Publisher Health

Researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have identified rare, naturally occurring T cells that are capable of targeting a protein found in SARS-CoV-2 and a range of other coronaviruses.
The findings suggest that a component of this protein, called viral polymerase, could potentially be added to COVID-19 vaccines to create a longer-lasting immune response and increase protection against new variants of the virus.
Most COVID-19 vaccines use part of the spike protein found on the surface of the virus to prompt the immune system to produce antibodies. However, newer variants — such as delta and omicron — carry mutations to the spike protein, which can make them less recognizable to the immune cells and antibodies stimulated by vaccination. Researchers say that a new generation of vaccines will likely be needed to create a more robust and wide-ranging immune response capable of beating back current variants and those that may arise in the future.
One way to accomplish this is by adding a fragment of a different viral protein to vaccines — one that is less prone to mutations than the spike protein and that will activate the immune system’s T cells. T cells are equipped with molecular receptors on their surfaces that recognize foreign protein fragments called antigens. When a T cell encounters an antigen its receptor recognizes, it self-replicates and produces additional immune cells, some of which target and kill infected cells immediately and others which remain in the body for decades to fight that same infection should it ever return.
The researchers focused on the viral polymerase protein, which is found not only in SARS-CoV-2 but in other coronaviruses, including those that cause SARS, MERS and the common cold. Viral polymerases serve as engines that coronaviruses use to make copies of themselves, enabling infection to spread. Unlike the spike protein, viral polymerases are unlikely to change or mutate, even as viruses evolve.
To determine whether or not the human immune system has T cell receptors capable of recognizing viral polymerase, the researchers exposed blood samples from healthy human donors (collected prior to the COVID-19 pandemic) to the viral polymerase antigen. They found that certain T cell receptors did, in fact, recognize the polymerase. They then used a method they developed called CLInt-Seq to genetically sequence these receptors. Next, the researchers engineered T cells to carry these polymerase-targeting receptors, which enabled them to study the receptors’ ability to recognize and kill SARS-CoV-2 and other coronaviruses.
More than 5 million people have died from COVID-19 worldwide. Current vaccines provide significant protection against severe disease, but as new, potentially more contagious variants emerge, researchers recognize that vaccines may need to be updated — and the new UCLA findings point toward a strategy that may help increase protection and long-term immunity. The researchers are now conducting further studies to evaluate viral polymerase as a potential new vaccine component.
Pavlo Nesterenko, a UCLA graduate student, is the study’s first author; the corresponding author is Dr. Owen Witte, who holds the presidential chair in developmental immunology in the UCLA Department of Microbiology, Immunology and Molecular Genetics and is founding director emeritus of the Broad Stem Cell Research Center. A full list of co-authors is available in the journal.
The study was published online today in the journal Cell Reports.
The research was supported by the Parker Institute for Cancer Immunotherapy, a Ruth L. Kirschstein Institutional National Research Service Award from the National Institutes of Health and the UCLA W.M. Keck Foundation COVID-19 Research Award Program.
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Materials provided by University of California – Los Angeles Health Sciences. Original written by Tiare Dunlap. Note: Content may be edited for style and length.

Medical University of South Carolina researchers describe the development of a school-based wellness initiative for combating childhood obesity by the MUSC Boeing Center for Children’s Wellness (BCCW) in the November issue of the Journal of School Health. Launched in 2007, the program is now available in 200 schools in 20 school districts across South Carolina, thanks to its flexible implementation model. Schools select from a menu of intervention options to tailor a wellness approach that is right for them.
It was South Carolina’s ranking in 2005 as eighth worst in the nation for childhood obesity that brought the urgency of the problem into focus and galvanized action around the issue, said BCCW director Janice Key, M.D., lead author of the article.
According to Key, it became clear early on that schools were the setting where obesity could best be addressed.
“Children are there for a large part of each day, and so they eat there, and they have an opportunity for exercise while they’re in school,” said Key. “It’s particularly important for anything to do with healthy lifestyles to include schools.”
