Publisher Health

A new study published in Science Advances shows female and male hearts respond differently to the stress hormone noradrenaline. The study in mice may have implications for human heart disorders like arrhythmias and heart failure and how different sexes respond to medications.
The team built a new type of fluorescence imaging system that allows them to use light to see how a mouse heart responds to hormones and neurotransmitters in real time. The mice were exposed to noradrenaline, also known as norepinephrine. Noradrenaline is both a neurotransmitter and hormone associated with the body’s “fight or flight” response.
The results reveal that male and female mouse hearts respond uniformly at first after exposure to noradrenaline. However, some areas of the female heart return to normal more quickly than the male heart, which produces differences in the heart’s electrical activity.
“The differences in electrical activity that we observed are called repolarization in the female hearts. Repolarization refers to how the heart resets between each heartbeat and is closely linked to some types of arrhythmias,” said Jessica L. Caldwell, first author of the study. Caldwell is a postdoctoral scholar in the UC Davis School of Medicine Department of Pharmacology.
“We know that there are sex differences in the risk for certain types of arrhythmias. The study reveals a new factor that may contribute to different arrhythmia susceptibility between men and women,” Caldwell said.
Heart disease is the leading cause of death in the U.S.
Heart disease is the leading cause of death for both men and women in the United States. It accounted for about 1 in every 4 male deaths and 1 in every 5 female deaths in 2020. Despite the impact on both sexes, cardiology research has largely been performed on male subjects.

In this study, the researchers were interested in looking at factors that may contribute to arrhythmias. Arrhythmias are a type of heart disorder where the electrical impulses that control heartbeats don’t function properly. They affect somewhere between 1.5% to 5% of the population.
Methods
The novel imaging system uses a mouse, called the CAMPER mouse, that has been genetically modified to emit light during a very specific chemical reaction in the heart — cAMP binding.
The cAMP molecule (an abbreviation of cyclic adenosine 3′,5;-monophosphate) is an intermediate messenger that turns signals from hormones and neurotransmitters, including noradrenaline, into action from heart cells.
The light signals from the CAMPER mouse are transmitted by a biosensor that uses fluorescence resonance energy transfer (FRET). This FRET signal can be picked up at high speed and high resolution by a new imaging system specially designed for hearts. This allows the researchers to record the heart’s reaction to noradrenaline in real time, along with changes in electrical activity.

This new imaging approach revealed the differences in the breakdown of cAMP in female and male mice and the associated differences in electrical activity.
Including female mice leads to discoveries
The researchers had not planned to study sex-based responses, according to Crystal M. Ripplinger, senior author of the study. But the researchers started seeing a pattern of different reactions, which led them to realize the differences were sex-based.
Ripplinger, an electrical and biomedical engineer, is a professor in the Department of Pharmacology.
When she started her lab at the UC Davis School of Medicine over a decade ago, she exclusively used male animals. That was the norm for most research at the time. But several years ago, she began including male and female animals in her studies.
“Sometimes the data between the two sexes is the same. But if the data start to show variation, the first thing we do is look at sex differences. Using both male and female mice has revealed clues into differences we would never have suspected. Researchers are realizing you can’t extrapolate to both sexes from only studying one,” Ripplinger said.
She notes that with the current study, it’s not clear what the differences in cAMP and electrical activity may mean.
“The response in the female mice may be protective — or it may not. But simply documenting that there is a measurable difference in the response to a stress hormone is significant. We are hoping to learn more in future studies,” Ripplinger said.
Additional authors on the study include I-Ju (Eric) Lee, Lena Ngo, Lianguo Wang, Donald M. Bers, Manuel F. Navedo and Julie Bossuyt from UC Davis; Sherif Bahriz from UC Davis and Mansoura University; Bing (Rita) Xu and Yang K. Xiang from UC Davis and VA Northern California.
This work was supported by grants from the National Institutes of Health, the American Heart Association, and the Veterans Administration Merit Grant.

