Publisher Health

Conventional wisdom holds that storing fat around your belly puts you at increased risk for type 2 diabetes. But surprising new findings from the University of Virginia School of Medicine suggest that naturally occurring variations in our genes can lead some people to store fat at the waist but also protect them from diabetes.
The unexpected discovery provides a more nuanced view of the role of obesity in diabetes and related health conditions. It also could pave the way for more personalized medicine — treatments tailored to the individual. For example, doctors might prioritize weight loss for patients whose genes put them at increased risk but place less emphasis on it for patients with protective gene variants, the researchers say.
“There is a growing body of evidence for metabolically healthy obesity. In this condition, people who would normally be at risk for cardiovascular diseases and diabetes because they are obese are actually protected from adverse effects of their obesity. In our study, we found a genetic link that may explain how this occurs in certain individuals,” said researcher Mete Civelek, PhD, of UVA’s Center for Public Health Genomics. “Understanding various forms of obesity is important to tailor treatments for individuals who are at high risk for adverse effects of obesity.”
As medicine grows more sophisticated, understanding the role of naturally occurring gene variations will play an important role in ensuring patients get the best, most tailored treatments. The new work by Civelek and his team, for example, indicates that variants can simultaneously predispose some people to store fat at the abdomen — thought to put them at increased risk for a cluster of health problems called metabolic syndrome — while also protecting them from type 2 diabetes. (Metabolic syndrome raises the risk for diabetes, stroke and other serious health issues.)
One of the metrics doctors use to determine if a patient has metabolic syndrome is abdominal obesity. This is often calculated by comparing the patient’s waist and hip measurements. But Civelek’s research suggest that, for at least some patients, it may not be that simple. In the future, doctors may want to check a patient’s genes to determine how to best guide the person down the road to good health.
“We found that among the hundreds of regions in our genomes which increase our propensity to accumulate excess fat in our abdomens, there are five which have an unexpected role,” said Yonathan Aberra, the lead author of the study and a PhD candidate at UVA’s Department of Biomedical Engineering, a joint program of the School of Medicine and School of Engineering. “To our surprise, these five regions decrease an individual’s risk for type 2 diabetes.”
In addition to producing surprising findings, Civelek’s research provides important new tools for his fellow researchers seeking to understand the complexities of gene variations. The sophisticated approach Civelek and his collaborators developed to identify the relevant variants and their potential effects will be useful for future research into metabolic syndrome and other conditions.
The tools could also prove invaluable in the development of new and better treatments for metabolic syndrome, the scientists say.
“We now need to expand our studies in more women and people from different genetic ancestries to identify even more genes that underlie the metabolically health obesity phenomenon,” Civelek said. “We plan to build on our findings to perform more experiments to potentially identify a therapeutic target.”
The research was supported by the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases, grant R01 DK118287; the National Heart Lung and Blood Institute, grant T32 HL007284; the American Diabetes Association, grant 1-19-IBS-105; and the National Science Foundation’s Louis Stokes Alliances for Minority Participation Bridge-to-the-Doctorate Virginia-North Carolina Alliance Fellowship.

A study led by the University of Eastern Finland suggests that adolescents who engage in active school transport and leisure-time physical activity perform better at secondary school than their inactive peers. Regular leisure-time physical activity, even in moderate doses, was also associated with lower odds of school burnout. The findings were published in the  European Journal of Public Health.
The relationship of physical activity with learning and academic achievement is complex. However, prior studies have found that especially school-based physical activity, such as physical education, can improve classroom performance — particularly in mathematics. Despite this, few studies have examined the association between active school transport and educational outcomes. Regarding physical activity and school wellbeing, most of the previous evidence is focused on university-level students.
In the recently published study of over 34,000 adolescents, researchers observed that active school transport was associated with higher odds of high perceived academic performance and self-reported competency in academic skills. The association was even stronger for leisure-time moderate-to-vigorous physical activity. Similar to prior studies, the relationship between leisure-time physical activity and mathematical skills stood out.
“The results regarding active school transport were particularly intriguing as researchers are increasingly interested in the health benefits of travel-related walking and cycling. Being physically active before school could, for example, enhance concentration in classroom, explaining our observations. However, due to the cross-sectional design, our study cannot establish causality,” says Juuso Jussila, a Doctoral Researcher at the University of Eastern Finland.
