Photo by Stephen Andrews: https://www.pexels.com/photo/shallow-focus-of-electrocardiogram-9408866/
Using light pulses as a model for electrical defibrillation, Göttingen scientists developed a method to assess and modulate the heart function. This has paved the way for an efficient and direct treatment for cardiac arrhythmias. This may be an alternative for the strong and painful electrical shocks currently used.
Cardiac arrhythmias account for around 15-20% of annual deaths worldwide. In case of acute and life-threatening arrhythmias, defibrillators can be used to restart the regular beating of the heart. A strong electrical pulse brings cardiac activity to a brief standstill before it can be resumed in an orderly way. Whereas this treatment can save lives very effectively, the strong electrical pulses can also have negative side effects such as damage of the heart tissue or strong pain.
“We developed a new and much milder method which allows the heart to get back into the right rhythm,” says Stefan Luther, Max Planck Research Group leader at the MPI-DS and professor the University Göttingen Medical Center. “Our results show that it is possible to control the cardiac system with much lower energy intensity,” he continues.
To test their method, the scientists, from the Max Planck Institute for Dynamics and Self-Organization (MPI-DS) and the University Göttingen Medical Center, used genetically modified mouse hearts that can be stimulated by light. In this setting, a sequence of optical light pulses is triggered using a closed-loop pacing algorithm. Each pulse is triggered in response to the measured arrhythmic activity.
With this pacing protocol, the team was able to effectively control and terminate cardiac arrhythmias even at low energy intensities that do not activate the heart, but only modulate its excitability.
“Instead of administering a single high-energy shock to restore normal heart rhythm, we use our understanding of the dynamics of cardiac arrhythmias to gently terminate them.” explains Sayedeh Hussaini, first author of the study.
“This results in a subtle treatment method with far less energy per pulse, more than 40 times less compared to the conventional strategy” she reports.
The research team will also use these findings to improve the control of arrhythmias using electrical pulses. This may result in advanced defibrillators causing less pain and side-effects for patients.
X-chromosome inactivation varies across different areas of brains. Here, fluorescent imaging data from a mouse reveal where the father’s X chromosome is most active (white) and least active (blue). Credit: Eric Szelenyi
A study using mice published in the journal Cell Reports suggests how chromosome inactivation may protect women from autism disorder inherited from their father’s X chromosome.
Because cells do not need two copies of the X chromosome, the cells inactivate one copy early in embryonic development, a well-studied process known as X chromosome inactivation. As a result of this inactivation, every female is made up of a mix of cells, some have an active X chromosome from her father and others from her mother, a phenomenon known as mosaicism.
For many years, it has been thought that this was random and would result, on average, in a roughly 50/50 mix of cells, with 50% having an active paternal X chromosome and 50% an active maternal X chromosome.
Now a new study finds that, in the mouse brain at least, this is not the case. Instead, there appears to be a bias in the process that results in the paternal X chromosome being inactivated in 60% of the cells rather than the expected 50%.
When the X-linked mutation that is the most common cause of autism spectrum disorder is inherited from the father, the pattern of X-chromosome inactivation in the brain circuitry of females can prevent the effects of that mutation, the study found.
“This bias may be a way to reduce the risk of harmful mutations, which occur more frequently in male chromosomes,” said corresponding author Eric Szelenyi, acting assistant professor of biological structure at the University of Washington School of Medicine in Seattle.
The X-chromosome is of particular interest because it carries more genes involved in brain development than any other chromosome. Mutations in the chromosome are linked to more than 130 neurodevelopmental disorders, including fragile X syndrome and autism.
In the study, the researchers first determined the ratio of X chromosome inactivation in healthy mice by analyzing roughly 40 million brain cells per mouse. The scientists did this by using high-throughput volumetric imaging and automated counting. This analysis revealed a systematic 60:40 ratio across all possible anatomical regions.
They then examined what would happen if they genetically added a mouse model for fragile X syndrome. This syndrome is the most common form of inherited intellectual and developmental disability in humans.
They first tested the mice for behaviors thought to be analogous to those impaired in people with fragile X syndrome. These tests evaluate such things as their sensorimotor function, spatial memory and tendencies towards anxiety and sociability.
They found that the mice who inherited the mutation on their mother’s X chromosome, which are less likely to be inactivated in the 60:40 ratio, were more likely to exhibit behaviour analogous to fragile X syndrome. They exhibited more signs of anxiety, less sociability, poor performance in spatial learning, and deficits in sensorimotor function.
But mice that inherited the mutation from one their father’s X chromosomes, which were more likely to be inactivated, did not appear impaired.
