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As heart cells mature in mice, the number of communication pathways called nuclear pores dramatically decreases, according to new research from University of Pittsburgh and UPMC scientists. While this might protect the organ from damaging signals, it could also prevent adult heart cells from regenerating, the researchers found.
The study, published today in Developmental Cell, suggests that quieting communication between heart cells and their environment protects this organ from harmful signals related to stresses such as high blood pressure, but at the cost of preventing heart cells from receiving signals that promote regeneration.
“This paper provides an explanation for why adult hearts do not regenerate themselves, but newborn mice and human hearts do,” said senior author Bernhard Kühn, M.D., professor of pediatrics and director of the Pediatric Institute for Heart Regeneration and Therapeutics at Pitt School of Medicine and UPMC Children’s Hospital of Pittsburgh. “These findings are an important advance in fundamental understanding of how the heart develops with age and how it has evolved to cope with stress.”
While skin and many other tissues of the human body retain the ability to repair themselves after injury, the same isn’t true of the heart. During human embryonic and fetal development, heart cells undergo cell division to form the heart muscle. But as heart cells mature in adulthood, they enter a terminal state in which they can no longer divide.
To understand more about how and why heart cells change with age, Kühn teamed up with fellow Pitt researchers and biomedical imaging experts Yang Liu, Ph.D., associate professor of medicine and bioengineering, and Donna Stolz, Ph.D., associate professor of cell biology and pathology and associate director of the Center for Biologic Imaging, to look at nuclear pores. These perforations in the lipid membrane that surround a cell’s DNA regulate the passage of molecules to and from the nucleus.
“The nuclear envelope is an impermeable layer that protects the nucleus like asphalt on a highway,” said Kühn, who is also a member of the McGowan Institute for Regenerative Medicine. “Like manholes in this asphalt, nuclear pores are pathways that allow information to get through the barrier and into the nucleus.”
Using super-resolution microscopy, Liu visualized and counted the number of nuclear pores in mouse heart cells, or cardiomyocytes. The number of pores decreased by 63% across development, from an average of 1,856 in fetal cells to 1,040 in infant cells to just 678 in adult cells. These findings were validated by Stolz who used electron microscopy to show that nuclear pore density decreased across heart cell development.

In the first nationally representative study of cognitive impairment prevalence in more than 20 years, Columbia University researchers have found almost 10% of U.S. adults ages 65 and older have dementia, while another 22% have mild cognitive impairment. People with dementia and mild cognitive impairment are more likely to be older, have lower levels of education, and to be racialized as Black or Hispanic. Men and women have similar rates of dementia and mild cognitive impairment.
Although dementia and mild cognitive impairment are known to be common in the United States, accurate, up-to-date measures of their national prevalence were scarce.
“Such data are critical for understanding the causes, costs, and consequences of dementia and mild cognitive impairment in the United States, and for informing policies aimed at reducing their impact on patients, families, and public programs,” says Jennifer J. Manly, PhD, the study’s lead author and professor of neuropsychology in neurology at the Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University.
Dementia rate 35% among people in their 90s
The study was based on data on 3,500 individuals enrolled in the nationally representative Health and Retirement Study. Between 2016 and 2017, each participant completed a comprehensive set of neuropsychological tests and in-depth interviews, which were used to develop an algorithm for diagnosing dementia or mild cognitive impairment.
Dementia and Mild Cognitive Impairment
Dementia is characterized by cognitive difficulties that begin in adulthood and affect a person’s ability to independently perform everyday activities. Mild cognitive impairment is a classification assigned to people who are thought to be transitioning between normal aging and dementia, but not everyone who has mild cognitive impairment will go on to develop dementia.

Prescribed fire — a tool increasingly used by forest managers and landowners to combat invasive species, improve wildlife habitat and restore ecosystem health — also could play a role in reducing the abundance of ticks and the transmission of disease pathogens they carry, according to a team of scientists.
For a recently published paper, the researchers reviewed the scientific literature on the effects of fire on forest composition and structure and its influence on ticks and their wildlife hosts. They concluded that prescribed burning can help restore forest habitats to a state less favorable to several species of disease-carrying ticks and could be an effective management tactic for reducing their populations.
The era of fire suppression, which began roughly in the early 1900s and has continued for more than a century, changed the species composition of Eastern forests, creating habitats and microclimates that favored the survival and spread of ticks, noted lead author Michael Gallagher, research ecologist at the Silas Little Experimental Forest, Northern Research Station, U.S. Department of Agriculture Forest Service, New Lisbon, New Jersey.