For those reasons, the state mandated school health advisory councils to oversee wellness policy and initiatives at the school district level. However, most of those initiatives were never implemented by schools.
The problem was not a lack of evidence-based strategies to reduce obesity and improve wellness. Over the years, many strategies had been tested in small studies and recommended by public health authorities. The challenge was getting schools to implement them.

Ambient temperature influences the results of some of the most used laboratory tests, and these distortions likely affect medical decision making, such as whether to prescribe medications, researchers report December 10th in the journal Med. The authors say that laboratories could statistically adjust for ambient temperature on test days when reporting lab results to account for day-to-day variability.
“When a doctor orders a laboratory test, she uses it to shed light on what’s going on inside your body, but we wondered if the results of those tests could also reflect something that’s going on outside of your body” says study co-author Ziad Obermeyer (@oziadias) of the University of California, Berkeley. “This is exactly the kind of pattern that doctors might miss. We’re not looking for it, and lab tests are noisy.”
To explore this question, Obermeyer and Devin Pope of the University of Chicago analyzed a large dataset of test results from 2009 to 2015, spanning several climate zones. In a sample of more than four million patients, they modeled more than two million test results as a function of temperature. They measured how day-to-day temperature fluctuations affected results, over and above the patients’ average values, and seasonal variation.
The results showed that temperature affected more than 90% of individual tests and 51 of 75 assays, including measures of kidney function, cellular blood components, and lipids such as cholesterol and triglycerides. “It’s important to note that these changes were small: less than one percent differences in most tests under normal temperature conditions,” Obermeyer says.
These small, day-to-day fluctuations did not likely reflect long-term physiological trends. For example, lipid panels checked on cooler days appeared to suggest a lower cardiovascular risk, leading to almost 10% fewer prescriptions for cholesterol-lowering drugs called statins to patients tested on the coolest days compared to the warmest days, even though these results probably did not reflect stable changes in cardiovascular risk.
Because the study wasn’t an experiment, the researchers could not pinpoint the exact mechanisms underlying the fluctuations in lab results. Possible explanations include blood volume, specific assay performance, specimen transport, or changes in lab equipment. “Whatever their cause, temperature produces undesirable variability in at least some tests, which in turn leads to distortions in important medical decisions,” Pope says.
One practical implication of the study is that laboratories could statistically adjust for ambient temperature on the test day when reporting lab results. Doing so could reduce weather-related variability at a lower cost than new laboratory assay technology or investments in temperature control in transport vans. In practice, decisions on adjustment would need to be at the discretion of the laboratory staff and the treating physician, potentially on a case-by-case basis.
According to the authors, the study may also have broader clinical implications. “The textbook way of thinking about medical research is bench to bedside. First, we come up with a hypothesis, based on theory, then we test it with data,” Obermeyer says. “As more and more big data comes online, like the massive dataset of lab tests we used, we can flip that process on its head: discover fascinating new patterns and then use bench science to get to the bottom of it. I think this bedside-to-bench model is just as important as its better-known cousin because it can open up totally new questions in human physiology.”
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For the first time, scientists have identified a rare population of potentially toxic senescent cells in human brains that can serve as a target for a new Alzheimer’s disease treatment.
The study, published in the Dec.10 edition of the journal Nature Aging, was led by Miranda Orr, Ph.D., assistant professor of gerontology and geriatric medicine, at Wake Forest School of Medicine and research health scientist at the W.G. Hefner VA Medical Center, and Habil Zare, Ph.D., assistant professor of cell systems and anatomy, at University of Texas Health San Antonio. The study was funded by the U.S. Department of Veterans Affairs and National Institute on Aging.
Senescent cells are old, sick cells that cannot properly repair themselves and don’t die off when they should. Instead they function abnormally and release substances that kill surrounding healthy cells and cause inflammation. Over time, they continue to build up in tissues throughout the body contributing to the aging process, neurocognitive decline and cancer.
