Publisher Health

Van Andel Institute scientists and collaborators have identified a key part of a mechanism that annotates genetic information before it is passed from fathers to their offspring.
The findings, published today in the journal Science Advances, shed new light on genomic imprinting, a fundamental, biological process in which a gene from one parent is switched off while the copy from the other parent remains active. Errors in imprinting are linked to a host of diseases, such as the rare disease Silver-Russell syndrome along with certain cancers and diabetes.
“Proper imprinting is crucial for lifelong health but, despite its importance, we still lack a full understanding of the factors that regulate this vital process,” said VAI Associate Professor Piroska Szabó, Ph.D., the study’s corresponding author. “Our findings reveal an RNA mechanism that governs establishment of imprinting and illuminates why it differs between fathers and mothers.”
Our genetic information is encoded in DNA, a long, winding molecule that is tightly packed to form 23 pairs of chromosomes, half of which come from one’s father and half from one’s mother. Sperm and eggs only contain 23 single chromosomes — half of the genetic material required for life. During fertilization, they each contribute their half, resulting in a zygote with a full set of 23 pairs of chromosomes.
But not all instructions in DNA are needed at the same time or in the same places. That’s where epigenetics come in. Epigenetic mechanisms annotate DNA with special chemical tags called methyl groups, which tell certain genes when to be active and when to be silent — all without changing the sequence of DNA itself.
Imprinting occurs when methyl groups are added to certain genes during either sperm or egg formation. This, in turn, is important for determining which parental copy of that gene is expressed in the offspring.
To better understand the processes that govern imprinting, Szabó and colleagues focused on an imprinting control region in the DNA that regulates the Igf2 gene. Igf2 plays key roles in fetal growth and only is active in the chromosome inherited from the father. Too little methylation in the IGF2 control region in humans can result in Silver-Russell syndrome, which is marked by reduced growth and increased risk of metabolic disease.

A study of twins shows that having a concussion early in life is tied to having lower scores on tests of thinking and memory skills decades later as well as having more rapid decline in those scores than twins who did not have a concussion, or traumatic brain injury (TBI). The study is published in the September 6, 2023, online issue of Neurology®, the medical journal of the American Academy of Neurology.
“These findings indicate that even people with traumatic brain injuries in earlier life who appear to have fully recovered from them may still be at increased risk of cognitive problems and dementia later in life,” said study author Marianne Chanti-Ketterl, PhD, MSPH, of Duke University in Durham, North Carolina. “Among identical twins, who share the same genes and many of the same exposures early in life, we found that the twin who had a concussion had lower test scores and faster decline than their twin who had never had a concussion.”
The study involved 8,662 men who were World War II veterans. The participants took a test of thinking skills at the start of the study when they were an average age of 67 and then again up to three more times over 12 years. Scores for the test can range from zero to 50. The average score for all participants at the beginning of the study was 32.5 points.
A total of 25% of the participants had experienced a concussion in their life.
Twins who had experienced a concussion were more likely to have lower test scores at age 70, especially if they had a concussion where they lost consciousness or were older than 24 when they had their concussion. Those twins with traumatic brain injury with loss of consciousness, more than one traumatic brain injury and who had their injuries after age 24 were more likely to have faster cognitive decline than those with no history of traumatic brain injury.
For example, a twin who experienced a traumatic brain injury after age 24 scored 0.59 points lower at age 70 than his twin with no traumatic brain injury, and his thinking skills declined faster, by 0.05 points per year.
These results took into account other factors that could affect thinking skills, such as high blood pressure, alcohol use, smoking status and education.
“Although these effect sizes are modest, the contribution of TBI on late life cognition, in addition to numerous other factors with a detrimental effect on cognition, may be enough to trigger an evaluation for cognitive impairment,” Chanti-Ketterl said. “With the trend we are seeing with increased emergency room visits due to sports or recreation activity injuries, combined with the estimated half million members of the military who suffered a TBI between 2000 and 2020, the potential long-term impact of TBI cannot be overlooked. These results may help us identify people who may benefit from early interventions that may slow cognitive decline or potentially delay or prevent dementia.”
A limitation of the study was that traumatic brain injuries were reported by the participants, so not all injuries may have been remembered or reported accurately.
The study was supported by the National Institute on Aging and the U.S. Department of Defense.

