nature.
Flipping the script on protein design
In recent years, scientists have successfully harnessed artificial intelligence networks that use deep learning to design novel protein structures, for example by predicting them based on an input sequence of amino acid building blocks. But for this study, the researchers were interested in protein folds that already exist in nature; what they needed was a more accessible, soluble version of these proteins.

“We had the idea to invert this deep learning pipeline that predicts protein structure: if we input a structure, can it tell us the corresponding amino acid sequence?” explains Goverde.
To achieve this, the team used the structure prediction platform AlphaFold2 from Google DeepMind to produce amino acid sequences for soluble versions of several key cell membrane proteins, based on their 3D structure. Then, they used a second deep learning network, ProteinMPNN, to optimize those sequences for functional, soluble proteins. The researchers were pleased to discover that their approach showed remarkable success and accuracy in producing soluble proteins that maintained parts of their native functionality, even when applied to highly complex folds that have so far eluded other design methods.
“The holy grail of biochemistry”
A particular triumph of the study was the pipeline’s success in designing a soluble analogue of a protein shape known as the G-protein coupled receptor (GPCR), which represents around 40% of human cell membrane proteins and is a major pharmaceutical target.
“We showed for the first time that we can redesign the GPCR shape as a stable soluble analogue. This has been a long-standing problem in biochemistry, because if you can make it soluble, you can screen for novel drugs much faster and more easily,” says LPDI scientist Martin Pacesa.
The researchers also see these results as a proof-of-concept for their pipeline’s application to vaccine research, and even cancer therapeutics. For example, they designed a soluble analogue of a protein type called a claudin, which plays a role in making tumors resistant to the immune system and chemotherapy. In their experiments, the team’s soluble claudin analogue retained its biological properties, reinforcing the pipeline’s promise for generating interesting targets for pharmaceutical development.

Biomedical engineers at Duke University have developed a new technique to better understand and test treatments for a group of extremely rare muscle disorders called dysferlinopathy or limb girdle muscular dystrophies 2B (LGMD2B). The approach grows complex, functional 3D muscle tissue from stem cells in the laboratory, creating a platform that replicates patient symptoms and treatment responses.
In its debut study, researchers reveal some of the biological mechanisms underlying the characteristic loss of mobility caused by LGMD2B. They also demonstrate that a combination of existing treatments may be able to alleviate some of the worst symptoms of the disease.
The results appear online June 18 in the journal Advanced Science.
LGMD2B affects only about eight people per million around the world. Unlike it’s more well-known and more common cousin Duchenne muscular dystrophy, the disease affects both men and women, presents later in life — in the late teens or early 20s — and is rarely fatal. However, LGMD2B patients develop severe weakness in the legs and shoulders, typically requiring them to use wheelchairs for the rest of their lives.
Caused by a genetic disorder, LGMD2B stops the body from creating a fully functional form of a protein called dysferlin. There are currently no approved treatments or cures. Part of the reason for this lack of options is the many functions of dysferlin, including sealing holes in muscle membranes, regulating calcium balances required for muscle contraction and controlling cellular metabolism. And for reasons unknown, affected muscles initially accumulate fat within the muscle fibers themselves before degenerating and ultimately being replaced by fat cells.
“This phenomenon is very rare even for muscular dystrophies,” said Nenad Bursac, professor of biomedical engineering at Duke. “It’s a burning question within the community of why that happens.”
One of the challenges facing researchers trying to solve these problems is that the mouse model used to approximate LGMD2B shows very mild symptoms compared to patients. Mice with the disease are still able to walk, and it does not present until nearly a year into their two-year long lifespan, making studies of the disease extremely slow. Dysferlin is expressed in other cell types, and blood levels of metabolic fuels such as cholesterol are also altered in mice and patients. Together, this complicates LGMD2B research by making it difficult to assess what cell types are responsible for the disease and if metabolic changes are due to the loss of dysferlin itself or whole-body effects.

To get around these challenges, Bursac and his research scientist Alastair Khodabukus turned to an engineered muscle platform that they have been developing for nearly a decade. The Bursac Lab was the first to grow contracting, functional human skeletal muscle in a Petri dish and has been improving its processes ever since to enable studies of muscle strength, metabolism and repair. This system allowed them to focus their study on only the effects of dysferlin on skeletal muscle without the complications of other cell types or altered blood metabolite profiles.
In the study, the researchers began with induced pluripotent stem cells (IPSCs) derived from patients living with LGMD supplied by The Jain Foundation, a charity focused on finding a cure for LGMD2B. Using their muscle-growing techniques, the lab matured these stem cells into muscle fibers and ran them through a battery of tests over the course of six weeks.
Like muscles found in patients themselves, the lab-grown versions displayed a wide variety of issues.
“Overall, our model repeated a lot of the clinical manifestations of the disease and observations made in real patients, but it was all done in a Petri dish,” said Bursac. “We’ve been able to gain new insights into the muscle-specific aspects of the disease.”
The researchers discovered that the loss in muscle strength was not the result of deficiencies in muscle structure or size, but in its handling of calcium. Muscle contractions are physically caused by reservoirs of calcium in muscle cells being released and binding to muscle proteins. Tests showed that the diseased muscle cells had sprung leaks in their calcium reserves, resulting in less calcium to release and weaker contractions.
The researchers also showed that the lack of dysferlin caused damage to the muscle cells to go unrepaired, and that an inability to burn fatty acids for energy production was at least partially to blame for the accumulation of fat within muscle fibers that has long puzzled the medical community.