Research conducted by Orr in 2018 found that senescent cells accumulated in mouse models of Alzheimer’s disease where they contributed to brain cell loss, inflammation and memory impairment. When the researchers used a therapy to clear the senescent cells, they halted disease progression and cell death.
“However, until now, we didn’t know to what extent senescent cells accumulated in the human brain, and what they actually looked like,” Orr said. “It was somewhat like looking for the proverbial needle in a haystack except we weren’t sure what the needle looked like.”
Using sophisticated statistical analyses, the research team was able to evaluate large amounts of data. In total, they profiled tens of thousands of cells from the postmortem brains of people who had died with Alzheimer’s disease. The researchers’ plan was to first determine if senescent cells were there, then how many there were and what types of cells they were. They succeeded.

A team of WEHI researchers has for the first time visualised a human cell death complex linked to autoimmune and inflammatory conditions, such as inflammatory bowel disease, and injuries associated with excessive cell death.
Using the Australian Synchrotron, the team solved the structure of the human cell death proteins MLKL and RIPK3 bound to each other, as well as human RIPK3 alone. When RIPK3 activates MLKL, it triggers a type of inflammatory cell death called necroptosis that kills the cell and alerts the immune system that it is under attack. However, when uncontrolled, necroptosis has been linked to human inflammatory diseases.
The findings will help scientists discover drugs that can target and suppress cell death by necroptosis, which could lead to new treatments for a range of autoimmune and inflammatory diseases including inflammatory bowel disease, renal injury and diabetes.
The research, published in the journal Nature Communications, was led by WEHI researchers Yanxiang Meng, Dr Katherine Davies, Associate Professor Peter Czabotar and Associate Professor James Murphy. The discovery is the latest in an almost 15-year-long journey to understand necroptosis for treating disease.
At a glance WEHI researchers have visualised the structures of human cell death protein RIPK3 alone, and RIPK3 bound to MLKL in a dormant state.

Patients with asthma often experience a worsening of asthmatic symptoms at night in so-called “nocturnal asthma.” According to reports, more than 50% of asthma deaths occur at night, exposing a link between nocturnal asthma symptoms and asthma deaths. Although some have proposed several triggers that explain the pathogenesis of nocturnal asthma, the precise mechanisms regulating this asthma phenotype remain obscure.
Now, a research group led by Kentaro Mizuta from Tohoku University Graduate School of Dentistry has discovered that melatonin, a sleep hormone, worsens asthma.
Asthma patients suffer from bronchoconstriction, where the smooth muscles of the bronchus — the pathway that moves air to and from your lungs — contract. To ease this, many take a bronchodilator, a medicine which widens the bronchus.
However, melatonin, which is often prescribed for insomnia, favors a state of bronchoconstriction and weakens the relaxing effect of a bronchodilator through the activation of the melatonin MT2 receptor.
To elucidate this, the research group identified the expression of the melatonin MT2 receptor in human airway smooth muscle. They observed that the activation of the melatonin MT2 receptor with higher doses of melatonin or melatonin receptor agonist ramelteon greatly potentiated the bronchoconstriction. Furthermore, melatonin attenuated the relaxing effects of the widely used bronchodilator β-adrenoceptor agonist.
“Although serum concentration of melatonin did not significantly induce the airway constriction, greater doses of melatonin, which is clinically used to treat insomnia, jet lag, or cancer, worsened asthma symptoms and impaired the therapeutic effect of bronchodilators,” said Mizuta.
First author of the paper Haruka Sasaki adds, “The pharmacological therapy that blocks the melatonin MT2 receptor could inhibit the detrimental effects of melatonin on airways.”
The research paper was published in the American Journal of Physiology Lung Cellular and Molecular Physiology on November 16, 2021.
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A study conducted at the University of Jyväskylä in the Faculty of Sport and Health Sciences measured arterial stiffness in women from wide age range. Increased stiffness is an independent risk factor for cardiovascular disease. Age was a strong determinant of arterial stiffness. Indicative of the role of hormones, menstrual cycle phase, contraceptive pill phase and menopausal state were also associated with arterial stiffness.
