Publisher Health

New modeling shows how synonymous mutations — those that change the DNA sequence of a gene but not the sequence of the encoded protein — can still impact protein production and function.
A team of researchers led by Penn State chemists modeled how genetic changes that alter the speed of protein synthesis, but not the sequence of amino acids that comprise the protein, can lead to misfolding that changes the protein’s activity level, and then corroborated their models experimentally.
The results demonstrate the importance of kinetics — the rate of protein synthesis — in addition to sequence for determining protein structure and function and could have implications in fields such as biopharmaceutics for fine tuning the activity of synthesized proteins.
Proteins are composed of long strings of amino acids that then fold up into three-dimensional functional structures. Each amino acid is encoded by a triplet of letters in the DNA alphabet of A, T, C and G called a codon, but there is redundancy built in to the system such that more than one codon can correspond to the same amino acid.
Therefore, a mutation that changes the DNA sequence of a gene won’t necessarily change the sequence of the encoded protein if the mutation results in a “synonymous codon.” To make a protein, DNA in the nucleus of a cell is first transcribed into a messenger RNA (mRNA). The mRNA is then transported out of the nucleus where it is translated into a nascent protein by a cellular organelle called a ribosome. After translation the protein is folded into its final functional form.
“We used to use ‘synonymous’ and ‘silent’ interchangeably to describe mutations that don’t change a protein’s sequence because it was thought that they wouldn’t alter the function of the protein,” said Ed O’Brien, professor of chemistry and a member of the Institute for Computational and Data Sciences at Penn State, and one of the leaders of the research team. “But, we’ve known for some time now that not all synonymous mutations are silent. Over two decades ago, it was shown that synonymous mutations could reduce the activity of proteins, but it was still unknown what was happening at the molecular level to cause this change.”
The research team used a multi-scale modeling approach, using theory and computation to simulate what is happening at the molecular level during protein synthesis, to predict changes in protein structure that could result from synonymous mutations and therefore alter the protein’s activity. A paper describing the research appears Dec. 5 in the journal Nature Chemistry.

Paying cash to people with obesity for losing a specific amount of weight or completing weight-reducing activities works better than offering stand-alone free tools, such as weight-loss programs, diet books, and wearable fitness trackers, a new study shows.
Led by researchers at NYU Grossman School of Medicine, the study tracked the weight-loss efforts for up to a year of 668 low-income, mostly Hispanic men and women whose average weight to start the trial was 218 pounds. All were randomly assigned to receive one of three sets of incentives for six months, including some who received cash payments and those who received none.
Publishing in the journal JAMA Internal Medicine online Dec. 5, the results showed that offering study participants cash directly, on average $440 in total, for losing at least 5% of their original body weight (about 10 pounds) was most effective over the short term. Forty-nine percent of those offered cash lost this amount of weight after six months. This number dropped to just 41% after a full year of follow-up.
Similarly, paying other study volunteers an average of $303 over the initial study period to meet weight-loss goals, such as attending at least two weight-loss counseling classes each month, weighing themselves at least three times per week, or exercising for at least 75 minutes per week, was also effective. Some 39% of these study participants lost 5% of their starting weight after six months, and almost 42% lost the minimum amount of weight after 12 months of monitoring.
All study participants were offered a free one-year voucher for the Weight Watchers program, which included classes, counseling, and tips for losing weight. Wearable fitness devices (Fitbits), digital scales, and food journals were also provided so that trial volunteers could keep track of their weight during the study and thereafter.
One in five of those who received zero financial incentives and who were only offered the free tools lost the minimum weight after six months. But this grew to almost a third after a year.

Researchers at The Tisch Cancer Institute uncovered inflammatory markers that may predict which COVID-19 patients are more likely to respond to therapies like the anti-cancer drug pacritinib, according to phase 2 trial results published in JAMA Network Open in December.