The shape and size of a grain of rice, the new device can conduct dozens of experiments at once to study the effects of new treatments on some of the hardest-to-treat brain cancers.
Researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, have designed a device that can help test treatments in patients with gliomas, a type of tumor that originates in the brain or spinal cord. The device, which is designed to be used during standard of care surgery, provides unprecedented insight into the effects of drugs on glioma tumors and caused no adverse effects on patients in a phase 1 clinical trial. Results from the pilot clinical trial for the device are published in Science Translational Medicine.
“In order to make the greatest impact on how we treat these tumors, we need to be able to understand, early on, which drug works best for any given patient,” said co-principal investigator and co-corresponding author Pierpaolo Peruzzi, MD, PhD, an assistant professor in the Department of Neurosurgery at Brigham and Women’s Hospital. “The problem is that the tools that are currently available to answer this question are just not good enough. So we came up with the idea of making each patient their own lab, by using a device which can directly interrogate the living tumor and give us the information that we need.”
About 20,000 people in the U.S. each year are diagnosed with gliomas, a type of tumor that affects the brain and spinal cord. Gliomas are also among the deadliest brain cancers and are notoriously difficult to treat.
One challenge in developing targeted therapies for glioma is that it can be difficult to test many different combinations of drugs in tumor cells, because it’s only possible to treat patients with one approach at a time. This has been a significant barrier for hard-to-treat cancers like gliomas, for which combination therapies are a promising avenue.
Peruzzi worked closely with co-principal investigator Oliver Jonas, PhD, an associate professor in the department of Radiology at the Brigham, to develop a device that can work around some of the barriers to precision medicine in gliomas. These microdevices are implanted in a patient’s tumor during surgery and removed before the surgery is complete.
“It’s important that we are able to do this in a way that best captures the features of each patient’s tumor and, at the same time, is the least disruptive of the standard of care,” said Peruzzi. “This makes our approach easy to integrate into patients’ treatment and allows its use in real life.”
In the time the device is implanted — about 2-3 hours — it administers tiny doses of up to 20 drugs into extremely small areas of the patient’s brain tumor. The device is removed during the surgery and the surrounding tissue is returned to the lab for analysis.

Not only does a lack of sleep make you feel awful, research has shown it impairs the brain. What’s more, sleep loss over long periods can even increase risk for Alzheimer’s and other neurological diseases. Researchers want to understand how sleep deprivation causes this harm. In a new study in ACS’ Journal of Proteome Research, a team working with mice has identified a protective protein whose level declines with sleep deprivation, leading to neuronal death.
Studies indicate that lack of sleep leads to neurological damage in the hippocampus, a part of the brain involved in learning and memory. To better understand the changes responsible for this effect, scientists have begun examining shifts in the abundance of proteins and RNA, which contains genetically encoded instructions derived from DNA. In this way, previous studies have identified some factors linking sleep loss to damage; however, researchers haven’t generally confirmed they play a role in cognitive function within larger animal populations. So, Fuyi Xu, Jia Mi and their colleagues set out to further explore how sleep loss damages the brain and to corroborate their findings.
To start off, the researchers evaluated how well mice navigated a simple maze and learned to recognize new objects after having been sleep deprived for two days. They then extracted the proteins in the animals’ hippocampi and identified those whose abundance changed. Then, to further narrow the possibilities, they looked at data linking these proteins to maze performance in related strains of mice that had not experienced sleep deprivation.
This approach led the researchers to pleiotrophin (PTN), which declined in the sleep-deprived mice. Through an analysis of RNA, the team identified the molecular pathway by which a loss of PTN causes cells in the hippocampus to die. When they looked at genetic studies in humans, they found that PTN is implicated in Alzheimer’s and other neurodegenerative diseases. This research has uncovered a new mechanism by which sleep protects brain function, according to the researchers, who also note that PTN levels could serve as an indicator of cognitive impairment resulting from insomnia.