“Before the arrival of Europeans, Eastern forests were ‘fire-dependent,’ characterized by fire-tolerant species such as pine, oak and chestnut,” Gallagher said. “Frequent low-to-moderate intensity fires would have fostered dry conditions, thinned the understory and diminished layers of leaf litter, which in turn would have created microclimates with lower humidity and higher temperatures.
“These lower-moisture, higher-temperature — or xeric — conditions were likely to limit ticks’ activity, interaction with reservoir hosts and overall populations,” he said.
Since fire has been suppressed and forests have recovered significantly from periods of deforestation caused by logging and agricultural land-clearing, fire-sensitive mesic forest species — those that thrive in and contribute to moister environments — have become dominant, a process known as mesophication, he explained.

A new study from North Carolina State University shows that exposure in utero to the flame retardant FireMaster® 550 (FM 550), or to its individual brominated (BFR) or organophosphate ester (OPFR) components, resulted in altered brain development in newborn rats. The effects — most notably evidence of mitochondrial disruption and dysregulated choline and triglyceride levels in brain tissue — were greater in male offspring than in females. The work adds to the body of evidence that both OPFRs and BFRs can be neurotoxic.
FM 550 is a flame-retardant mixture first identified a decade ago. It was developed to replace PBDEs, a class of fire retardants being phased out due to safety concerns.
“While some new flame retardant mixtures still contain BFRs, the OPFRs are a popular substitute for PBDEs, since it is believed that OPFRs don’t accumulate in the body and thus cannot be as harmful,” says Heather Patisaul, associate dean for research in NC State’s College of Sciences and corresponding author of the study. “Specifically, it was thought that OPFRs wouldn’t impact acetylcholinesterase — a key neurotransmitter. But it looks as though OPFRs still impact choline signaling and are just as bad if not worse than PBDEs for the developing brain.”
Patisaul and her colleagues performed transcriptomic and lipidomic studies on the prefrontal cortexes of newborn rats whose mothers had been exposed to FM550, or to BFR or OPFR elements individually, during gestation.
“Getting genetic information from transcriptomics is what researchers commonly do to tease out potential connections between toxicity and health effects,” Patisaul says. “In this case, we also wanted to see if the lipid, or fat, composition of the brain was altered — our brains are essentially balls of fat, and lipidomics can reveal how exposure may affect the brain in its earliest developmental stages.”
Both the transcriptomic and lipidomic analyses showed evidence of mitochondrial disruption, although the disruptions were more pronounced in the offspring that had been exposed to OPFRs. Mitochondria are found in almost every cell and serve as cells’ energy generators, playing a vital role in cellular respiration.

An intranasal vaccine against SARS-CoV-2 could quickly get to the respiratory tract, where the virus most commonly causes symptoms. And a spray or droplets could be a more palatable option for people who fear needles. But so far, only a few countries have approved COVID nasal vaccines. Now researchers report in ACS Nano that they’ve developed one that can fight off the original virus and two variants in hamsters.
The current batch of injected COVID vaccines have been effective at combating SARS-CoV-2 infection around the globe. But these shots enter the body in the muscle tissue, whereas the virus enters and causes many of the typical COVID symptoms in the respiratory tract. Thus, intranasal immunizations with a spray or droplets could be a better option. Although India and a couple of other countries have approved intranasal COVID vaccines in recent months, the road to formulating successful intranasal vaccines is not an easy one. For example, AstraZeneca announced this month that its intranasal candidate failed to produce a strong immune response in nasal tissues and offered less systemic protection than the intramuscular version. So, Madhavan Nallani, Pierre Vandepapeliere and colleagues wanted to formulate an intranasal COVID vaccine that would stimulate an immune response both systemically and in the respiratory tract, and that would also work against SARS-CoV-2 variants.
The researchers based their vaccine on the spike protein from the SARS-CoV-2 beta variant, separately encapsulating the antigen and an immune-stimulating adjuvant into nanoparticles known as artificial cell membrane polymersomes. They packaged the two components separately so that they could more easily change the spike component to one from another variant if needed. Intramuscular co-administration of the parts produced a strong immune response in both mice and hamsters. When the hamsters injected with the new vaccine were exposed to live virus, however, they still developed an infection. In contrast, intranasal coadministration in hamsters produced a strong systemic immune response. It also cleared viruses from the respiratory tract and prevented infection-associated lung damage. Regardless of how the vaccine was administered, it provided protection against multiple variants, including omicron. Based on these results, the researchers are now recruiting participants for a Phase 1 clinical trial.
The authors acknowledge funding by the National Health Innovation Centre Gap Funding Award Singapore.