“There were no surprises regarding the strong association between leisure-time physical activity and perceived academic achievement due to support from prospective and intervention studies. Although we do not know all the explanatory mechanisms, improved coordination and perceptual-motor skills, required in various team sports, for example, can at least partially explain these observations. Leisure-time physical activity is also typically more intense than active school transport, leading to increases in brain-derived neurotrophic factor in our circulation and, thus, improvements in cognitive performance.”
Leisure-time physical activity was also inversely associated with school burnout. As little as 30 minutes of weekly moderate-to-vigorous activity was associated with 24% lower odds of school burnout. Adolescents who engaged in leisure-time physical activity for 4 to 6 hours a week had 46% lower odds of school burnout compared to their physically inactive peers. Both leisure-time physical activity and active school transport were also positively associated with school enjoyment.
“To the best of my knowledge, this was the first large-scale study to examine the association between physical activity and school burnout among adolescents. Leisure-time physical activity can be an effective way to disconnect from schoolwork and the potential stress related to it. If we can increase the amount leisure-time physical activity among youth, both learning and wellbeing benefits can be significant,” Jussila summarises.
The study was conducted in collaboration with the Finnish Institute for Health and Welfare and the nationwide School Health Promotion study. Jussila works as a researcher in the Climate Nudge project, which is funded by the Strategic Research Council at the Academy of Finland.

A gene encoding a protein linked to tau production — tripartite motif protein 11 (TRIM11) — was found to suppress deterioration in small animal models of neurodegenerative diseases similar to Alzheimer’s disease (AD), while improving cognitive and motor abilities, according to new research from the Perelman School of Medicine at the University of Pennsylvania. Additionally, TRIM11 was identified as playing a key role in removing the protein tangles that cause neurodegenerative diseases, like AD. The findings are published today in Science.
AD is the most common cause of dementia in older adults, with an estimated 6 million Americans currently living with the disease. It is a progressive brain disorder that slowly destroys memory and thinking skills. Foundational research at Penn Medicine led by Virginia M.Y. Lee, PhD, the John H. Ware III Professor in Alzheimer’s Research in Pathology and Laboratory Medicine, and the late John Q. Trojanowski, MD, PhD, a former professor of Geriatric Medicine and Gerontology in Pathology and Laboratory Medicine, reveals that one of the underlying causes of neurodegenerative diseases is neurofibrillary tangles (NFTs) of tau proteins, which cause the death of neurons, leading to the symptoms of AD, like loss of memory.
In addition to AD, aggregation of tau proteins into NFTs is associated with over 20 other dementias and movement disorders including progressive supranuclear palsy, Pick’s disease, and chronic traumatic encephalopathy, collectively known as tauopathies. Nevertheless, how and why tau proteins clump together and form the fibrillar aggregates that make up NFTs in patients with these diseases remains unclear. This major gap in knowledge has made the development of effective therapies challenging for researchers.
“Most organisms have protein quality control systems that remove defective proteins, and prevent the mis-folding and accumulation of tangles — like the ones we see with tau proteins in the brain of those with taupathies — but until now we didn’t know how this works in humans, or why it malfunctions in some individuals and not others,” said senior author, Xiaolu Yang, PhD, a professor of Cancer Biology at Penn. “For the first time, we have identified the gene that oversees tau function, and have a promising target for developing treatments to prevent and slow the progression of Alzheimer’s disease and other related disorders.”
Yang and his team, including first author Zi-Yang Zhang, PhD, a postdoctoral researcher in Yang’s lab, previously found that TRIM proteins play an important role in protein quality control in animal cells. After examining over 70 human TRIMs, they found that TRIM11 has a major role in suppressing tau aggregation. TRIM11 possesses three main functions related to the quality control of tau proteins. First, it binds to tau proteins, especially the mutant variants that cause disease, and helps eliminate them. Second, it acts as a “chaperone” for tau, preventing the proteins from mis-folding. Finally, TRIM11 dissolves pre-existing tau aggregates.