The B.C.G. vaccine, more than a century old, has shown some promise against diabetes. The university’s move left parents and outside investigators concerned.Researchers at N.Y.U. Langone Health have pulled out of a trial investigating the use of an old tuberculosis vaccine to treat children with Type 1 diabetes only months after they began enrolling participants on Long Island.The vaccine, called Bacillus-Calmette-Guerin, or B.C.G., has generated intense interest among various patient advocacy groups, including those focused on Alzheimer’s disease and cancer, as well as diabetes. Some recent research suggests that the vaccine, first administered in 1921, also may protect against Covid-19 and respiratory diseases because of its broad effects on the immune system.A large trial of the vaccine’s effects on blood sugar in adults with Type 1 diabetes is nearing completion. Scientists had hoped to test the B.C.G. vaccines on children as well, since good management of Type 1 diabetes leads to fewer complications related to diabetes.The lead investigators of the pediatric trial, who are at Massachusetts General Hospital in Boston, are proceeding with the study, but N.Y.U. Langone’s abrupt withdrawal could potentially jeopardize its viability if they are unable to collect data on the children at the N.Y.U. site.A total of 150 children were to be included in the study, and the N.Y.U. team had already given the vaccine to at least 18 youngsters. They were to be followed for five years; each was to receive eight safety-check visits in the first year after their inoculations.“Who’s monitoring our daughter medically now, and who’s monitoring the injection site?” said Kevin Miller of Smithtown, N.Y., whose 14-year-old daughter enrolled in the study last year.“I’m sure there is something in the fine print of all the papers we signed that says they have a legal right to do this,” Mr. Miller added, “but I don’t necessarily know that means it’s right to leave kids like my daughter and others hung out to dry.”N.Y.U. Langone officials said in a statement that an institutional review board, which approved the study in December 2020, decided to end participation after reviewing more research about the B.C.G. vaccine.A statement said that the university “determined that withdrawal from the study will not affect the safety of enrolled participants,” and said that the children could continue to see N.Y.U. physicians for their usual diabetes care.An earlier study by the scientists at Massachusetts General found that two doses of B.C.G. vaccine reduced blood sugar levels to near normal in a very small group of adults with Type 1 diabetes. Other studies of B.C.G., using different versions of the vaccine and following Type 1 diabetes subjects for varying periods of time, have yielded mixed results.The new trial is Phase II, aimed at evaluating the efficacy of the vaccine treatment. Usually when such trials are stopped, it is because of a safety concern. Enrollment of new participants ceases, but subjects who have already received the intervention continue to be followed.N.Y.U. has made no mention of a safety problem, however, and will no longer follow the participants for purposes of the study.The lead investigator of the trial, Dr. Denise Faustman, director of the immunobiology laboratory at Massachusetts General Hospital, said that N.Y.U.’s withdrawal was a serious deviation from trial protocol that may call into question the final results.“The Food and Drug Administration cares most about safety in children and the protection of children, and to miss any safety visit is a serious violation of the protocol,” she said.Dr. Denise Faustman, director of the immunobiology laboratory at Massachusetts General Hospital, said that N.Y.U.’s withdrawal was a serious deviation from trial protocol.Tony Luong for The New York TimesControlling blood sugar in patients with diabetes is critical in preventing serious long-term complications such as vision loss, nerve damage, kidney disease and amputations. One hypothesis is that B.C.G. may tamp down the production of abnormal white blood cells that attack the body’s own tissues, including insulin-generating cells in the pancreas.The idea has long been controversial, and Dr. Faustman has struggled to raise money to support her studies. In 2018, when she published the research suggesting that B.C.G. lowered blood sugar levels, the J.D.R.F. — formerly the Juvenile Diabetes Research Foundation, a major funder of research — and the American Diabetes Association took the unusual step of issuing a joint public statement expressing skepticism about the findings.In response to questions about its position on Dr. Faustman’s research into the B.C.G. vaccine, Chelsea-Lyn Rudder, a spokeswoman for J.D.R.F., said that the foundation’s position “remains unchanged.”“J.D.R.F. prioritizes research funding that has the highest likelihood of accelerating the delivery of therapies to cure and prevent Type 1 diabetes,” Ms. Rudder added, “while maintaining strategic funding in research that improves the lives of those with the disease.”The B.C.G. vaccine is more than a century old and generic, and drug makers have shown little interest in investing in research and development related to it. Newer treatments often carry eye-popping prices. One newly approved drug, teplizumab, may delay the onset of Type 1 diabetes by a few years but costs nearly $200,000 for a two-week treatment course.Though N.Y.U. officials did not explain the review board’s decision to halt the trial, a letter from Massachusetts General Hospital responding to the N.Y.U. action references two scientific papers, both of which reported ambiguous results and called for carrying out more randomized controlled trials on B.C.G. vaccines in people with Type 1 diabetes.The review board at Massachusetts General said that the two papers that were brought to their attention did not raise any concerns about an “unanticipated problem” and that there was no reason to stop Dr. Faustman’s trial.