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A lifestyle intervention of diet and exercise in pregnancy protects against cardiovascular risk in infants, a new study has found.
The study, published recently in the International Journal of Obesity by researchers from King’s College London and funded by the British Heart Foundation, found that 3-year-old children were more likely to exhibit risk factors for future heart disease if their mother was clinically obese during pregnancy. A behavioural lifestyle intervention reduced this risk.
In the UK, more than half the women attending antenatal care are clinically overweight or obese. There is increasing evidence to suggest that obesity in pregnancy is associated with cardiometabolic dysfunction in children, and that serious cardiovascular disease may begin in the womb.
The UPBEAT trial, conducted at Guy’s and St Thomas’ NHS Foundation Trust, randomised women with obesity (a BMI of over 30 kg/m2) in early pregnancy to a diet and exercise intervention or to standard pregnancy care. The intervention included one-to-one counselling, restricting dietary intake of saturated fat, eating foods with a low glycaemic index such as vegetables and legumes, moderate and monitored physical activity and tools to record exercise. The intervention arm saw improvements in weight gain in pregnancy, physical activity, a healthier diet, and a healthier metabolic profile across pregnancy.
Follow-up of the children at three years of age showed that children of women with clinical obesity had evidence of cardiac remodelling, a risk factor for future cardiovascular disease. Changes included increased heart muscle thickness, elevated resting heart rate, evidence of early impairment to the heart’s relaxation function and increased sympathetic nerve activity (‘fight or flight’ response) compared to women of normal weight. The children of women who were allocated to the intervention arm were protected from these early changes in heart structure and function.
Study lead Dr Paul Taylor, from King’s College London, said: “Maternal obesity appears to adversely impact the developing fetal nervous system and fetal heart development which is apparent up to 3 years-of-age. A complex lifestyle intervention in pregnancy was associated with protection against cardiac remodelling in infants. We can hypothesise that these changes to the heart and its function will get worse over time, putting the child at increased risk of cardiovascular disease in the future.”
The study suggests that maternal obesity may have a lasting impact on the child’s cardiovascular health. Promoting dietary changes and physical activity during pregnancy may reduce this risk.
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A Rice University lab is leading the effort to reveal potential threats to the efficacy and safety of therapies based on CRISPR-Cas9, the Nobel Prize-winning gene editing technique, even when it appears to be working as planned.
Bioengineer Gang Bao of Rice’s George R. Brown School of Engineering and his team point out in a paper published in Science Advances that while off-target edits to DNA have long been a cause for concern, unseen changes that accompany on-target edits also need to be recognized — and quantified.
Bao noted a 2018 Nature Biotechnology paper indicated the presence of large deletions. “That’s when we started looking into what we can do to quantify them, due to CRISPR-Cas9 systems designed for treating sickle cell disease,” he said.
Bao has been a strong proponent of CRISPR-Cas9 as a tool to treat sickle cell disease, a quest that has brought him and his colleagues ever closer to a cure. Now the researchers fear that large deletions or other undetected changes due to gene editing could persist in stem cells as they divide and differentiate, thus have long-term implications for health.
“We do not have a good understanding of why a few thousand bases of DNA at the Cas9 cut site can go missing and the DNA double-strand breaks can still be rejoined efficiently,” Bao said. “That’s the first question, and we have some hypotheses. The second is, what are the biological consequences? Large deletions (LDs) can reach to nearby genes and disrupt the expression of both the target gene and the nearby genes. It is unclear if LDs could result in the expression of truncated proteins.
“You could also have proteins that misfold, or proteins with an extra domain because of large insertions,” he said. “All kinds of things could happen, and the cells could die or have abnormal functions.”
His lab developed a procedure that uses single-molecule, real-time (SMRT) sequencing with dual unique molecular identifiers (UMI) to find and quantify unintended LDs along with large insertions and local chromosomal rearrangements that accompany small insertions/deletions (INDELs) at a Cas9 on-target cut site.

Heme, the iron-holding molecule that gives blood its red color, is essential for life. Yet, ironically, it can be quite toxic if not properly handled. In fact, numerous diseases — from various cancers to cardiovascular diseases — are associated with defects in heme homeostasis.
The way heme is biosynthesized and degraded has been known for decades, but how it is mobilized from sites of synthesis and storage for use in cells has not been clear. Researchers at the Georgia Institute of Technology have developed new tools and approaches to image, monitor, and probe heme in biological systems to study how organisms handle this essential but potentially cytotoxic metabolite. Their findings are published in the journal Nature.