“We replicated something seen in patients and showed that it’s not due to environmental factors within the body, but issues within the muscle itself,” Khodabukus said.
The researchers then tested the effects of two drug candidates to potentially treat the disease that have been identified through mouse models but have not yet been tested in humans. One called dantrolene is supposed to stop calcium from leaking from muscle cells’ reservoirs. The second, called vamorolone, was recently approved for use with Duchenne muscular dystrophy patients, although researchers do not fully understand how it works.
Together, the drugs prevented the calcium leak and helped the cell membrane repair itself, restoring much of the muscles’ strength. And while they also helped reduce the amount of fat accumulated within the muscles, they did not fully prevent it, nor did they help the muscles efficiently burn fats for fuel.
Moving forward, the group is planning to add immune and fat cells to their experiments for greater complexity. They also are looking to further understand disruptions to cellular metabolism and to find new drugs that fully restore all strength, repair and metabolic deficit.
“Right now, we have a basic muscle-only system, which is great to see the effects of the disease within the muscle itself, but what is also important is the crosstalk between immune cells, fat cells and muscle cells,” Khodabukus said. “By building out our system more, we’ll hopefully be able to fully figure out what is driving the loss of muscle and its replacement by fat in these patients.”
This research was supported by the National Institutes of Health (UG3TR002142, U01EB028901, R01AR070543, R01AR079223, R01ARO82979, R21AR078269, UH3TR002142) and the Jain Foundation.

Research led by in part by The University of Texas Health Science Center at San Antonio (UT Health San Antonio) finds that the most common cerebral small-vessel disease feature seen in brain magnetic resonance imaging is a primary vascular factor associated with dementia risk.
Results of the major international study emphasize the significance of that feature, known as white matter hyperintensity (WMH) burden, in preventive strategies for dementia.
“Our findings provide converging evidence that WMH is a major vascular factor associated with dementia risk,” said Muralidharan Sargurupremraj, PhD, an assistant professor at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases at UT Health San Antonio. “They also support WMH as a surrogate marker for clinical trials to prevent dementia by controlling vascular risk.”
Sargurupremraj is the first and co-corresponding author of the research, titled, “Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia,” published May 22 in JAMA Network Open, a monthly open-access medical journal published by the American Medical Association.
The study notes that with increasing life expectancy, the prevalence of dementia is expected to reach 75 million people globally by 2030, which makes devising strategies to prevent or delay its occurrence a major public health priority. The scientific community widely recognizes that most dementia cases, including Alzheimer’s disease, are related to a combination of vascular and neurodegenerative lesions.
And cerebral small-vessel disease is thought to be the main underlying contribution to cognitive decline and dementia, with nearly half of dementia cases showing both Alzheimer’s and cerebral small-vessel disease neuropathologic characteristics, the study notes.
Still, while observational studies had shown evidence of an association between white matter hyperintensity burden and increased risk of stroke and dementia, causal evidence had been limited. White matter hyperintensities are lesions in the brain that show up as areas of increased brightness in T2-weighted magnetic resonance imaging.

In the new study, researchers were able to provide evidence of a causal link between vascular traits and Alzheimer’s disease, using genetic instrument variable analyses known as Mendelian randomization — a method that leverages the natural randomization of genetic alleles to test how differences in the genetic effect on modifiable exposure influence disease risk.
Specifically, in a two-year analysis ending July 24, 2022, and using Alzheimer’s disease genome-wide association studies of up to 75,000 European dementia cases, they found causal evidence of an association of larger WMH burden with increased risk of the disease, accounting for pulse-pressure effects.
The study also highlighted the importance of combining several complementary epidemiological approaches and data types, and of accounting for caveats of instrumental variable analyses when exploring the impact of vascular traits on late-onset diseases like dementia.
“As vascular disease is a treatable contributor to dementia risk, our findings have broad significance for prevention strategies of Alzheimer’s and dementia as a whole,” Sargurupremraj concluded.
The researchers advise future studies to examine whether their findings can be generalized to non-European populations.
Other institutions and entities represented in the study include the University of Bordeaux (France); University of Washington; University of Michigan; University of Tartu (Estonia); Erasmus MC University Medical Center, Rotterdam (Netherlands); Boston University and the National Heart, Lung, and Blood Institute Framingham Heart Study; Icelandic Heart Association (Iceland); Washington University, St. Louis; University of Oxford (United Kingdom); Department of Public Health, Bordeaux (France); University of Pittsburgh; University of Lille (France); Radboud University, Nijmegen (Netherlands); Universidad Adolfo Ibáñez, Santiago (Chile); University of Iceland (Iceland); Oslo University Hospital, Oslo (Norway); Norwegian University of Science and Technology; Imperial College London (United Kingdom); National Institute on Aging; and Bordeaux University Hospital (France).
UT Health San Antonio is a primary driver of San Antonio’s leading $44.1 billion health care and biosciences sector, and is the largest academic research institution in South Texas with an annual research portfolio of $413 million.