The human vasculature consists of arteries, veins, and capillaries where blood circulates in a certain direction. As the heart pumps blood, the arteries that carry blood throughout the body also work. The arteries alternately dilate and contract, allowing blood to progress. This propagation is known as a pulse wave. The walls of the arteries should be elastic enough, though not too much so, to allow the pulse wave to proceed without the walls of the arteries rupturing. As the blood vessels age, the arterial wall stiffens. Stiffening increases the risk of cardiovascular disease and the risk of cardiac mortality. Female sex hormones have been shown to affect several factors that regulate vascular wall elasticity, so high estrogen levels are thought to be one of the mechanisms by which young adult women acquire a lower risk of cardiovascular disease than their male peers. Studies measuring both hormone levels and arterial stiffness in women differing due to their age or use of hormonal products are scarce.
“Our study combined two datasets including young adults and middle-aged women. It allowed for a comprehensive examination of the different hormonal statuses involved in women’s lives,” says Associate Professor Eija Laakkonen from the Gerontology Research Center and the Faculty of Sports and Health Science, University of Jyväskylä. “We were able to study the associations of the natural menstrual cycle and the use of birth control pills, as well as the natural menopause and the use of hormone therapy with the flexibility of the arteries.”
The entire study consisted of women aged 19 to 58 years. The older the women were, the stiffer their arteries were. Of the hormones measured, estradiol and follicle-stimulating hormone were associated with arterial stiffness, but age was a stronger determinant of stiffness than hormone levels were. Examination of the subsets showed hormonal state to be associated with arterial stiffness. The attenuation of the pulse wave was faster in the late follicular and ovulation phases than it was during menstrual bleeding. Combined oral contraceptive users have varying hormonal levels due to taking pills containing estrogen and progestogen for the first three weeks and then changing to hormone-free pills for a week during which withdrawal bleeding occurs. While taking the hormonal pills, the arteries were more elastic than they were during bleeding. Among menopausal women, postmenopausal women on hormone therapy had the stiffest arteries.
“Based on this study, we can conclude that age is a significant regulator of vascular functions, but hormones also play a role in regulating arterial elasticity at different stages of a woman’s life,” Laakkonen says. “In the future studies, it would be worthwhile to closely inspect and compare the effects of endogenous and exogenous hormones on arterial wall properties to better understand the regulation of arterial properties at different hormonal stages women live through. Such comprehensive studies have not been done yet.”
The research was carried out at the Faculty of Sport and Health Sciences of the University of Jyväskylä using the research data from the studies Estrogen, microRNAs and the risk of metabolic dysfunction (EsmiRs) and the Endogenous and exogenous hormones and performance in women (MEndEx). The EsmiRs study is led by Associate Professor Eija Laakkonen and MendEx is led by Lecturer Johanna Ihalainen. EsmiRs has been funded by the Academy of Finland and MendEx by the Urheiluopistosäätiö.
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Tumors are heterogeneous, which means that different parts of the same tumor can be genetically distinct. This phenomenon, known as intratumor heterogeneity, is steadily gaining in significance within the field of cancer research. Cellular and molecular differences within the same tumor play an important role in many different cancers due to their implications for diagnosis and the use of targeted therapies. According to a recently published study by Charité, the MDC and the German Cancer Consortium (DKTK), this also applies to neuroblastoma, a malignant solid tumor of the peripheral nervous system which is relatively common in children. Neuroblastomas develop from groups of unmature nerve cells mostly in the adrenal glands or along the spine, from where they expand into the abdominal cavity.
Summarizing the researchers’ key findings, the study’s first author, Dr. Karin Schmelz of Charité’s Department of Pediatric Oncology and Hematology, says: “In our study, we were able to show that the genetic changes typically associated with neuroblastoma can both disappear and emerge over the course of the disease. These mutations are not evenly distributed throughout the tumor; rather, they occur in distinct sections or even in individual cells, giving the tumor a mosaic-like appearance.”