A good night’s sleep has many proven health benefits, and a new Scripps Research study suggests one more: preventing opioid relapse.
In the new study, published online in Neuropharmacologyon August 12, 2023, scientists gave an experimental insomnia treatment to rats experiencing oxycodone withdrawal. The researchers found that the animals were far less likely to seek out drugs again in the future — even after ending the treatment. These findings could eventually lead to therapies to help prevent opioid addiction or relapse in humans.
“These results are very encouraging,” says Rémi Martin-Fardon, PhD, associate professor of molecular medicine at Scripps Research and senior author of the study. “We hope in the future this compound may be useful for not only treating sleep disorders, but also drug use disorders.”
Opioids including oxycodone are used to treat pain, but carry a risk of misuse and opioid dependence in people who use them regularly. In 2021, opioid overdoses killed more than 80,000 people in the United States, according to the U.S. Centers for Disease Control and Prevention (CDC).
Researchers know that during opioid withdrawal — which can last for days in people who are dependent on the drug — people experience a range of symptoms including nausea, vomiting, sweating, chills, pain, anxiety and insomnia.
Martin-Fardon and Jessica Illenberger, PhD, a postdoctoral research fellow at Scripps Research and first author of the study, wondered whether treating the insomnia associated with opioid withdrawal might help prevent relapse. This is why they turned to an experimental insomnia drug known as DORA-12, which is like the FDA-approved drug Belsomra (suvorexant).
“A lot of drug use and relapse are primarily motivated by a person’s desire to alleviate these withdrawal symptoms,” says Illenberger. “The idea behind testing this treatment was that if people or animals sleep better during that withdrawal period, then when they wake up, perhaps they won’t feel so much craving and won’t be as likely to relapse.”
In a previous study, the researchers found that suvorexant decreased the amount of oxycodone that opioid-dependent rats self-administered during binge sessions. In the new study, the team focused more on the withdrawal period from oxycodone.

The treadmill exercise test with electrocardiogram (ECG), also known as an exercise stress test, is one of the most familiar tests in medicine. While exercise testing typically is focused on diagnosing coronary artery disease, a recent study from Mayo Clinic finds that exercise test abnormalities, such as low functional aerobic capacity, predicted non-cardiovascular causes of death such as cancer in addition to cardiovascular-related deaths. These new findings are published in Mayo Clinic Proceedings.
The exercise stress test is noninvasive, easily available and provides important diagnostic information. In addition to the ECG itself, the test produces data on functional aerobic capacity, heart rate recovery and chronotropic index, the standardized measure of heart rate during exercise that reflects age, resting heart rate and fitness.
“In our exercise testing cohort, non-cardiovascular deaths were more frequently observed than cardiovascular deaths,” says Thomas Allison, Ph.D., M.P.H., director of Mayo Clinic’s Integrated Stress Testing Center and the study’s senior author. “Though this was a cardiac stress test, we found that cancer was the leading cause of death, at 38%, whereas only 19% of deaths were cardiovascular. Exercise test results including low exercise capacity, low peak heart rate, and a slow recovery of the heart rate after exercise test were associated with increased mortality.”
The study looked at 13,382 patients who had no baseline cardiovascular issues or other serious diseases and who had completed exercise tests at Mayo Clinic between 1993 and 2010, then were followed closely for a median period of 12.7 years.
The findings suggest that clinicians should focus not only on ECG results but on data in the exercise test results such as low functional aerobic capacity, low chronotropic index and abnormal heart rate recovery. Patients should be encouraged to increase their physical activity if these results are atypical, even if the ECG results show no significant cardiovascular-related risk, Dr. Allison says.