Transitioning to a new environment, as many college freshman do, can increase feelings of loneliness, and feelings of loneliness in college students have dramatically increased in the last decade, according to the National College Health Assessment. Additionally, a 2021 survey reported that 44% of U.S. college students described their weight as more than normal, i.e. either in the overweight or obese category. Though loneliness has been linked to unhealthy weight and physical inactivity, there is a lack of research on dietary behaviors in college students and the role it can play in obesity in college students.
With data from the Mason: Health Starts Here cohort study, Master of Nutrition alum Li Jiang found that loneliness was related to altered diet quality and physical inactivity. The research was done as part of Jiang’s master’s thesis, and Mason Nutrition and Food Studies Department Chair Lawrence J. Cheskin, Associate Professor Lilian de Jonge, former faculty member Cara Frankenfeld, and former postdoctoral fellow Ziaul H. Rana also contributed to the project.
“Our study supports a potential need for further research in understanding unhealthful dietary behavior and physical activity which may be related to loneliness, an emotion that impacts many college students,” says Jiang.
Sedentary (19.2%) and low active (53.8%) behaviors were more frequent in students reporting high loneliness (score ranges of 4-6 and 7-9) than those reporting low loneliness (score of 10-12). Students reporting more loneliness had higher fat diets than students reporting less loneliness.
“Interventions to reduce loneliness may have a positive effect on health promotion in this population. This data go along with other initial findings from the Health Starts Here study that college students are not meeting healthy dietary guidelines or getting enough physical activity,” said Cheskin, who has an MD.
The study is a cross-sectional study that analyzed baseline data collected in the first wave of Mason: Health Start Here in 2019, and was funded by George Mason University’s Institute for BioHealth Innovation.
“Loneliness is associated with unhealthful dietary behaviors and physical inactivity among US college students,” was published in November 2022 in the Journal of American College Health.
Mason: Health Starts Here is a first-of-its-kind transdisciplinary student cohort study to understand and improve the health and well-being of university students. This research will follow a broad sample of young adults, specifically Mason students, over time to capture the diversity of their experiences in college and how it affects their health and well-being.

Contrary to popular belief, rest may not always be the best cure after a concussion, new study published in JAMA Network Open finds. In fact, an early return to school may be associated with a lower symptom burden after suffering a concussion and, ultimately, faster recovery.
“We know that absence from school can be detrimental to youth in many ways and for many reasons,” says Christopher Vaughan, Psy.D., neuropsychologist at Children’s National Hospital and the study’s lead author. “The results of this study found that, in general, an earlier return to school after a concussion was associated with better outcomes. This helps us feel reassured that returning to some normal activities after a concussion — like going to school — is ultimately beneficial.”
In this cohort study, data from over 1,600 youth aged 5 to 18 were collected across nine pediatric emergency departments in Canada. Because of the large sample size, many factors associated with greater symptom burden and prolonged recovery were first accounted for through the complex statistical approach used to examine the data. The authors found that an early return to school was associated with a lower symptom burden 14 days post-injury in the 8 to 12 and 13 to 18-year-old age groups.
“Clinicians can now confidently inform families that missing at least some school after a concussion is common, often between 2 and 5 days, with older kids typically missing more school,” Dr. Vaughan says. “But the earlier a child can return to school with good symptom management strategies and with appropriate academic supports, the better that we think that their recovery will be.”
The findings suggest that there could be a mechanism of therapeutic benefit to the early return to school. This could be due to: Socialization (or avoiding the deleterious effects of isolation). Reduced stress from not missing too much school. Maintaining or returning to a normal sleep/wake schedule. Returning to light-to-moderate physical activity sooner (also consistent with previous literature).