“Cancer is driven by evolutionary processes,” says Dr. Roland Schwarz, Group Leader of the MDC’s Evolutionary and Cancer Genomics research group and one of the study’s last authors, Cancer cells undergo constant genetic change; they are engaged in a fight for survival, including against other cancer cells. Each cancer has its own phylogenetic tree, which depicts the way in which a tumor evolves; some cancer cells become metastatic, while others develop treatment resistance.
The researchers analyzed a total of 140 neuroblastoma samples. The biopsy samples were collected from 10 pediatric patients at various points during the clinical course and covered multiple tumor regions. Sample analysis involved the use of multiple modern sequencing techniques followed by computer-assisted evaluation.
The researchers focused their analysis on the neuroblastoma-associated genes ALK, MYCN and FGFR1, which play an important role in both clinical course and treatment. According to their results, changes in the ALK and MYCN genes were not present continuously throughout the course of the disease, nor were they found in all tumor cells. Changes in the ALK and FGFR1 genes can offer useful treatment targets, particularly in relapsed patients. The researchers found that, in some patients, ALK mutations which were present at the time of diagnosis had disappeared by the time the tumor was surgically removed. Furthermore, changes in the FGFR1 gene were only found in distinct tumor regions. The researchers were also able to identify an instability in the number of gene copies present in neuroblastoma cells. In some cases, cancer cell clones showed early divergence from the primary tumor, breaking away to infiltrate other organs where they formed metastases.
“The process of recording detailed spatial and temporal changes in the copy numbers of specific genes is extremely complex,” explains bioinformatics expert Dr. Schwarz. Notwithstanding these challenges, his research group developed an algorithm capable of producing a precise reconstruction of these copy numbers. In 2020, Dr. Schwarz and his international colleagues used this method to produce evidence of continuous structural evolution in a range of different cancers. “We have now been able to extend this to neuroblastoma, where we were able to show in detail how the cancer genome undergoes structural changes,” says Dr. Schwarz.
Last author Prof. Dr. Angelika Eggert, Head of Charité’s Department of Pediatric Oncology and Hematology, explains: “We are now in a better position to understand how neuroblastoma cells behave. This knowledge is essential in relation to patients who suffer a recurrence of their disease because their treatment often requires the use of personalized and targeted therapies. When a tumor presents as genetically heterogeneous, targeted molecular therapy may well capture a majority of the abnormal tissue but, crucially, will not capture all of the affected cells. The cancer will then be able to regrow from those remaining cells.”
Explaining the significance of their research in light of existing knowledge, Prof. Eggert says: “Our findings have less relevance for neuroblastoma diagnosis and therapy selection. This is because diagnosis is already reliable, thanks to technologies that have undergone decades of testing, such as imaging, urine testing and single tissue biopsies, and because chemotherapy targeting fast-growing cells remains the treatment of choice for the primary tumor. However, if the disease recurs following treatment, targeted treatment options become particularly important. Treatment selection which is based on a single tissue biopsy from a single tumor region is unlikely to adequately address the tumor’s genetic heterogeneity. When a relapse occurs, we should therefore consider using state-of-the-art sequencing techniques to analyze tumor tissue samples harvested from multiple regions. This would provide us with as much detail as possible about the disease, enabling us to further improve the decision-making process pertaining to the selection of personalized therapies.”
The researchers are now testing other methods in the hope of resolving some of the technical challenges which remain. These include the use of single-cell-based technologies and liquid biopsies, a new type of blood test which analyzes genetic information shed by tumors into the bloodstream. Using the analysis of multiple blood samples over the course of disease, these techniques will provide evidence of any genetic changes taking place — without the need for invasive surgical biopsies. Both of these techniques and their clinical application are undergoing intensive study at Charité, the Berlin Institute of Health at Charité (BIH) and the MDC.

