Publisher Health

Researchers at the Centre for Genomic Regulation (CRG) in Barcelona have discovered a mechanism involving ribosomes which helps the heart toggle between a ‘regular maintenance mode’ for day-to-day function and an ‘energy-boost mode’ which aids recovery for high-demand situations including heart attacks. The findings are published in a ‘Breakthrough Article’ in the journal Nucleic Acids Research.
Ribosomes are the molecular factories that manufacture proteins in all living cells. Historically, they have been perceived as simple but vital workhorses which lack the ability to regulate a cell’s function. However, there is increasing evidence that these fundamental units — which come in different shapes and forms — carry out specialised tasks, which are yet to be discovered.
Using different experimental techniques and latest-generation sequencing technologies, the researchers found that cardiomyocytes, the cells responsible for the heart contracting, and skeletal muscle cells, which are connected to bones and are critical for strength and movement, have different types of ribosomes compared to all other types of cells in the body.
“For a long time, we thought that ribosomes were the same in every single cell of the human body. This makes them impractical drug targets as you could be healing one body part while damaging many others. The existence of specialised ribosomes and their specificity to heart and muscle cells is a turning point because it means it is possible to develop medicines that target specific ribosomes for the purpose of treating cardiovascular disease,” explains Dr. Eva Novoa, corresponding author of the study and researcher at the Centre for Genomic Regulation.
Ribosomes are made of proteins. While the ribosomes in most human cells contain ribosomal protein L3 (RPL3), the ribosomes in cardiomyocytes and skeletal muscle cells contain ribosomal protein L3-like (RPL3L). The crucial difference between the proteins, which share 77% of their amino acid sequence, is their tail. The study shows that cells will exclusively use one protein or the other. Whichever protein ends up being used, the corresponding tail sticks out on the surface of the ribosome, changing its shape and surface, which in turn affects how it binds to other proteins and receptors.
The researchers found that cardiomyocyte and skeletal muscle ribosomes showed no benefit in terms of protein synthesis compared to other ribosomes. However, the researchers were surprised to find that knocking the RPL3L gene out in mice showed both cardiomyocytes and skeletal muscle cells creating ribosomes with RPL3 instead. In stark contrast, knocking out RPL3 was lethal.
Researchers found that this newfound compensation mechanism also naturally occurred in response to a heart attack or myocardial infarction, with cardiomyocytes replacing all their existing stock of RPL3L-containing ribosomes with ribosomes containing RPL3 instead. The different shape of the new ribosomes enables them to make physical contact with mitochondria, the batteries of the cells, and significantly boosts the production of ATP, the universal currency used for energy. The effect was detected within six hours after infarction and peaked after 72 hours.
This ribosome replacement mechanism also occurs during cardiac hypertrophy, a response of the heart to increased workload which can be either physiological, such as after exercise, or pathological, due to disease. RPL3-containing ribosomes in cardiomyocytes peak after 96 hours in response to cardiac hypertrophy.
The study provides some clues for why the heart and muscle use RPL3L for ribosomes in the first place. The researchers found that RPL3L is only present in the ribosomes of adult cardiomyocytes, while fetal tissues exclusively use RPL3. At the same time, mice lacking RPL3L had lower lean muscle mass at 55-weeks old compared to mice with RPL3L.
“When we are born, our hearts need lots of energy to grow. At this point, cardiomyocytes only express RPL3, swapping to RPL3L only once the heart is fully mature. We don’t know exactly why, but the cells could be making the switch to fine tune the mitochondrial activity in resting conditions and possibly decrease levels of free radicals, dangerous by-products of mitochondrial metabolism. This could explain how the heart delicately balances two different modes — one where ribosomes boost energy levels and one where the heart is kept in maintenance mode,” explains first author of the study and PhD candidate Ivan Milenkovic.
The discovery of this mechanism can be exploited to improve cardiac health and function, and establishes ribosomes as a new frontier for therapeutic strategies that prevent or heal damage to the heart. The researchers are now researching the molecular mechanisms in further detail to distinguish pathological and physiological cardiac hypertrophy, including exercise experiments with mice to assess how the presence or absence of RPL3L in cardiomyocytes affects physical performance.