The next frontier of continuous health monitoring could be skin deep.
Biomedical engineers at the University of Cincinnati say interstitial fluid, the watery fluid found between and around cells, tissues or organs in the body, could provide an excellent medium for early disease diagnosis or long-term health monitoring.
In a paper published in the journal Nature Biomedical Engineering, they outlined the potential advantages and technological challenges of using interstitial fluid.
“Why we see it as a valuable diagnostic fluid is continuous access. With blood, you can’t easily take continuous readings,” said UC doctoral graduate Mark Friedel, co-lead author of the study.
“Can you imagine going about your day with a needle stuck in your vein all day? So we need other tools.”
Researchers are looking for alternatives to monitor a person’s health and wellness. Sweat is a good medium for measuring certain things like stress or anxiety because it contains hormones such as cortisol. But the body is stingy with other chemicals that are not so easily released in sweat, Friedel said.

“Sweat glands are big filters that don’t allow everything to pass through,” he said. “So more than half of the things we want to monitor have no access to sweat at all.”
Blood is the gold standard for health monitoring. But people also have liters of interstitial fluid that make up as much as 15% of their body weight.
“The key feature of blood that makes it so advantageous is we understand blood really well,” Friedel said. “If you have something in your blood, we know what will happen to your heart or your liver,” he said.
Researchers said interstitial fluid contains many of the same chemicals in the same proportions as blood, offering a potential alternative to costly and time-consuming lab work.
The study outlined the various ways doctors can sample interstitial fluid, from applying suction to the skin to deploying microdialysis.

“As biomedical engineers, one of our greatest goals is to help people better manage their health by making diagnostics more accessible,” said co-lead author Ian Thompson at Stanford University.
“A big barrier to this accessibility is that most current diagnostics rely on blood sampling, which can be painful and requires trained personnel to perform. Thus, in recent years there has been growing interest in using interstitial fluid just under the skin as a diagnostic sample that is more accessible and less painful to extract.”
In UC College of Engineering and Applied Science professor Jason Heikenfeld’s Novel Devices Lab, students are developing sensors to measure hormones and other chemicals in interstitial fluid. They use microneedles less than 1 millimeter in length that pierce the skin through a tiny patch.
“If you had a splinter, it probably went deeper into your skin than our microneedles,” Friedel said. “They’re generally painless. I don’t feel it most of the time. The most uncomfortable part is removing the tape that holds the device down.”
But even if you don’t know it’s there, your body does, Friedel said. And this minute reaction can affect the test results.
“There’s a Schrödinger’s observer effect with interstitial fluid. Any time you try to collect and measure it, you inherently change the fluid itself,” Friedel said. “If you stick a needle in your skin, your body becomes inflamed and then your [sample] levels change. For continuous biomonitoring, we want to know those concentrations as they are when you’re not being poked with a tiny needle.
“That’s why it’s such a challenging fluid that hasn’t been used outside of diabetes monitoring.”
Still, researchers say, interstitial fluid holds enormous promise for monitoring health through wearable technology. This could help doctors track the efficacy of drugs to ensure proper dosage or provide early diagnosis of illness by monitoring the immune system.
But Friedel said there is still a lot to learn.
“We’re trying to unlock the box and read the instructions inside to understand what’s in interstitial fluid and what the potentials are for exploiting it,” he said.
Friedel and Thompson worked with co-author Heikenfeld, UC’s James L. Winkle College of Pharmacy, the Sandia National Laboratories in New Mexico and Southeast Missouri State University.
The study was funded through grants from the National Science Foundation, the U.S. Air Force Office of Scientific Research and the U.S. Office of Naval Research.