A silicon device that can change skin tissue into blood vessels and nerve cells has advanced from prototype to standardized fabrication, meaning it can now be made in a consistent, reproducible way. As reported in Nature Protocols, this work, developed by researchers at the Indiana University School of Medicine, takes the device one step closer to potential use as a treatment for people with a variety of health concerns.
The technology, called tissue nanotransfection, is a non-invasive nanochip device that can reprogram tissue function by applying a harmless electric spark to deliver specific genes in a fraction of a second. In laboratory studies, the device successfully converted skin tissue into blood vessels to repair a badly injured leg. The technology is currently being used to reprogram tissue for different kinds of therapies, such as repairing brain damage caused by stroke or preventing and reversing nerve damage caused by diabetes.
“This report on how to exactly produce these tissue nanotransfection chips will enable other researchers to participate in this new development in regenerative medicine,” said Chandan Sen, director of the Indiana Center for Regenerative Medicine and Engineering, associate vice president for research and Distinguished Professor at the IU School of Medicine.
Sen also leads the regenerative medicine and engineering scientific pillar of the IU Precision Health Initiative and is lead author on the new publication.
“This small silicon chip enables nanotechnology that can change the function of living body parts,” he said. “For example, if someone’s blood vessels were damaged because of a traffic accident and they need blood supply, we can’t rely on the pre-existing blood vessel anymore because that is crushed, but we can convert the skin tissue into blood vessels and rescue the limb at risk.”
In the Nature Protocols report, researchers published engineering details about how the chip is manufactured.
Sen said this manufacturing information will lead to further development of the chip in hopes that it will someday be used clinically in many settings around the world.
“This is about the engineering and manufacturing of the chip,” he said. “The chip’s nanofabrication process typically takes five to six days and, with the help of this report, can be achieved by anyone skilled in the art.”
Sen said he hopes to seek FDA approval for the chip within a year. Once it receives FDA approval, the device could be used for clinical research in people, including patients in hospitals, health centers and emergency rooms, as well as in other emergency situations by first responders or the military.
Other study authors include Yi Xuan, Subhadip Ghatak, Andrew Clark, Zhigang Li, Savita Khanna, Dongmin Pak, Mangilal Agarwal and Sashwati Roy, all of IU, and Peter Duda of the University of Chicago.
This research is funded by the National Institutes of Health.
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Organ-on-a-chip technology has provided a push to discover new drugs for a variety of rare and ignored diseases for which current models either don’t exist or lack precision. In particular, these platforms can include the cells of a patient, thus resulting in patient-specific discovery.
As an example, even though sickle cell disease was first described in the early 1900s, the range of severity in the disease causes challenges when trying to treat patients. Since this disease is most prevalent among economically poor and underrepresented minorities, there has been a general lack of stimulus to discover new treatment strategies due to socioeconomic inequity, making it one of the most serious orphan conditions globally.
Tanmay Mathur, doctoral student in Dr. Abhishek Jain’s lab in the Department of Biomedical Engineering at Texas A&M University, is developing personalized blood vessels to improve knowledge and derive treatments against the vascular dysfunction seen in sickle cell disease and other rare diseases of the blood and vessels.
Current cells used in blood vessel models use induced pluripotent stem cells (IPSCs), which are derived from a patient’s endothelial cells. However, Mathur said these cells have limitations — they expire quickly and can’t be stored for long periods of time.
Mathur’s research offers an alternative — blood outgrowth endothelial cells (BOECs), which can be isolated from a patient’s blood. All that is needed is 50 to 100 milliliters of blood.
“The equipment and the reagents involved are also very cheap and available in most clinical settings,” Mathur said. “These cells are progenitor endothelial cells, meaning they have high proliferation, so if you keep giving them the food they want, within a month, we will have enough cells so that we can successfully keep on subculturing them forever.”
However, the question is do BOECs work like IPSCs in the context of organ-on-chips, a microdevice that allows researchers to create these blood vessel models. That’s a question Mathur recently answered in a paper published in the Journal of the American Heart Association.