Using postmortem brain tissues of 23 individuals with AD and 14 health controls from the Center for Neurodegenerative Disease Research tissue bank — created and maintained by Lee and Trojanowski — researchers validated these findings, and found that levels of TRIM11 protein are substantially reduced in the brains of individuals with AD, compared to healthy control individuals.
To determine the potential utility of TRIM11 as a therapeutic agent, researchers used adeno-associated viral vector (AAV), a tool commonly used in gene therapy, to deliver the TRIM11 gene into the brain of multiple mouse models. Researchers found that mice with tau pathologies receiving the TRIM11 gene exhibited a marked decrease in the development and accumulation of NFTs, and had much improved cognitive and motor abilities.
“Not only do these findings tell us that TRIM11 could play an important role in protecting people from Alzheimer’s and similar diseases, but we also see that we might be able to develop future therapies that replenish TRIM11 in individuals with lower levels,” said Yang. “We are eager to work with our colleagues to explore the possibility of developing gene therapies that halt the progression of neurodegenerative disease.”
This study was supported by the National Institutes of Health (R01CA243520, UL1TR000003) and funding received by Penn under a sponsored research agreement with Wealth Strategy Holding Limited.
Note:Yang is an inventor on patents and patent applications owned by the University of Pennsylvania related to TRIM proteins, and is a co-founder and equity holder of Evergreen Therapeutics LLC, which received investments from Wealth Strategy Holding Limited. Penn and Yang have either received, or may receive in the future, financial consideration related to the licensing of certain Penn intellectual property to Evergreen Therapeutics LLC.

Early genetic testing can improve cancer outcomes, but individuals often don’t undergo this screening if they lack a family history or can’t afford a test. A clinical laboratory team at Oregon Health & Science University is hoping to change that for residents of their state by providing free genetic screening for inherited cancer and familial hypercholesteremia to all adults with an Oregon address. After screening over 13,000 Oregonians since 2018, the team presents their methods, findings, and lessons learned on July 27 in The American Journal of Human Genetics.
“We’re hoping that this can really be used as a model for other states that want to do low-cost population screening,” says first author Timothy O’Brien, a staff scientist at Knight Diagnostic Laboratories. “We’ve provided a kind of roadmap where up-and-coming screening programs can look at us and see both what worked and what could be improved upon.”
The team recruited participants through social media ads and tabling at events like farmers markets. They even set up vending machines where individuals could retrieve and return testing kits that collected a mouthwash saliva sample. After the onset of the COVID-19 pandemic, individuals could request a testing kit through the mail. Once participants gave their consent through a HIPAA-compliant app, samples were processed at a clinical laboratory to screen for disease-causing variants in 31 genes related to inherited cancer and 1 gene related to familial hypercholesteremia.
“We wanted to report on any disease-causing variant that was deemed to be actionable, which means there’s something you can do about it,” says senior author Sue Richards, a Professor Emeritus of Molecular & Medical Genetics at Oregon Health & Science University. “It could be something like changing your screening habits, taking a prophylactic surgery or medication, or consulting with your clinician.”
710 out of over 13,000 participants screened positive for a disease-causing variant. All participants with confirmed positive results received a call from a genetic counselor to explain their results, how the results impact their disease risk, and recommendations for medical management. “Genetic counseling is critical to this program,” says Richards. “It’s not easy for the public to understand these genetic testing reports because they’re fairly technical, and it’s important to understand that just because they carry a disease-causing variant may not mean that they will develop that type of cancer. The counselor also talks to them not only about their own health and family history but also how they pass that information along to other family members, since they are at risk of having the variant as well.”
When the laboratory team first started this project, they had to scale up the lab’s genetic testing workflow to about ten times its original capacity by focusing on a select group of disease-causing variants and employing the help of robots, which performed more tedious tasks. This allowed the group to process up to 1,000 samples per month with one lab technologist at the estimated cost of $50 per participant. To reduce the possibility of a laboratory mix-up resulting in a false positive, all participants with positive results were asked to undergo secondary screening using a different genetic sequencing method. Even so, the researchers report zero clinically relevant sample mix-ups out of the 20,000 specimens that they sequenced.
From their sequencing results, the researchers have also assembled a large repository of data that can be used to analyze the genetic risk factors of Oregon’s population and conduct additional research studies. Approximately 5% of participants screened positive for a disease-causing inherited cancer variant, which was higher than several prior population-screening studies have reported and may be because people with a personal or family history of cancer were more likely to seek testing.