“What was most interesting is that using each animal’s behavioural performance was most accurately predicted by X chromosome inactivation in brain circuits, rather than just looking at the brain as a whole, or single brain regions,” said Szelenyi. “This suggests that having more mutant X-active cells due to maternal inheritance increases overall disease risk, but specific mosaic pattern within brain circuitry ultimately decides which behaviors are impacted the most.”
“This suggests that the 20% difference in mutant X-active cells created by the bias can be protective against X mutations from the father, which occur more commonly,” he said.
The findings may also explain why symptoms of X-linked syndromes, like X-linked autism spectrum disorder, vary more in females than males.
Colourised scanning electron micrograph of HIV (yellow) infecting a human T9 cell (blue). Credit: NIH
Australian researchers have discovered a previously unknown rogue immune cell that can cause poor antibody responses in chronic viral infections. The finding, published in the journal, Immunity, may lead to earlier intervention and possibly prevention of some types of viral infections such as HIV or hepatitis.
One of the remaining mysteries of the human immune system is why ‘memory’ B cells often only have a weak capacity to protect us from persistent infections.
In an answer to this, researchers from the Monash University Biomedicine Discovery Institute have now discovered that chronic viral infection induces a previously unknown immune B memory cell that does not produce high levels of antibodies.
Importantly the research team, led by Professor Kim Good-Jacobson and Dr Lucy Cooper, also determined the most effective time during the immune response for therapeutics such as anti-viral and anti-cancer drugs to better boost immune memory cell development.
“What we discovered was a previously unknown cell that is produced by chronic viral infection. We also determined that early intervention with therapeutics was the most effective to stop this type of memory cell being formed, whereas late intervention could not,” Professor Good-Jacobson said.
According to Dr Cooper, chronic viral infections have been known to alter our ability to form effective long-term protective antibody responses, but how that happens is unknown.
“In the future, this research may result in new therapeutic targets, with the aim to reduce the devastating effect of chronic infectious diseases on global health, specifically those that are not currently preventable by vaccines,” she said.
“Revealing this new immune memory cell type, and what genes it expresses, allows us to determine how we can target it therapeutically and whether that will lead to better antibody responses.”
The research team are also looking to see whether this population is a feature of long COVID, which results in some people having a reduced capacity to fight off the symptoms of COVID infection long after the virus has dissipated.
An unexpected discovery surprised a scientist at the Max Planck Institute for Intelligent Systems in Stuttgart: nanometre-sized diamond particles, which were intended for a completely different purpose, shone brightly in a magnetic resonance imaging experiment – outshining the actual contrast agent, the heavy metal gadolinium.
The researchers, publishing their serendipitous discovery in Advanced Materials, believe that diamond nanoparticles, in addition to their use in drug delivery to treat tumour cells, might one day become a novel MRI contrast agent.
While the discovery of diamond dust’s potential as a future MRI contrast agent may never be considered a turning point in science history, its signal-enhancing properties are nevertheless an unexpected finding which may open-up new possibilities: diamond dust glows brightly even after days of being injected.
Perhaps it could replace gadolinium, which has been used in clinics to enhance the brightness of tissues to detect tumours, inflammation, or vascular abnormalities for more than 30 years. But when injected into a patient’s bloodstream, gadolinium travels not only to tumour tissue but also to surrounding healthy tissue. It is retained in the brain and kidneys, persisting months to years after the last administration and its long-term effects are not yet known. Gadolinium also causes a number of other side effects, and the search for an alternative has been going on for years.
Serendipity often advances science
Could diamond dust, a carbon-based material, become a well-tolerable alternative because of an unexpected discovery made in a laboratory at the Max Planck Institute for Intelligent Systems in Stuttgart?
Dr Jelena Lazovic Zinnanti was working on an experiment using nanometre-sized diamond particles for an entirely different purpose. The research scientist, who heads the Central Scientific Facility Medical Systems at MPI-IS, was surprised when she put the 3–5nm particles into tiny drug-delivery capsules made of gelatin. She wanted these capsules to rupture when exposed to heat. She assumed that diamond dust, with its high heat capacity, could help.
“I had intended to use the dust only to heat up the drug carrying capsules,” Jelena recollects.
“I used gadolinium to track the dust particles’ position. I intended to learn if the capsules with diamonds inside would heat up better. While performing preliminary tests, I got frustrated, because gadolinium would leak out of the gelatin – just as it leaks out of the bloodstream into the tissue of a patient. I decided to leave gadolinium out. When I took MRI images a few days later, to my surprise, the capsules were still bright. Wow, this is interesting, I thought! The diamond dust seemed to have better signal enhancing properties than gadolinium. I hadn’t expected that.”
Jelena took these findings further by injecting the diamond dust into live chicken embryos. She discovered that while gadolinium diffuses everywhere, the diamond nanoparticles stayed in the blood vessels, didn’t leak out and later shone brightly in the MRI, just as they had done in the gelatin capsules.