A University of Calgary research group — which includes several Bachelor of Health Sciences alumni joined forces with members of the World Health Organization (WHO) to tackle a global health question. What is the best protection against COVID-19? Analyzing data from controlled studies throughout the world, researchers discovered people with hybrid immunity are the most protected against severe illness and reinfection. Hybrid immunity occurs when someone has had at least the full series of vaccines and has a prior infection, in any order. The study published in The Lancet Infectious Diseases helps public policy makers understand the optimal timing of vaccinations.
“The results reinforce the global imperative for vaccination,” says Dr. Niklas Bobrovitz, DPhil, BHSc ’11, MSc’14 and first author on the study. “A common question throughout the pandemic was whether previously infected people should also get vaccinated. Our results clearly indicate the need for vaccination, even among people that have had COVID-19.”
The global emergence and rapid spread of the Omicron variant of concern required scientists and policymakers to reassess population protection against Omicron infection and severe disease. In the study, investigators were able to look at immune protection against Omicron after a prior SARS-CoV-2 infection (the virus that causes COVID-19), vaccination, or hybrid immunity.
“Protection against hospitalization and severe disease remained above 95 per cent for 12 months for individuals with hybrid immunity,” says Dr. Lorenzo Subissi, MSc, PhD, WHO-Scientist and senior author on the study. “We know more variants are going to emerge. The study shows to reduce infection waves, vaccinations could be timed for roll-out just prior to expected periods of higher infection spread, such as the winter season.”
The systematic review and meta-analysis find that protection against Omicron infection declines substantially by 12 months, regardless of whether you’ve had an infection, vaccinations, or both, which means that vaccination is the best way to periodically boost your protection and to keep down levels of infection in the population. In total, 4,268 articles were screened and 895 underwent full-text review. A difficult task before the assistance of experts in health informatics.
“This study demonstrates the power of machine translation. We were able to break through language barriers, most of the time systematic reviews aren’t done in every language they are limited to one or two,” says Dr. Tyler Williamson, PhD, director of the Centre for Health Informatics at the Cumming School of Medicine. “These former BHSc classmates along with the large diverse team they brought together have emerged as global leaders in SARS-CoV-2 research and delivered decision-grade evidence to the world.” And while the findings demonstrate that vaccination along with a prior infection carries the most protection, the scientists warn against intentional exposure to the virus.
“You should never try to get COVID-19,” says Bobrovitz. “The virus is unpredictable in how it will affect your system. For some, it can be fatal or send you to hospital. Even if you have a mild infection, you risk developing long COVID.”
The group says the next phase of this research would be to investigate how the bivalent vaccine performs against severe disease.
The study is supported by WHO COVID-19 Solidarity Response Fund and the Coalition for Epidemic Preparedness Innovation (CEPI). The views reported do not necessarily reflect the official position of WHO or CEPI.
Findings from the study complement data on the serotracker dashboard which monitors studies and news reports to track seroprevalence data — the percentage of people in a population who have antibodies against the novel coronavirus. The website aggregates serology data from studies and news reports in different populations, and built-in filters allow users to compare seroprevalence levels between countries, occupations, and demographic groups.
Other contributors to the paper are Harriet Ware, Xiaomeng Ma, Zihan Li, Reza Hosseini, Christian Cao, Anabel Selemon, Mairead Whelan, Zahra Premji, Hanane Issa, Brianna Cheng, Laith J. Abu Raddad, David Buckeridge, Maria Van Kerkhove, Vanessa Piechotta, Melissa Higdon, Annelies Wilder-Smith, Isabel Bergeri, Daniel Feikin, Rahul Arora and Minal Patel representing universities and institutions in the U.S., United Kingdom, Qatar, Switzerland Germany, and Canada.

In patients with Huntington’s disease, neurons in a part of the brain called the striatum are among the hardest-hit. Degeneration of these neurons contributes to patients’ loss of motor control, which is one of the major hallmarks of the disease.
Neuroscientists at MIT have now shown that two distinct cell populations in the striatum are affected differently by Huntington’s disease. They believe that neurodegeneration of one of these populations leads to motor impairments, while damage to the other population, located in structures called striosomes, may account for the mood disorders that are often see in the early stages of the disease.
“As many as 10 years ahead of the motor diagnosis, Huntington’s patients can experience mood disorders, and one possibility is that the striosomes might be involved in these,” says Ann Graybiel, an MIT Institute Professor, a member of MIT’s McGovern Institute for Brain Research, and one of the senior authors of the study.
Using single-cell RNA sequencing to analyze the genes expressed in mouse models of Huntington’s disease and postmortem brain samples from Huntington’s patients, the researchers found that cells of the striosomes and another structure, the matrix, begin to lose their distinguishing features as the disease progresses. The researchers hope that their mapping of the striatum and how it is affected by Huntington’s could help lead to new treatments that target specific cells within the brain.
This kind of analysis could also shed light on other brain disorders that affect the striatum, such as Parkinson’s disease and autism spectrum disorder, the researchers say.
Myriam Heiman, an associate professor in MIT’s Department of Brain and Cognitive Sciences and a member of the Picower Institute for Learning and Memory, and Manolis Kellis, a professor of computer science in MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and a member of the Broad Institute of MIT and Harvard, are also senior authors of the study. Ayano Matsushima, a McGovern Institute research scientist, and Sergio Sebastian Pineda, an MIT graduate student, are the lead authors of the paper, which appears in Nature Communications.