Pacritinib, which has been approved as a cancer therapy by the Food and Drug Administration (FDA), is classified as a JAK2 inhibitor; it blocks messaging pathways in the immune system that promote inflammation. The researchers suggested that it could serve as a model to guide the selection of several other approved immunotherapies that have been shown to improve outcomes in patients with severe COVID-19, including the JAK2 inhibitor baricitinib and the IL-6 inhibitor tocilizumab.
“While we identified subtypes of COVID-19 patients with hyperinflammation who could actually benefit from pacritinib, our study failed to show superiority of pacritinib to standard-of-care management of hospitalized COVID-19 adults with acute respiratory distress syndrome for a variety of reasons,” says senior author John Mascarenhas, MD, Professor of Medicine at the Icahn School of Medicine at Mount Sinai and Director of the Center of Excellence for Blood Cancers and Myeloid Disorders. “We believe one reason may have been that the study was limited by the early dropout of participants who actually improved with this agent and therefore did not feel it was necessary to continue treatment and these patients were not captured as responders in the analysis.”
Dr. Mascarenhas believes that despite recent advances in immunomodulatory treatment, an unmet need still exists for therapeutic strategies to prevent disease progression in hospitalized patients. “Pacritinib showed an excellent safety profile in our trial,” he notes, “which is why further studies are needed to show how pacritinib or other agents like it might be beneficial to certain populations of patients with hyperinflammation that are at significant risk for poor outcomes.”
JAK inhibitors are a class of medicines that inhibit the activity of one or more of the Janus kinase enzymes (JAK1, JAK2, JAK3, and TYK2) that are known to promote inflammation. They do this by transmitting signals from proteins known as cytokines that attach to receptors on immune cells to produce pro-inflammatory cytokines. JAK inhibitors interfere with this process by blocking the enzyme signaling pathway and calming the body’s immune system. Pacritinib is a selective JAK inhibitor, meaning it affects the enzymes JAK2 and IRAK1, but spares JAK1. This distinction is important because JAK1 is responsible for the differentiation and activity of immune cells that contribute to antiviral and antitumor responses. IRAK1 or IL-1 receptor associated kinase 1 is integral to an inflammatory signaling pathway that culminates in NFκB activation which also regulates expression of inflammatory cytokines.
The study, known as PRE-VENT, was launched in June 2020 across 21 centers with 200 patients in the early stage of the pandemic. It became the first to demonstrate that certain inflammatory markers like Interleukin 6 (IL-6), a cytokine thought to be a main driver of inflammation, may predict which COVID-19 patients are most likely to respond to immunotherapy. In May 2022, the JAK1/2 inhibitor baricitinib became the first immunomodulatory drug to win approval from the FDA for COVID-19 (in combination with remdesivir), and in June 2021 the IL-6 inhibitor tocilizumab was granted emergency use authorization (EUA) for the treatment of COVID-19. Both of these agents directly and indirectly target the IL-6 signaling pathway and thus support the PRE-VENT finding that IL-6 elevation could be an important biomarker for determining which COVID-19 patients are most likely to benefit from certain immunomodulatory agents.
Pacritinib has been primarily studied in outpatient oncology settings, and following the completion of PRE-VENT was approved by the FDA for the treatment of patients with myelofibrosis, a chronic leukemia that disrupts the body’s production of blood cells. Moreover, it is being investigated for other hematologic malignancies, including acute myeloid leukemia (AML), according to Dr. Mascarenhas, who led the phase 3 study that resulted in the drug’s approval for myelofibrosis.

Women with prolonged mental health problems up to three years after childbirth may be suffering from irregular immune system responses, according to new research by Cedars-Sinai investigators. The findings are published in the American Journal of Reproductive Immunology.
“We found that women who had clinically elevated symptoms of depression, anxiety, and/or post-traumatic stress disorder (PTSD) two to three years after delivery had genetic evidence of a higher prevalence of immune system defense mechanism activation,”said Eynav Accortt, PhD, principal investigator of the study and director of the Reproductive Psychology Program at Cedars-Sinai.