In a collaboration with Zhejiang University and the University of Maryland School of Medicine, the research team discovered a previously uncharacterized protein, HRG-9 (also called TANGO2), that helps to mobilize heme from sites of synthesis or storage for use in metabolism. The discovery of a new protein that ensures heme is made bio-available may serve as a new therapeutic target in many disease contexts — either to limit heme, to starve cells of this essential nutrient, or to cause heme to over accumulate and render it toxic to cells.
“Since mutations in the TANGO2 gene cause a hereditary disease characterized by developmental delays and defects in metabolism, our finding that TANGO2 plays a role in heme homeostasis suggests that the development of heme-centered therapies may treat such diseases,” said Amit Reddi, associate professor in the School of Chemistry at Georgia Tech and co-PI on the paper.
The researchers hope that understanding the mechanisms of heme trafficking will provide clues about how such ‘essential toxins’ are safely trafficked throughout the cell. It could also inspire therapeutic strategies to treat diseases associated with heme dysregulation, including anemias, porphyrias, and certain neurodegenerative and cardiovascular disorders.
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Investigations in Japan have uncovered some molecular mechanisms behind mitochondrial dysfunction in chronic heart failure.
Chronic heart failure causes the cell’s powerhouses to dysfunction, in part due to overconsumption of an important intermediary compound in energy production. Supplementing the diet to compensate for this could prove a promising strategy for treating heart failure. The findings were published in the journal PNAS by Hokkaido University scientists and colleagues in Japan.
Mitochondria are small organelles found in almost every cell and are responsible for converting carbohydrates, fats and proteins into energy to power biochemical reactions. Chronic heart failure is known to be associated with mitochondrial dysfunction, but much is still unknown about how this happens at the molecular level.
A research team consisting of molecular biologist Hisataka Sabe (Hokkaido University), cardiovascular medicine specialists Shingo Takada (Hokkaido University and Hokusho University) and Shintaro Kinugawa (Kyushu University) and their colleagues studied the biochemical processes that occur in mice with chronic heart failure caused by surgically blocking part of the blood supply to their hearts. They specifically looked at heart cells outside the boundaries of dead tissue.
They found a significant reduction in a compound called succinyl-CoA, which is an intermediary in the cell’s tricarboxylic acid cycle. This cycle, which happens inside mitochondria, plays an important role in breaking down organic molecules to release energy.
Further investigations revealed that this reduction of succinyl-CoA levels was at least in part caused by its overconsumption for the synthesis of heme, which is essential for mitochondrial oxidative phosphorylation. This latter process is needed for transferring and synthesizing energy-carrying and storage molecules by mitochondria.
Adding a compound called 5-aminolevulinate acid (5-ALA) to the drinking water of mice immediately after cutting off the blood supply to part of the heart significantly improved their heart function, treadmill running capacity and survival. At the molecular level, it improved the oxidative phosphorylation capacity of heart muscle mitochondria and appeared to restore their succinyl-CoA levels.
Further research is needed to clarify other factors involved in reducing mitochondrial succinyl-CoA levels in heart failure. For example, the scientists found evidence that succinyl-CoA may also be overconsumed in heart failure-affected mitochondria in order to break down ketones as a source of energy. But more investigations are needed to understand why this might happen and whether there really is a direct link between the two.
“Our results further the understanding of the detailed metabolic changes that occur in chronic heart failure and could contribute to the development of more natural prevention and treatment for the condition,” say the team members. “In addition, a combination of nutritional interventions that can correct the metabolic distortions that occur in chronic heart failure — as revealed in this study — and currently used therapeutic drugs could be very effective in the treatment of this disease.”
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An international consortium of researchers led by the University of Sydney, has developed technology to enable the manufacturing of materials that mimic the structure of living blood vessels, with significant implications for the future of surgery.
Preclinical testing found that following transplantation of the manufactured blood vessel into mice, the body accepted the material, with new cells and tissue growing in the right places — in essence transforming it into a ‘living blood vessel.’
Senior author Professor Anthony Weiss from the Charles Perkins Centre said while others have tried to build blood vessels with various degrees of success before, this is the first time scientists have seen the vessels develop with such a high degree of similarity to the complex structure of naturally occurring blood vessels.
“Nature converts this manufactured tube over time to one that looks, behaves and functions like a real blood vessel,” said Professor Weiss.
“The technology’s ability to recreate the complex structure of biological tissues shows it has the potential to not only manufacture blood vessels to assist in surgery, but also sets the scene for the future creation of other synthetic tissues such as heart valves.”
Co-author Dr Christopher Breuer of the Center for Regenerative Medicine at Nationwide Children’s Hospital and the Wexner Medical Center in Columbus, USA said he is excited about the potential of the research for children.