This higher-than-expected prevalence could also be because prior studies screened for a different set of genes. The American College of Medical Genetics and Genomics (ACMG) details a minimum set of genes not related to the individual’s condition but recommended to analyze in those undergoing clinical testing. However, if the researchers had only examined genes from this list, they would have missed 59% of disease-causing variants in their study population. In addition, the most common disease-causing variants detected in the study were not on ACMG’s list. This highlights how expanding the range of genes being tested can have a significant impact on how many people receive positive results in large screening studies.
The team plans on continuing their screening program in the future and increasing efforts to reach a more diverse population of participants. Currently, 76% of study participants are female, so the study is looking at how to recruit more male participants. In addition, by translating their consent app into Spanish, the researchers plan on reaching more of Oregon’s Spanish-speaking population.
“The overall goal of this project was really to help Oregonians and empower them with this health information,” says O’Brien. “We feel like we’ve been able to accomplish that and hope that this continues to be a strong proponent of health for Oregonians in the future.”

When a hunting dog picks up the scent of a deer, it sometimes freezes. On the spot. The same thing can happen to people who need to concentrate on a challenging task.
Now researchers have made a discovery that adds to our knowledge of what happens in the brain when we suddenly stop moving.
“We have found a group of nerve cells in the midbrain which, when stimulated, stop all movement. Not just walking; all forms of motor activity. They even make the mice stop breathing or breathe more slowly, and the heart rate slow down,” explains Professor Ole Kiehn, who is co-author on the study.
“There are various ways to stop movement. What is so special about these nerve cells is that once activated they cause the the movement to be paused or freeze. Just like setting a film on pause. The actors movement suddenly stop on the spot,” says Ole Kiehn.
When the researchers ended activating the nerve cells, the mice would start the movement exactly where it stopped. Just like when pressing “play” again.
“This ‘pause-and-play pattern’ is very unique; it is unlike anything we have seen before. It does not resemble other forms of movement or motor arrest we or other researchers have studied. There, the movement does not necessarily start where it stopped, but may start over with a new pattern,” says PhD Haizea Goñi-Erro, who is first author of the study.
The nerve cells stimulated by the researchers are found in the midbrain in an area called the pedunculopontine nucleus (PPN), and they differ from other nerve cells there by expressing a specific molecular marker called Chx10. The PPN is common to all vertebrates including humans. So even though the study was performed in mice, the researchers expect the phenomenon to apply to humans too.

Investigators at the Icahn School of Medicine at Mount Sinai have designed an innovative RNA-based strategy to activate dendritic cells — which play a key role in immune response — that eradicated tumors and prevented their recurrence in mouse models of melanoma.
The findings, which suggest that the approach has the potential to be effective against tumors that have already spread to other parts of the body and against different cancer types, were reported in the July 27 issue of Nature Nanotechnology.
Cancer cells employ strategies to switch off various stages of the cancer-immunity cycle, the process by which dendritic cells educate T cells to kill cancer cells. This immunosuppressive environment that impedes activation of cancer-killing T cells allows tumors to grow, say the researchers.
“Most approaches to boost this critical role of dendritic cells — or adoptive cell therapies — aim to increase the activation signals provided to dendritic cells when specific molecules on their surface bind to tumor cells. However, these have not been as successful in clinical trials as hoped. This is because tumors have a tendency to evolve in different ways to switch off each stage of the cancer-immunity cycle,” says Yizhou Dong, PhD, corresponding author of the study, Professor of Oncological Sciences, and a member of the Icahn Genomics Institute and the Marc and Jennifer Lipschultz Precision Immunology Institute at Icahn Mount Sinai.
The researchers named their approach CATCH. As part of the regimen, the researchers used new types of lipid nanoparticles to deliver two mRNA therapeutics — a process similar to that used successfully for COVID-19 vaccines — to ensure the dendritic cells were sufficiently activated to enhance the cancer-immunity cycle in established tumors.