Neuron vulnerability
Huntington’s disease leads to degeneration of brain structures called the basal ganglia, which are responsible for control of movement and also play roles in other behaviors, as well as emotions. For many years, Graybiel has been studying the striatum, a part of the basal ganglia that is involved in making decisions that require evaluating the outcomes of a particular action.
Many years ago, Graybiel discovered that the striatum is divided into striosomes, which are clusters of neurons, and the matrix, which surrounds the striosomes. She has also shown that striosomes are necessary for making decisions that require an anxiety-provoking cost-benefit analysis.
In a 2007 study, Richard Faull of the University of Auckland discovered that in postmortem brain tissue from Huntington’s patients, the striosomes showed a great deal of degeneration. Faull also found that while those patients were alive, many of them had shown signs of mood disorders such as depression before their motor symptoms developed.
To further explore the connections between the striatum and the mood and motor effects of Huntington’s, Graybiel teamed up with Kellis and Heiman to study the gene expression patterns of striosomal and matrix cells. To do that, the researchers used single-cell RNA sequencing to analyze human brain samples and brain tissue from two mouse models of Huntington’s disease.

Within the striatum, neurons can be classified as either D1 or D2 neurons. D1 neurons are involved in the “go” pathway, which initiates an action, and D2 neurons are part of the “no-go” pathway, which suppresses an action. D1 and D2 neurons can both be found within either the striosomes and the matrix.
The analysis of RNA expression in each of these types of cells revealed that striosomal neurons are harder hit by Huntington’s than matrix neurons. Furthermore, within the striosomes, D2 neurons are more vulnerable than D1.
The researchers also found that these four major cell types begin to lose their identifying molecular identities and become more difficult to distinguish from one another in Huntington’s disease. “Overall, the distinction between striosomes and matrix becomes really blurry,” Graybiel says.
Striosomal disorders
The findings suggest that damage to the striosomes, which are known to be involved in regulating mood, may be responsible for the mood disorders that strike Huntington’s patients in the early stages of the disease. Later on, degeneration of the matrix neurons likely contributes to the decline of motor function, the researchers say.
In future work, the researchers hope to explore how degeneration or abnormal gene expression in the striosomes may contribute to other brain disorders.
Previous research has shown that overactivity of striosomes can lead to the development of repetitive behaviors such as those seen in autism, obsessive compulsive disorder, and Tourette’s syndrome. In this study, at least one of the genes that the researchers discovered was overexpressed in the striosomes of Huntington’s brains is also linked to autism.
Additionally, many striosome neurons project to the part of the brain that is most affected by Parkinson’s disease (the substantia nigra, which produces most of the brain’s dopamine).
“There are many, many disorders that probably involve the striatum, and now, partly through transcriptomics, we’re working to understand how all of this could fit together,” Graybiel says.
The research was funded by the Saks Kavanaugh Foundation, the CHDI Foundation, the National Institutes of Health, the Nancy Lurie Marks Family Foundation, the Simons Foundation, the JPB Foundation, the Kristin R. Pressman and Jessica J. Pourian ’13 Fund, and Robert Buxton.