A groundbreaking study led by experts from Indiana University School of Medicine has shed new light on the genetic underpinnings of Alzheimer’s disease. The team’s research, rooted in human genetics studies, has unearthed a critical mutation within a key gene operating in the brain’s immune cells, potentially elevating the risk of Alzheimer’s disease.
The research team included several IU investigators within Stark Neurosciences Research Institute — Gary Landreth, PhD, the Martin Professor of Alzheimer’s Research; Bruce Lamb, PhD, executive director of Stark Neuroscience Research Institute; Stephanie Bissel, PhD, assistant professor of genetics; Kwangsik Nho, PhD, associate professor of radiology and imaging sciences; and Adrian Oblak, PhD, assistant professor of radiology and imaging sciences. Their research was recently published in the journal Immunity.
Andy Tsai, PhD, a graduate of the Medical Neurosciences Graduate Program, was the driving force behind the research, encompassing his PhD thesis. Tsai, now a postdoctoral fellow at Stanford University Medical School, has significantly contributed to unraveling the mysteries of Alzheimer’s disease.
The focal point of the investigation revolved around the phospholipase C gamma 2 (PLCG2) gene, intricately entwined within microglia — central to the brain’s immune response. This genetic anomaly, discovered through analysis of the gene’s biological workings, showcased the impact of specific rare variants. The study found that the M28L variant heightened the susceptibility to Alzheimer’s disease, whereas the P522R variant exhibited a risk-reducing effect.
Innovative mouse models of Alzheimer’s disease developed by the NIH-funded MODEL-AD Center allowed researchers to substantiate their findings. Immune cells harboring risk-reducing gene variants demonstrated a reduction in amyloid plaques, while those carrying the risk-elevating variants exhibited a surge in plaque accumulation. The study unveiled specific gene clusters orchestrating these alterations in immune cell behavior within microglia.
Microglia, often regarded as the brain’s first line of defense against infections, toxins and damage, has garnered attention for its significant role in influencing disease susceptibility.
“The microglial response affects neurons which then affects the capacity to learn and form new memories,” Landreth said.
Extensive collaboration within Stark Neurosciences Research Institute enabled a comprehensive evaluation of the gene’s implications. This included a comparison between preclinical data from animal models and real-world human data on Alzheimer’s disease.
“This represents a collaboration that could’ve only been achieved at Stark,” Landreth said. “We used human genetics to investigate and identify a mechanism, and indeed we have.”
The study’s paramount importance lies in explaining the critical role of microglial immune responses and their potential to impact disease risk, positively or negatively. This discovery promises to reshape the understanding of Alzheimer’s disease and carve a path toward targeted therapeutics, which is being pursued by the NIH-funded TREAT-AD Center.

New “hypervirulent” strains of the bacterium Klebsiella pneumoniae have emerged in healthy people in community settings, prompting a National Institutes of Health research group to investigate how the human immune system defends against infection. After exposing the strains to components of the human immune system in a laboratory “test tube” setting, scientists found that some strains were more likely to survive in blood and serum than others, and that neutrophils (white blood cells) are more likely to ingest and kill some strains than others. The study, published in mBio, was led by researchers at NIH’s National Institute of Allergy and Infectious Diseases (NIAID).
“This important study is among the first to investigate interaction of these emergent Klebsiella pneumoniae strains with components of human host defense,” Acting NIAID Director Hugh Auchincloss, M.D., said. “The work reflects the strength of NIAID’s Intramural Research Program. Having stable research teams with established collaborations allows investigators to draw on prior work and quickly inform peers about new, highly relevant public health topics.”
More than a century ago scientists identified K. pneumoniae as a cause of serious, often fatal, human infections, mostly in people already ill or with weakened immune systems and especially people in hospitals. Over a span of many decades, some strains developed resistance to multiple antibiotics, and became difficult to treat. This bacterium, often called classical Klebsiella pneumoniae (cKp), ranks as the third most common pathogen isolated from hospital bloodstream infections. Certain other Klebsiella pneumoniae strains cause severe infections in healthy people in community settings (outside of hospitals) even though they are not multidrug-resistant. They are known as hypervirulent Klebsiella pneumoniae, or hvKp. More recently, strains with both multidrug resistance and hypervirulence characteristics, so-called MDR hvKp, have emerged in both settings.
NIAID scientists have studied this general phenomenon before. In the early 2000s they observed — and actively investigated — virulent strains of methicillin-resistant Staphylococcus aureus (MRSA) bacteria that had emerged in U.S. community settings and caused widespread infections in otherwise healthy people.
Now, the same NIAID research group at Rocky Mountain Laboratories in Hamilton, Montana, is investigating similar questions about the new Klebsiella strains, such as whether the microbes can evade human immune system defenses. Their findings were unexpected: the hvKp strains were more likely to survive in blood and serum than MDR hvKp strains. And neutrophils had ingested less than 5% of the hvKp strains, but more than 67% of the MDR hvKp strains — most of which were killed.
The researchers also developed an antibody serum specifically designed to help neutrophils ingest and kill two selected hvKp and two selected MDR hvKp strains. The antiserum worked, though not uniformly in the hvKp strains. These findings suggest that a vaccine approach for prevention/treatment of infections is feasible.
Based on the findings, the researchers suggest that the potential severity of infection caused by MDR hvKp likely falls in between the classical and hypervirulent forms. The work also suggests that the widely used classification of K. pneumoniae into cKp or hvKp should be reconsidered.
The researchers also are exploring why MDR hvKp are more susceptible to human immune defenses than hvKp: Is this due to a change in surface structure caused by genetic mutation? Or perhaps because combining components of hypervirulence and antibiotic resistance reduces the bacterium’s ability to replicate and survive in a competitive environment.
As a next step, the research team will determine the factors involved in MDR hvKp susceptibility to the body’s immune defenses using mouse infection models. Ultimately, this knowledge could inform treatment strategies to prevent or decrease disease severity.