“These women also appeared to have a reduction in the activity of genes related to antiviral immune responses that can offer the body protection from pathogens,” said Accortt, a clinical psychologist.
According to the Centers for Disease Control and Prevention, about 1 in 8 women experience significant symptoms of perinatal mood and anxiety disorders that can interfere with overall health, daily activities and family life. Much of the research into maternal mental health to date has focused on the perinatal period and the first year after childbirth.
Cedars-Sinai investigators surveyed 33 women about their mental health over a longer period, two to three years after giving birth. Study participants also provided a blood sample, and scientists performed bioinformatic analyses of differential gene expression.
“Delayed or persistent postpartum anxiety, depression and PTSD is an area that is woefully understudied,” said Sarah Kilpatrick, MD, PhD, chair of the Department of Obstetrics and Gynecology at Cedars-Sinai and one of the study’s co-authors.
“In this preliminary research, we have identified genetic differences related to inflammation when comparing women experiencing prolonged symptoms of mood and anxiety disorders to those who did not report poor mental health. Additional studies will be needed for a deeper dive into the role inflammation may play in postpartum mental illness,” said Kilpatrick.
A primary goal of this work is to design a blood test that would detect which women are at the highest risk for serious and prolonged postpartum mood disorders, according to Accortt.
“A blood test could help us develop early interventions that provide medical and mental health treatments and support. We want to figure out why some women are at greater risk for depression, anxiety and PTSD. No one should have to suffer for years after childbirth,” said Accortt.
Jennifer Nicoloro-SantaBarbara, PhD, currently an investigator and instructor in the Department of Psychiatry at Harvard Medical School, is first author on the publication.
Funding: Support for the study was provided by Cedars-Sinai Precision Health, the Cousins Center for Psychoneuroimmunology, the University of California, Los Angeles, and a National Institute of Mental Health grant, number T32MH015750 (JNSB).
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Researchers from Tokyo Medical and Dental University (TMDU) find that spheroids grown in suspension mature into human intestinal organoids when transferred to a bioreactor and differentiate into complex intestinal tissue upon transplantation.
Growing human body parts in the lab is a common trope of horror movies and sci-fi books. But growing miniature organ-like tissues in the lab is already within our reach. Researchers from Japan have developed a new approach that enables intestinal mini-organs to be grown more easily and efficiently in the lab. This holds immense promise for regenerative medicine.
In a study published in November in Cell Reports Methods, researchers from Tokyo Medical and Dental University (TMDU) reveal that applying a few specialized lab techniques yields intestine-like tissues of predictable size and composition.
Organoids are organ-like balls of cells that are grown in the lab from spheroids (even smaller balls) of human cells and mimic the properties of the organ from which the “seed” cell was taken. Organoids are used for studying organ function in a lab setting and are also promising tools in the field of regenerative medicine.
“There are established methods for growing human intestinal organoids (HIOs) from induced pluripotent stem cells (iPSCs),” states Junichi Takahashi, first author of the study. “However, these techniques are challenging to perform. They result in spheroids of varying sizes and are limited by the growth conditions, which can result in deformed and unhealthy spheroids over time.”
To develop a more robust and consistent way to generate HIOs, the researchers explored the use of cell culture plates made with an ultra-low attachment polymer to encourage the cells to detach and grow in suspension. They also tested the effects of growing the resulting spheroids in a bioreactor, a specialized incubator that keeps the growth medium constantly flowing to improve the health of the cells.
“Using our technique, we were able to grow spheroids of a predictable, consistent size that could be modified by modulating the number of cells seeded into the plates,” says Tomohiro Mizutani, corresponding author of the study. “Furthermore, transferring the spheroids to a bioreactor allowed them to grow even larger, into healthy HIOs.”
These organoids were surrounded by mesenchyme, which is a type of tissue found between organs in the human body. Importantly, when the organoids were transplanted into mice, they continued to grow and differentiate, developing a complex tissue architecture reflecting that of mature intestine. “Our findings show that intestinal tissue can be generated from iPSC-derived HIOs by inducing spheroids in suspension and maturing them in a bioreactor,” says Takahashi.