New research led by investigators at Massachusetts General Hospital (MGH), a founding member of Mass General Brigham (MGB), indicates that socioeconomic and genetic factors likely interact in an additive way to affect people’s risks of developing obesity and type 2 diabetes. The findings, which are published in Diabetes Care, suggest that interventions to improve socioeconomic deprivation may decrease metabolic diseases at the individual and community levels, especially among people with concomitant high genetic risk.
Genetic and socioeconomic factors — one intrinsic and unmodifiable and one extrinsic and potentially modifiable — have both been shown to increase the risk of metabolic diseases, but the relative contributions of the two and the degree to which they may interact to impact a person’s risk are poorly understood. To investigate, scientists examined the independent and additive effects of genetic and socioeconomic risk in 26,737 and 223,843 participants of European genetic ancestry from the Mass General Brigham Biobank and the UK Biobank, respectively, as well as in 3,468 and 7,459 participants of non-European ancestry in the respective biobanks. The team examined individuals’ genetic data at millions of points across the genome as well as information related to education, income, and employment from their area of residence. Because educational attainment had the strongest association with type 2 diabetes and obesity out of all area-level socioeconomic variables examined, this was used as the primary socioeconomic risk measure.
Results indicated that people in the highest quintile of both genetic and socioeconomic risk had a more than seven-fold higher prevalence of type 2 diabetes (22.2% vs. 3.1%) and a more than three-fold higher prevalence of obesity (69.0% vs. 20.9%) compared with those in the combined lowest risk quintiles.
There was a significant positive interaction between genetic and socioeconomic risk on an additive scale. This suggests that the absolute increase in metabolic disease prevalence with unfavorable socioeconomic risk was much greater for those at higher genetic risk than for those at lower genetic risk. For example, adverse area-level socioeconomic risk was associated with increased type 2 diabetes prevalence across the spectrum of genetic risk, but the absolute increase in prevalence was greatest in those at highest genetic risk: +9.2% in the highest genetic risk quintile vs. +1.7% in the lowest genetic risk quintile. Overall, the additive effects of genetic and socioeconomic factors accounted for 13.2% and 16.7% of type 2 diabetes and obesity prevalence, respectively.
“We believe that this research calls for a whole-person approach to metabolic disease prevention and that public health interventions may be most impactful if targeted to those who also have elevated genetic risk,” says lead author Sara Cromer, MD, an Endocrinologist in the Department of Medicine at MGH and an Instructor at Harvard Medical School. “The next steps in this research include expanding models to include more risk factors (such as lifestyle factors and behaviors), improving models for individuals of non-European ancestry, exploring the predictive value of area-level socioeconomic measures in diverse populations, and examining the gene-socioeconomic status interplay in regards to other outcomes.”
Senior author Miriam Udler, MD, PhD, an endocrinologist the department of Medicine at MGH, an investigator in the MGH Center for Genomic Medicine, and an assistant professor at Harvard Medical School, adds that the study highlights not only the high prevalence of metabolic disease among individuals with both genetic and socioeconomic risk factors, but also that genetic risk for these diseases is not deterministic. “People at high genetic risk who live in low-risk socioeconomic regions have similar rates of type 2 diabetes and obesity as those with low genetic risk living in certain socioeconomic risk regions,” she says. “More research is needed to understand exactly why this is.”
Co-authors include Chirag M. Lakhani, Josep M. Mercader, Timothy D. Majarian, Philip Schroeder, Joanne B. Cole, Jose C. Florez, Chirag J. Patel, Alisa K. Manning, Sherri-Ann M. Burnett-Bowie, Jordi Merino, and Miriam S. Udler.
This study was supported by the National Institutes of Health and the American Diabetes Association.

Rutgers research that may eventually enable far earlier autism diagnoses shows that typically developing infants perceive audio-video synchrony better than high-risk for autism infants.