A research team, affiliated with UNIST has achieved a groundbreaking milestone in tissue regeneration by developing a technology that utilizes autologous blood to produce three-dimensional microvascular implants. These implants hold immense potential for various applications requiring vascular regeneration, including the treatment of chronic wounds.
Led by Professor Joo H. Kang from the Department of Biomedical Engineering at UNIST, the team successfully developed a microfluidic system capable of processing blood into an artificial tissue scaffold. Unlike previous methods that relied on cell-laden hydrogel patches using fat tissues or platelet-rich plasma, this innovative approach enables the creation of robust microcapillary vessel networks within skin wounds. The utilization of autologous whole blood ensures compatibility and promotes effective wound healing.
The technology leverages microfluidic shear stresses to align bundled fibrin fibers along the direction of blood flow streamlines while activating platelets. This alignment and activation process results in moderate stiffness within the microenvironment — optimal conditions for facilitating endothelial cell maturation and vascularization. When applied as patches to rodent dorsal skin wounds, these implantable vascularized engineered thrombi (IVETs) demonstrated superior wound closure rates (96.08 ± 1.58%), increased epidermis thickness, enhanced collagen deposition, hair follicle regeneration, reduced neutrophil infiltration, and accelerated wound healing through improved microvascular circulation.
Chronic wounds pose significant challenges as they often fail to heal properly over time and can lead to complications associated with diabetes and vascular diseases. In severe cases, they may result in sepsis — a life-threatening condition with high mortality rates — due to insufficient oxygen supply and nutrients caused by loss of blood vessels.
By harnessing the power of microfluidic technology, Professor Kang’s team transformed autologous blood into IVETs suitable for transplantation. These IVETs were implanted into full-thickness skin wounds in experimental mice, resulting in rapid and scarless recovery of the entire damaged area. The study demonstrated successful regeneration of blood vessels within the wound site, facilitated movement of immune cells crucial for wound healing, and accelerated overall recovery.
Furthermore, the team evaluated the efficacy of IVET transplantation by infecting methicillin-resistant Staphylococcus aureus (MRSA) — an antibiotic-resistant bacterium — into the skin damage area. When artificial blood clots made from autologous blood were implanted into infected mice, quick vascular recovery was observed alongside enhanced migration of proteins and immune cells to combat bacterial infection. Additionally, collagen formation and hair follicle regeneration occurred without scarring.
These groundbreaking findings pave the way for advanced techniques in tissue engineering and wound healing using autologous blood-based implants. With further development and refinement, this technology holds tremendous potential to revolutionize treatment strategies for chronic wounds while contributing to advancements in regenerative medicine.

Human immune cells are capable of coordinating their own movement more independently than previously thought. InFLAMES researcher Jonna Alanko has discovered that immune cells do not just passively follow the chemical cues in their environment. Quite the contrary, they can also shape these cues and navigate in complex environments in a self-organised manner.
Directional cell movement is an essential and fundamental phenomenon of life. It is an important prerequisite for individual development, reformation of blood vessels, and immune response, among others.
A study conducted by Postdoctoral Researcher Jonna Alanko focused on the movement and navigation of immune cells within the body. Chemokines, a class of signalling proteins, play a crucial role in guiding immune cells to specific locations. Chemokines are formed, for instance, in the lymph nodes and create chemical cues called chemokine gradients for cells to follow within the body. According to Alanko, these chemokine gradients are like a trail of scent left in the air, it gets lighter the further you are from its source.
The traditional idea has been that immune cells recognise their target by following existing chemokine gradients. In other words, the cells following these cues have been seen as passive actors, which is not the case in reality.
“We were able to prove for the first time that contrary to the previous conception, immune cells do not need an existing chemokine gradient to find their way. They can create gradients themselves and thereby migrate collectively and efficiently even in complex environments,” explains Alanko.
Cells consume chemokines
Immune cells have receptors with which they can sense a chemokine signal. One of these receptors is called CCR7 and can be found in dendritic cells.