Given that more complex intestinal tissues have been generated using traditional techniques, it is likely that this new approach could be easily adapted to create more complex organoids, such as intestine-like tissue containing blood vessels or nerves. These lab-grown tissues will be invaluable for regenerative medicine applications in the future.
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A six-month study led by Johns Hopkins Medicine researchers concludes that the use of portable home air purifiers can improve some markers of cardiovascular health in people with chronic obstructive pulmonary disease, or COPD. People suffering from COPD often experience shortness of breath, chest tightness and chronic cough. Cardiovascular diseases such as arrythmias, heart failure, stroke and heart attack commonly accompany COPD, and both COPD and cardiovascular disease are leading causes of death around the world, according to the World Health Organization.
The new research, described online Oct. 26 in the American Journal of Respiratory and Critical Care Medicine, is a secondary study of a larger Johns Hopkins-led project, the CLEAN AIR study. The CLEAN AIR study, which investigated the effects of indoor air pollution on COPD, found that people with COPD experienced improved symptoms after using portable air purifiers indoors.
“We’ve seen that air pollution in the home, where people spend a majority of their time, contributes to impairments in respiratory health. We hypothesized this pollution is a big driver of cardiovascular disease and cardiac events in people with COPD,” says lead author Sarath Raju, M.D., M.P.H., an assistant professor of medicine who specializes in obstructive lung diseases at the Johns Hopkins University School of Medicine.
Researchers recruited 85 men and women from the original CLEAN AIR study, who were adults (average age 65) with COPD. The participants lived primarily in the Baltimore area.
First, researchers had trained technicians take air samples of indoor particulate matter of varying sizes from participants’ homes. These indoor air pollutants are composed of such things as mold and pet dander. One of the tiniest kinds of particulate matter, PM 2.5 — smaller than the diameter of a human hair — can be detrimental to respiratory and heart health by infiltrating the bloodstream through the lungs and causing inflammation. The level of PM 2.5 indoors should stay at or below 12 micrograms per cubic foot for the air to be considered healthy to breathe. Participants’ homes had an average of 13.8 micrograms per cubic foot of PM 2.5.
Then, 46 randomized participants received two portable air cleaners with HEPA and carbon filters to use at home; the other participants received placebo air cleaners that circulated air but had the filters removed.

CRISPR, the Nobel Prize-winning gene editing technology, is poised to have a profound impact on the fields of microbiology and medicine yet again.
A team led by CRISPR pioneer Jennifer Doudna and her longtime collaborator Jill Banfield has developed a clever tool to edit the genomes of bacteria-infecting viruses called bacteriophages using a rare form of CRISPR. The ability to easily engineer custom-designed phages — which has long eluded the research community — could help researchers control microbiomes without antibiotics or harsh chemicals, and treat dangerous drug-resistant infections. A paper describing the work was recently published in Nature Microbiology.
“Bacteriophages are some of the most abundant and diverse biological entities on Earth. Unlike prior approaches, this editing strategy works against the tremendous genetic diversity of bacteriophages,” said first author Benjamin Adler, a postdoctoral fellow in Doudna’s lab. “There are so many exciting directions here — discovery is literally at our fingertips!”
Bacteriophages, also simply called phages, insert their genetic material into bacterial cells using a syringe-like apparatus, then hijack the protein-building machinery of their hosts in order to reproduce themselves — usually killing the bacteria in the process. (They’re harmless to other organisms, including us humans, even though electron microscopy images have revealed that they look like sinister alien spaceships.)
CRISPR-Cas is a type of immune defense mechanism that many bacteria and archaea use against phages. A CRISPR-Cas system consists of short snippets of RNA that are complementary to sequences in phage genes, allowing the microbe to recognize when invasive genetic material has been inserted, and scissor-like enzymes that neutralize the phage genes by cutting them into harmless pieces, after being guided into place by the RNA.