If follow-up research demonstrates that most infants who miss unmatched audio and video develop autism spectrum disorder (ASD), physicians may be able to diagnose the condition years earlier — a potentially important step as early treatment strongly predicts better outcomes.
“We’re a long way from validating this as a diagnostic tool, but the results definitely suggest it could be a diagnostic tool,” said Michael Lewis, University Distinguished Professor of Pediatrics and Psychiatry and director of the Institute for the Study of Child Development at Rutgers Robert Wood Johnson Medical School.
Lewis, the senior author of the study, and other researchers have long known children with ASD struggle to perceive audio-visual speech as a unified event, and they’ve hypothesized that this difficulty may contribute to social impairments and language deficits in such children.
To study whether these difficulties arise before it’s currently possible to diagnose ASD, generally around age 3, the researchers assembled two groups of infants ages 4 to 24 months, one comprising children whose developmental delays indicate an elevated risk of ASD and the other comprising typically developing children.
The researchers, whose work was published in the European Journal of Pediatrics, showed participants from both groups two types of videos with progressively longer time separation between image and sound. The first videos featured a ball making noises as it bounced against a wall. The second showed a woman talking.
When watching videos of the ball, the two groups performed similarly. When watching videos of the woman, however, the differences were stark. Typically, developing children perceive audio-visual gaps that are, on average, a tenth of a second smaller than those perceived by the kids with developmental delays.
Although this result confirmed the researchers’ initial hypothesis, some findings were surprising. The ability to perceive audio-visual mismatch wasn’t associated with vocabulary size in children old enough to have a vocabulary.
If a high percentage of the children who were slowest to identify mismatched audio and video go on to be diagnosed with autism — and the findings are repeated with far more children than the 88 who participated in this study — audio-visual tests might prove a revolutionary diagnostic tool for a condition that’s becoming far more common, Lewis said.
However, scientific validation is just the first step to adoption, he said. Insurers would need to pay for tests, and pediatricians would need to embrace them before they could be used to begin providing support services to children in need.
“Earlier diagnosis won’t allow us to cure ASD anytime soon, but it will allow for the earlier provision of support services that can help such children in areas of weakness and direct them toward areas of strength,” Lewis said. “The goal is to create happy people whose schooling and, eventually, careers are well suited to them, and that’s certainly an achievable goal for most.”

Researchers from Indiana University School of Medicine have successfully developed a blood test for anxiety. The test examines biomarkers that can help them objectively determine someone’s risk for developing anxiety, the severity of their current anxiety and which therapies would likely treat their anxiety the best.
Now that the test has been validated by researchers, it is currently being developed for wider use by physicians by MindX Sciences.
“Many people are suffering from anxiety, which can be very disabling and interfere with daily life,” said professor of psychiatry Alexander Niculescu, MD, PhD. “The current approach is to talk to people about how they feel to see if they could be on medications, but some medications can be addictive and create more problems. We wanted to see if our approach to identify blood biomarkers could help us match people to existing medications that will work better and could be a non-addictive choice.”
Niculescu’s past research has led to the development of blood tests for pain, depression/bipolar disorder and post traumatic stress disorder. This latest work, published in Molecular Psychiatry, uses similar methods for anxiety. The study included three independent cohorts — discovery, validation and testing. Participants would complete a blood test every 3-6 months or whenever a new psychiatric hospitalization occurred. By examining the RNA biomarkers in the blood, researchers could identify a patient’s current state of anxiety and matches them with medications and nutraceuticals, showing how effective different options could be for them based on their biology.
“In addition to medications, there are other methods to treat anxiety, such as cognitive behavioral therapy or lifestyle changes,” Niculescu said. “But having something objective like this where we can know what someone’s current state is as well as their future risk and what treatment options match their profile is very powerful in helping people.”
A person’s biomarkers can also change over time. Niculescu said the test can help evaluate a person’s risk of developing higher levels of anxiety in the future as well as how other factors might impact their anxiety, like hormonal changes.
“There are people who have anxiety and it is not properly diagnosed, then they have panic attacks, but think they’re having a heart attack and up in the ER with all sorts of physical symptoms,” Niculescu said. “If we can know that earlier, then we can hopefully avoid this pain and suffering and treat them earlier with something that matches their profile.”