Researchers at The University of Texas MD Anderson Cancer Center have demonstrated that therapeutically restoring ‘youthful’ levels of a specific subunit of the telomerase enzyme can significantly reduce the signs and symptoms of aging in preclinical models. If these findings are confirmed in clinical studies, there may be therapeutic implications for age-related diseases such as Alzheimer’s, Parkinson’s, heart disease and cancer.
The study, published today in Cell, identified a small molecule compound that restores physiological levels of telomerase reverse transcriptase (TERT), which normally is repressed with the onset of aging. Maintenance of TERT levels in aged lab models reduced cellular senescence and tissue inflammation, spurred new neuron formation with improved memory, and enhanced neuromuscular function, which increased strength and coordination.
The researchers show that TERT functions not only to extend telomeres, but also acts as a transcription factor to affect the expression of many genes directing neurogenesis, learning and memory, cellular senescence, and inflammation.
“Epigenetic repression of TERT plays a major role in the cellular decline seen at the onset of aging by regulating genes involved in learning, memory, muscle performance and inflammation,” said corresponding author Ronald DePinho, M.D., professor of Cancer Biology. “By pharmacologically restoring youthful TERT levels, we reprogrammed expression of those genes, resulting in improved cognition and muscle performance while eliminating hallmarks linked to many age-related diseases.”
Loss of TERT is connected with aging through multiple mechanisms
Aging is associated with various epigenetic changes that influence functional and physiological decline. One of the hallmarks of aging is the gradual shortening of telomeres, the chromosomal end structures that help maintain their stability. Free radicals also can modify and harm telomere sequences.
When telomeres become extremely short or modified, they trigger a continual DNA damage response, which can lead to cell senescence — a phenomenon in which cells release inflammatory factors that can cause tissue damage, prompting aging and cancer.

Telomerase is a protein complex responsible for synthesizing and extending telomeres. However, its activity is reduced over time due to the epigenetic silencing of TERT, particularly at the onset of natural aging or Alzheimer’s and other age-related diseases.
The DePinho laboratory previously showed that deactivating the TERT gene in vivo led to premature aging, which could be reversed through TERT reactivation. The researchers also observed that certain cells, such as neurons and cardiac cells, were rejuvenated without undergoing the normal cell division required to synthesize telomeres.
Their observations led them to hypothesize that TERT had other functions beyond synthesizing telomeres and that overall telomerase levels were important in the aging process. Based on these findings, the researchers, led by DePinho and first author Hong Seok Shim, Ph.D., aimed to develop a drug to restore TERT levels.
Small molecule restores TERT levels, reversing hallmarks of aging
A high-throughput screen of over 650,000 compounds identified a small-molecule TERT activating compound (TAC) that epigenetically de-represses the TERT gene and restores physiological expression present in young cells.
In preclinical models equivalent to adults over age 75, TAC treatment for six months led to new neuron formation in the hippocampus (memory center) and improved performance in cognitive tests. Additionally, there was an increase in genes involved in learning, memory and synaptic biology, consistent with TERT’s ability to interact with and control the activity of transcription factor complexes regulating diverse genes.

TAC treatment also significantly reduced inflammaging — an age-related increase in inflammatory markers linked with multiple diseases — in both blood and tissue samples and also eliminated senescent cells by repressing the p16 gene, a key senescence factor.
TAC improved neuromuscular function, coordination, grip strength and speed in these models, reversing sarcopenia — a condition under which muscle mass, strength and performance naturally worsen with advancing age.
Additionally, TAC treatment in human cell lines increased telomere synthesis with reduced DNA damage signal at telomeres and extended the proliferative potential of these cells, demonstrating the activity of TAC in ex vivo human models.
“These preclinical results are encouraging, as TAC is easily absorbed by all tissues, including the central nervous system. Yet further studies are needed to properly assess its safety and activity in long-term treatment strategies,” DePinho said. “However, our deeper understanding of the molecular mechanisms driving the aging process has uncovered viable drug targets, allowing us to explore opportunities to intercept the causes of a variety of major age-related chronic diseases.”
This study was supported by the National Institutes of Health (R01 CA084628, P30 CA016672 and S10 RR029552), the G. Harold and Leila Y Mathers Charitable Foundation and the Belfer Family Foundation Neurodegeneration Consortium. This study was a collaborative effort with Peter Schultz and Michael Bollong at the Scripps Institute.