Using multiple bioassays to gain insights on the effects of the CATCH regimen on different types of immune cells, the researchers showed that their strategy not only reactivated the cycle but also removed obstacles at other stages. This caused a change in the tumor’s microenvironment, shifting it from having cell types that weaken T cells’ ability to fight cancer to having cell types that actually support and enhance their ability to fight tumors.
Beyond the positive findings in mouse models of melanoma, the researchers conducted further tests to evaluate the effectiveness of the CATCH regimen in restarting the cancer immunity cycle more broadly. Their investigations revealed encouraging results, as the regimen reduced tumors in mouse models of B cell lymphoma by 83 percent. They also tested it in mouse models of breast cancer, where approximately half of the mice favorably responded.
Next, the researchers plan feasibility and safety testing for using the CATCH regimen in early-phase clinical trials for patients.
“Dendritic cells have been a key focus for the development of new cancer therapies as these cells organize the cancer-immunity cycle. In theory, the CATCH regimen using this particular RNA-based technology has the potential to provide a much more effective approach for using dendritic cells for cancer immunotherapy to treat a wide range of solid tumors,” says Brian Brown, PhD, Director of the Icahn Genomics Institute and Associate Director of the Marc and Jennifer Lipschultz Precision Immunology Institute at Icahn Mount Sinai.
The study was funded in part by National Cancer Institute grant P30 CA016058 and National Institute of General Medical Sciences grant R35GM144117.

A process of surgically joining the circulatory systems of a young and old mouse slows the aging process at the cellular level and lengthens the lifespan of the older animal by up to 10%.
Appearing online July 27 in the journal Nature Aging, a team led by Duke Health researchers found that the longer the animals shared circulation, the longer the anti-aging benefits lasted once the two were no longer connected.
The findings suggest that the young benefit from a cocktail of components and chemicals in their blood that contributes to vitality, and these factors could potentially be isolated as therapies to speed healing, rejuvenate the body and add years to an older individual’s life.
“This is the first evidence that the process, called heterochronic parabiosis, can slow the pace of aging, which is coupled with the extension in lifespan and health,” said senior author James White, Ph.D., assistant professor in the departments of Medicine and Cell Biology at Duke University School of Medicine and the Duke Aging Center.
White and colleagues set out to determine whether the benefits of heterochronic parabiosis — surgically fusing two animals of different ages to enable a shared circulatory system — were fleeting, or more long-lasting.
Earlier studies at Duke and elsewhere documented anti-aging benefits in tissues and cells of the older mice after three weeks of parabiosis. These studies found that the older mice became more active and animated, and their tissue showed evidence of rejuvenation.
“Our thought was, if we see these anti-aging effects in three weeks of parabiosis, what happens if you bring that out to 12 weeks,” White said. “That’s about 10% of a mouse’s lifespan of three years.”
White said the ages of the mice were also important, with the young mouse aged four months, and the older mouse aged two years.

Promising new research suggests a total of just 4.5 minutes of vigorous activity that makes you huff and puff during daily tasks could reduce the risk of some cancers by up to 32 percent.
Published in JAMA Oncology and led by the University of Sydney, Australia, the study used data from wearable devices to track the daily activity of over 22,000 ‘non-exercisers’. Researchers then followed the group’s clinical health records for close to seven years to monitor for cancer.
As few as four to five minutes of vigorous intermittent lifestyle physical activity or ‘VILPA’ was associated with a substantially lower cancer risk compared to those who undertook no VILPA.
Vigorous Intermittent Lifestyle Physical Activity, or VILPA for short, was coined by researchers at the University of Sydney’s Charles Perkins Centre to describe the very short bursts of activity — around one minute each — we do with gusto each day. This includes activities like vigorous housework, carrying heavy shopping around the grocery store, bursts of power walking or playing high-energy games with the kids.
“VILPA is a bit like applying the principles of High-Intensity Interval Training (HIIT) to your everyday life,” said lead author Professor Emmanuel Stamatakis of the Charles Perkins Centre.
He said adults who don’t exercise are at increased risk of developing certain cancers like breast, endometrial or colon, but until recently the impact of less structured forms of vigorous physical activity was unable to be measured.
“We know the majority of middle-aged people don’t regularly exercise which puts them at increased cancer risk but it’s only through the advent of wearable technology like activity trackers that we are able to look at the impact of short bursts of incidental physical activity done as part of daily living,” said first author Professor Stamatakis.