Organic chemists at UCLA have created the first synthetic version of a molecule recently discovered in a sea sponge that may have therapeutic benefits for Parkinson’s disease and similar disorders. The molecule, known as lissodendoric acid A, appears to counteract other molecules that can damage DNA, RNA and proteins and even destroy whole cells.
And in an interesting twist, the research team used an unusual, long-neglected compound called a cyclic allene to control a crucial step in the chain of chemical reactions needed to produce a usable version of the molecule in the lab — an advance they say could prove advantageous in developing other complex molecules for pharmaceutical research.
Their findings are published in the journal Science.
“The vast majority of medicines today are made by synthetic organic chemistry, and one of our roles in academia is to establish new chemical reactions that could be used to quickly develop medicines and molecules with intricate chemical structures that benefit the world,” said Neil Garg, UCLA’s Kenneth N. Trueblood Professor of Chemistry and Biochemistry and corresponding author of the study.
A key factor complicating the development of these synthetic organic molecules, Garg said, is called chirality, or “handedness.” Many molecules — including lissodendoric acid A — can exist in two distinct forms that are chemically identical but are 3D mirror images of each other, like a right and left hand. Each version is known as an enantiomer.
When used in pharmaceuticals, one enantiomer of a molecule may have beneficial therapeutic effects while the other may do nothing at all — or even prove dangerous. Unfortunately, creating organic molecules in the laboratory often yields a mixture of both enantiomers, and chemically removing or reversing the unwanted enantiomers adds difficulties, costs and delays to the process.
To address this challenge and quickly and efficiently produce only the enantiomer of lissodendoric acid A that is found almost exclusively in nature, Garg and his team employed cyclic allenes as an intermediate in their 12-step reaction process. First discovered in the 1960s, these highly reactive compounds had never before been used to make molecules of such complexity.
“Cyclic allenes,” Garg said, “have largely been forgotten since their discovery more than half a century ago. This is because they have unique chemical structures and only exist for a fraction of a second when they are generated.”
The team discovered that they could harness the compounds’ unique qualities to generate one particular chiral version of cyclic allenes, which in turn led to chemical reactions that ultimately produced the desired enantiomer of the lissodendoric acid A molecule almost exclusively.
While the ability to synthetically produce an analog of lissodendoric acid A is the first step in testing whether the molecule may possess suitable qualities for future therapeutics, the method for synthesizing the molecule is something that could immediately benefit other scientists involved in pharmaceutical research, the chemists said.
“By challenging conventional thinking, we have now learned how to make cyclic allenes and use them to make complicated molecules like lissodendoric acid A,” Garg said. “We hope others will also be able to use cyclic allenes to make new medicines.”
Co-authors of the research were UCLA doctoral students Francesca Ippoliti (now a postdoctoral scholar at the University of Wisconsin), Laura Wonilowicz and Joyann Donaldson (now of Pfizer Oncology Medicinal Chemistry); UCLA postdoctoral researchers Nathan Adamson and Evan Darzi (now CEO of the startup ElectraTect, a spinoff from Garg’s lab); and Daniel Nasrallah, a UCLA assistant adjunct professor of chemistry and biochemistry.

Traumatic injury to the brain, spinal cord and optic nerve in the central nervous system (CNS) are the leading cause of disability and the second leading cause of death worldwide. CNS injuries often result in a catastrophic loss of sensory, motor and visual functions, which is the most challenging problem faced by clinicians and research scientists. Neuroscientists from City University of Hong Kong (CityU) recently identified and demonstrated a small molecule that can effectively stimulate nerve regeneration and restore visual functions after optic nerve injury, offering great hope for patients with optic nerve injury, such as glaucoma-related vision loss.
“There is currently no effective treatment available for traumatic injuries to the CNS, so there is an immediate need for potential drug to promote CNS repair and ultimately achieve full function recovery, such as visual function, in patients,” said Dr Eddie Ma Chi-him, Associate Head and Associate Professor in the Department of Neuroscience and Director of the Laboratory Animal Research Unit at CityU, who led the research.
Enhancing mitochondrial dynamics and motility is key for successful axon regeneration
Axons, which are a cable-like structure that extends from neurons (nerve cells), are responsible for transmitting signals between neurons and from the brain to muscles and glands. The first step for successful axon regeneration is to form active growth cones and the activation of a regrowth programme, involving the synthesis and transport of materials to regrow axons. These are all energy-demanding processes, which require the active transport of mitochondria (the powerhouse of the cell) to injured axons at the distal end.
Injured neurons therefore face special challenges that require long-distance transport of mitochondria from the soma (cell body) to distal regenerating axons, where axonal mitochondria in adults are mostly stationary and local energy consumption is critical for axon regeneration.
A research team led by Dr Ma identified a therapeutic small molecule, M1, which can increase the fusion and motility of mitochondria, resulting in sustained, long-distance axon regeneration. Regenerated axons elicited neural activities in target brain regions and restored visual functions within four to six weeks after optic nerve injury in M1-treated mice.