Over millennia, the perpetual evolutionary battle between phage offense and bacterial defense forced phages to specialize. There are a lot of microbes, so there are also a lot of phages, each with unique adaptations. This astounding diversity has made phage editing difficult, including making them resistant to many forms of CRISPR, which is why the most commonly used system — CRISPR-Cas9 — doesn’t work for this application.

Research by RCSI University of Medicine and Health Sciences has provided new insights into the mechanism behind how our circadian 24-hour body clock influences our immune response to vaccines, depending on the time of day.
The paper published in Nature Communications examined the changes taking place in the mitochondria of a key immune cell involved in the vaccine response and could help improve the design and timing of administration of future vaccines to maximise effectiveness.
It had been previously found that humans mount a greater response to certain vaccines depending on the time of day at which the vaccine is administered, however the reason behind this wasn’t clearly understood. This research has uncovered that our circadian clock is changing the shape of mitochondria within dendritic cells. The variations in the structure of mitochondria influence how well dendritic cells function throughout the day.
Research author Professor Annie Curtis, School of Pharmacy and Biomolecular Sciences at RCSI said: “Our discovery has shed light on a crucial aspect of our body’s response to vaccination and highlights the importance of circadian rhythms in immunity. We can apply this understanding in vaccine development to ensure we receive the maximum benefits from vaccination.”
The circadian clock within dendritic cells is controlling whether mitochondria form one of two shapes either long strings, ‘networked’, or broken into small punctate pieces. It is within the networked formation that vaccination is most effective as dendritic cells have a better ability break up the vaccine into small pieces for interaction with our immune cells (T cells). Within the study, researchers used an approach to induce the networked phase which could have implications in vaccine design allowing us to optimise our immune response, irrespective of time of day.
The majority of this study was supported through funding provided by the Science Foundation Ireland Career Development Award (CDA) programme by the Irish Research Council through a Laureate Award and an RCSI Strategic Academic Recruitment Program (StAR) award. Further support was provided by a Conacyt grant, a SFI Investigator Award and a European Research Council Consolidator Award.
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University of South Australia engineers have designed a system to remotely measure blood pressure by filming a person’s forehead and extracting cardiac signals using artificial intelligence algorithms.
Using the same remote-health technology they pioneered to monitor vital health signs from a distance, engineers from the University of South Australia and Baghdad’s Middle Technical University have designed a non-contact system to accurately measure systolic and diastolic pressure.
It could replace the existing uncomfortable and cumbersome method of strapping an inflatable cuff to a patient’s arm or wrist, the researchers claim.
In a new paper published in Inventions, the researchers describe the technique, which involves filming a person from a short distance for 10 seconds and extracting cardiac signals from two regions in the forehead, using artificial intelligence algorithms.
The systolic and diastolic readings were around 90 per cent accurate, compared to the existing instrument (a digital sphygmomanometer) used to measure blood pressure, that is itself subject to errors.
Experiments were performed on 25 people with different skin tones and under changing light conditions, overcoming the limitations reported in previous studies.

With low or no-carbohydrate diets rising in popularity in recent times, the humble potato is now regularly overlooked in favour of other vegetables.
In fact, research literature has previously indicated potatoes may have a detrimental effect on health, such as possibly increasing the likelihood of developing Type 2 diabetes.
However, new Edith Cowan University (ECU) research has shown while spuds may not have all the same benefits as some other vegetables — such as lowering risk of Type 2 diabetes — health issues associated with potatoes may actually be due to how people are preparing them and what they’re eating them with.
More than 54,000 people reported their dietary intake for the long-term Danish Diet, Cancer and Health study.
A recent analysis of this study led by Dr Nicola Bondonno from ECU’s Nutrition and Health Innovation Research Institute, found people who consumed the most vegetables were 21 per cent less likely to develop Type 2 diabetes than those who consumed the least amount of vegetables.
PhD candidate Pratik Pokharel carried out work on the analysis and said while potatoes didn’t have the same impact on Type 2 diabetes, they also didn’t have any negative effect.