Two leading sequencing techniques are no longer at odds, thanks to an international effort led by scientists at University of California San Diego. In a study published July 27, 2023 in Nature Biotechnology, the researchers debuted a new reference database called Greengenes2, which makes it possible to compare and combine microbiome data derived from either 16S ribosomal RNA gene amplicon (16S) or shotgun metagenomics sequencing techniques.
“This is a significant moment in microbiome research, as we’ve effectively rescued over a decade’s worth of 16S data that might have otherwise become obsolete in the modern world of shotgun sequencing,” said senior author Rob Knight, PhD, professor in the departments of Pediatrics at UC San Diego School of Medicine and Bioengineering and Computer Science at UC San Diego Jacobs School of Engineering. “Standardizing results across these two methods will significantly improve our chances of discovering microbiome biomarkers for health and disease.”
Microbiome studies depend on scientists’ ability to identify which microorganisms are present in a sample. To do this, they sequence the genetic information in the sample and compare it to reference databases that list which sequences belong to which organisms. 16S and shotgun sequencing are the two techniques most widely used in microbiome research, but they often yield different results.
“Many researchers assumed that data from 16S and shotgun sequencing were simply too different to ever be integrated,” said first author of the study Daniel McDonald, PhD, scientific director of The Microsetta Initiative at UC San Diego School of Medicine. “Here we show that is not the case, and provide a reference database that researchers can now use to do just that.”
The original Greengenes database had been widely used in the microbiome field for well over a decade. It was the reference database used by notable projects including the National Institutes of Health Human Microbiome Project, the American Gut Project, the Earth Microbiome Project and many others.
However, one of its fundamental limitations was that it relied on the sequence of a single gene, 16S, to identify the organisms in a sample. This well-studied gene has long been used as a taxonomic marker, with each organism having its own 16S “barcode.” This method can describe the contents of a microbiome sample with genus-level resolution, but it cannot always identify specific species or strains of microbes, which is important for clinical work.
Modern microbiome studies have since transitioned to using shotgun sequencing, which looks at DNA from all over the organisms’ genomes, rather than focusing on only one gene. This powerful approach gives researchers more species-level specificity and also provides insight into the microbes’ function.

In a promising form of immunotherapy known as CAR T-cell (chimeric antigen receptor) therapy, the patient’s T cells are engineered to better recognize and attack antigens on the surface of cancer cells. In treatments currently approved for use in battling lymphoma and leukemia, however, the therapy has a drawback: Amidst the cancer-killing frenzy, many engineered T cells become tainted with the remnants of cancer antigens, which causes them to turn on other T cells. This eventually depletes the body of cancer-fighting cells and opens the door for a recurrence of cancer.
A new Yale study, however, has identified a way to tame the self-destructive tendencies of these killer T cells. Simply fusing a molecular tail onto the engineered T cells used in therapy, researchers say, can inhibit their proclivity to attack each other. The study was published July 27 in the journal Nature Immunology.
“It’s like putting a sword back in the sheath after it has done its work,” said Sidi Chen, associate professor of genetics at Yale School of Medicine and senior author of the study.
For the study, the Yale team — which was led by co-first authors Xiaoyu Zhou and Hanbing Cao — fused CTLA-4 cytoplasmic tails (CCTs) to engineered CAR T cells. CCTs are a portion of a naturally occurring human protein, known as CTLA-4, which is known to keep the immune system in check by regulating T cells. Researchers observed that the cells fused with these tails were less exhausted and survived longer than CAR T cells without the tails.
“The CAR T cells with the engineered tails were less reactive but more persistent” in killing cancer cells, said Zhou, a postdoctoral associate in Chen’s lab.
Chen says it would be relatively easy for existing companies to fuse CCTs to CAR T cells, and that improvements in therapy might help expand treatments to solid tumors as well.
Chen is affiliated with the Yale Cancer Center, the Yale Stem Cell Center, the Yale Center for Biomedical Data Science, and the Systems Biology Institute and Center for Cancer Systems Biology at Yale’s West Campus. The work is supported by National Institutes of Health, the U.S. Department of Defense, and several foundations.