Small molecule M1 promotes mitochondrial dynamics and sustains long-distance axon regeneration
“Photoreceptors in the eyes [retina] forward visual information to neurons in the retina. To facilitate the recovery of visual function after injury, the axons of the neurons must regenerate through the optic nerve and relay nerve impulses to visual targets in the brain via the optic nerve for image processing and formation,” explained Dr Ma.
To investigate whether M1 could promote long-distance axon regeneration after CNS injuries, the research team assessed the extent of axon regeneration in M1-treated mice four weeks after injury. Strikingly, most of the regenerating axons of M1-treated mice reached 4mm distal to the crush site (i.e. near optic chiasm), while no regenerating axons were found in vehicle-treated control mice. In M1-treated mice, the survival of retinal ganglion cells (RGCs, neurons that transmit visual stimuli from the eye to the brain) was significantly increased from 19% to 33% four weeks after optic nerve injury.
“This indicates that the M1 treatment sustains long-distance axon regeneration from the optic chiasm, i.e. midway between the eyes and target brain region, to multiple subcortical visual targets in the brain. Regenerated axons elicit neural activities in target brain regions and restore visual functions after M1 treatment,” Dr Ma added.
M1 treatment restores visual function
To further explore whether M1 treatment can restore visual function, the research team gave the M1-treated mice a pupillary light reflex test six weeks after the optic nerve injury. They found that the lesioned eyes of M1-treated mice restored the pupil constriction response upon blue light illumination to a level similar to that of non-lesioned eyes, suggesting that M1 treatment can restore the pupil constriction response after optic nerve injuries.

In addition, the research team assessed the response of the mice to a looming stimulus — a visually induced innate defensive response to avoid predators. The mice were placed into an open chamber with a triangular prism-shaped shelter and a rapidly expanding overhead-black circle as a looming stimulus, and their freeze and escape behaviours were observed. Half of the M1-treated mice responded to the stimulus by hiding in a shelter, showing that M1 induced robust axon regeneration to reinnervate subcortical visual target brain regions for complete recovery of their visual function.
Potential clinical application of M1 for repairing nervous system injury
The seven-year-long study highlights the potential of a readily available, non-viral therapy for CNS repair, which builds on the team’s previous research on peripheral nerve regeneration using gene therapy.
“This time we used the small molecule, M1, to repair the CNS simply by intravitreal injection into the eyes, which is an established medical procedure for patients, e.g. for macular degeneration treatment. Successful restoration of visual functions, such as pupillary light reflex and response to looming visual stimuli was observed in M1-treated mice four to six weeks after the optic nerve had been damaged,” said Dr Au Ngan-pan, Research Associate in the Department of Neuroscience.
The team is also developing an animal model for treating glaucoma-related vision loss using M1 and possibly other common eye diseases and vision impairments such as diabetes-related retinopathy, macular degeneration and traumatic optic neuropathy. Thus, further investigation is warranted to evaluate the potential clinical application of M1. “This research breakthrough heralds a new approach that could address unmet medical needs in accelerating functional recovery within a limited therapeutic time window after CNS injuries,” said Dr Ma.

In 2011, 12-year-old Oliver died when his heart stopped during a school swimming lesson. He had an undiagnosed heart condition. His father Mark King started the Oliver King Foundation and campaigned for all schools in England to have defibrillators.With help from some of Oliver’s school friends and former footballer Jamie Carragher, Mr King’s mission succeeded.Now the rollout has started, with the life saving devices being distributed to state schools who don’t already have one. According to the Department for Education, 20,000 defibrillators will be delivered to almost 18,000 state-funded schools by the end of the academic year.Mr King spoke to BBC Breakfast about the milestone.