Niculescu said this new test could also be used in combination with the other blood tests his research has led to, providing a more comprehensive view of a patient’s mental health and risk of future mental health concerns. Researchers can also use the test to develop new treatments for anxiety that are more targeted to individual biomarkers.
“This is something that could be a panel test as part of a patient’s regular wellness visits to evaluate their mental health over time and prevent any future distress,” Niculescu said. “Prevention is better in the long run, so our goal is to be able to provide a comprehensive report for patients and their physicians using simply one tube of blood.”

Researchers at Universidad Carlos III de Madrid (UC3M) have created software and hardware for a 4D printer with applications in the biomedical field. In addition to 3D printing, this machine allows for controlling extra functions: programming the material’s response so that shape-changing occurs under external magnetic field, or changes in its electric properties develops under mechanical deformation. This opens the door to the design of soft robots or smart sensors and substrates that transmit signals to different cellular systems, among other applications.
This research line focuses on the development of soft multifunctional structures, which consist of materials with mechanical properties that mimic biological tissues such as the brain or skin. In addition, they are capable of changing their shape or properties when actuated via external stimuli, such as magnetic fields or electric currents.
Until now, this team of researchers had made several advances in the design and manufacturing of these structures, but they were very limited in terms of shape-design and programming of intelligent responses. The work presented in their latest study, published in the journal Advanced Materials Technologies, has allowed them to open up new possibilities by developing a novel4D printing methodology. “This technology allows us to not only control the way we print three-dimensional structures, but also to give them the ability to change their properties or geometry in response to the action of external magnetic fields, or the ability to modify their electric properties when they deform,” explains one of the researchers, Daniel García González, head of the ERC 4D-BIOMAP (GA 947723) project and associate professor in UC3M’s Department of Continuum Mechanics and Structure Theory.
This type of printing is complex since the material to be extruded transitions from liquid to solid during the printing process. It is therefore necessary to understand the material dynamics to adapt the manufacturing process and obtain a material which is sufficiently liquid when it flows through the printer nozzle but, at the same time, solid enough to maintain a specific shape. To this end, they have developed an interdisciplinary methodology that combines theoretical and experimental techniques allowing them to build the printing device from scratch, both the physical part of the device (the hardware) and the computer programmes that allow it to be controlled (the software).
A self-healing material
The researchers have also developed a new material concept that is capable of healing itself autonomously without the need for external action, according to another recent publication in the journal Composites Part B: Engineering. “This material consists of a soft polymer matrix embedded with magnetic particles with a remanent field. For practical purposes, it is as if we had small magnets distributed in the material, so that, if it breaks, when the resulting parts are brought together again, they will physically join recovering their structural integrity,” says Daniel García González.
Thanks to these advances, which have led to several registered patents, these scientists have been able to print three types of functional materials: some that change their shape and properties in response to external magnetic fields; others with self-healing capability; and others whose electrical properties (conductivity) vary according to their shape or deformation. With the first type of material, they have developed smart substrates to transmit forces and signals to cellular systems, so that they can influence biological processes such as cell proliferation or migration. These materials can also be used to design soft robots whose performance can be controlled by magnetic fields.
The combination of materials with self-healing capabilities and whose electric conduction properties vary with deformation opens up enormous possibilities in the development of sensors. “We can think of sensors that, attached to our body, collect information about our movement from variations in electric conductivity. In addition, the material’s self-healing capability allows the design of sensors with binary signals. For example, if we have had a knee injury and need to limit rotation to a maximum value, we can incorporate a small band of this material over our joint. This way, when we exceed this maximum rotation, the material will break showing an abrupt change in its electric properties, thus providing a warning signal. However, when returning the knee to a relaxed state, the material’s healing capability will result in recovery of the electric signal. This way we can monitor our movements and warn of risky conditions after surgery or during rehabilitation periods,” says Daniel Garcia González.
Video interview with Daniel García: https://youtu.be/NpK6YaHzDGU