While other scientists had published papers showing how they used diamond particles attached to gadolinium for magnetic resonance imaging, no one had ever shown that diamond dust itself could be a contrast agent. Two years later, Jelena became the lead author of a paper now published in Advanced Materials.
“Why the diamond dust shines bright in our MRI still remains a mystery to us,” says Jelena.
She can only assume the reason is the dust’s magnetic properties: “I think the tiny particles have carbons that are slightly paramagnetic. The particles may have a defect in their crystal lattice, making them slightly magnetic. That’s why they behave like a T1 contrast agent such as gadolinium. Additionally, we don’t know whether diamond dust could potentially be toxic, something that needs to be carefully examined in the future.”
A common practice of shoulder surgeons may be impairing the success of rotator cuff surgery, a new study from orthopaedic scientists and biomedical engineers at Columbia University suggests.
During the surgery, surgeons often remove the bursa, a cushion-like tissue, while repairing torn tendons in the shoulder joint – but the study, which is published in Science Translational Medicine, suggests that the small tissue in fact plays a role in helping the shoulder heal.
“It is common to remove the bursa during shoulder surgery, even for the simple purpose of visualising the rotator cuff,” says Stavros Thomopoulos, PhD, the study’s senior author and the Robert E. Carroll and Jane Chace Carroll Laboratories Professor of Orthopaedic Surgery at Columbia University Vagelos College of Physicians and Surgeons.
“But we really don’t know the role of the bursa in rotator cuff disease, so we don’t know the full implications of removing it,” Thomopoulos says. “Our findings in an animal model indicate that surgeons should not remove the bursa without carefully considering the consequences.”
The challenge of rotator cuff surgery
Most damage to tendons in the rotator cuff comes from wear and tear that accumulates over years of repetitive motions. Among people over 65, about half have experienced a rotator cuff tear, which can make simple daily tasks like combing one’s hair difficult and painful.
More than 500 000 rotator cuff surgeries are performed each year in the US to repair these injuries, restore range of motion, and alleviate pain, but failure is common – ranging from one in five surgeries in young patients to as high as 94% in elderly patients with large tears.
Rotator cuff repairs usually fail because of poor healing between tendon and bone where the tendon is reattached to the bone.
Bursa: friend or foe?
The bursa is a thin, fluid-filled sac originally thought to protect the tendons by providing a cushion between the tendons and adjacent bones.
The bursa often becomes inflamed, sometimes concurrently, when underlying tendons are injured, and surgeons often remove the tissue because they suspect it is a source of shoulder inflammation and pain. But recent studies suggest the tissue may be playing other biological roles besides mechanical cushioning, including promoting healing of injuries to the tendons in the shoulder.
To explore the role of the bursa in rotator cuff disease, Thomopoulos and graduate student Brittany Marshall examined rats with repaired rotator cuff injuries, with and without bursa removal.
Bursa removal impairs uninjured tendons
After the rats underwent repair of a rotator cuff injury, the researchers measured the mechanical properties of the repaired tendon and an adjacent undamaged tendon, the quality of the underlying bone, and changes to protein and gene expression.
The researchers found that the presence of the bursa protected the undamaged tendon by maintaining its mechanical properties and protected the bone by maintaining its morphometry. When the bursa was removed, strength of the undamaged tendon deteriorated and the bone quality deteriorated.
“The loss of mechanical integrity in the uninjured tendon in the absence of the bursa was striking,” Thomopoulos says. Uninjured tendons in the shoulder frequently degenerate over time after the initial injury, and “the animal data imply that retaining the bursa may prevent or delay progression of this pathology.”
In the damaged tendon, the researchers found that the bursa promoted an inflammatory response and activated wound healing genes, but no changes were seen in the mechanical properties of the repaired tendon two months after the repair. It’s possible that differences in mechanical properties would be detected after a longer healing period, Thomopoulos says, something that the research team is currently investigating.
“Overall, what we’re seeing is a beneficial role of the bursa for rotator cuff health, in contrast with the historical view that the inflamed bursa is detrimental,” says Thomopoulos.
The researchers documented similar changes to cells and proteins in bursa samples from patients who underwent surgery to repair rotator cuff injuries, suggesting comparable processes may occur in people.
The bursa as a drug delivery depot
If the bursa is not removed, the tissue could be used to deliver drugs to the repaired tendon to improve healing.
Thomopoulos and Marshall explored this possibility by injecting corticosteroid microspheres into the bursa of their rat model after tendon injury. Steroids are often used to treat musculoskeletal injuries and reduce inflammation.
“The treatment results are somewhat preliminary and require additional timepoints and mechanical characterisation before we can draw strong conclusions,” Thomopoulos says, “but our initial data supports the idea that the bursa can be therapeutically targeted to improve rotator cuff healing.”
