Publisher Health

The SARS-CoV-2 papain-like protease (PLpro) plays an essential role in processing viral proteins needed for replication. In addition, the enzyme can cut and inactivate some human proteins important for an immune response. Now, researchers reporting in ACS Infectious Diseases have found other targets of PLpro in the human proteome, including proteins involved in cardiovascular function, blood clotting and inflammation, suggesting a link between the inactivation of these proteins and COVID-19 symptoms.
Viruses like SARS-CoV-2 make multiple proteins as one long “polyprotein.” Viral enzymes called proteases recognize specific amino acid sequences in this polyprotein and cut them to release individual proteins. However, some human proteins also contain these sequences (known as homologous host-pathogen sequences, or SSHHPS), including ones involved in generating the innate immune response, which could help protect the virus from the host. Patricia Legler and colleagues wanted to comprehensively identify human proteins that contain SSHHPS, examine their functions and see whether PLpro can cleave them in a test tube.
The researchers developed a computational method to search a database of all known human proteins for sequences similar or identical to the SARS-CoV-2 SSHHPS. The analysis revealed that the proteins with highest sequence identity were those that had cardiovascular, inflammatory, kidney, respiratory or blood-related functions. For example, two of the proteins containing SSHHPS were cardiac myosins, one was an anti-coagulant and another was an anti-inflammatory protein. Inactivation of these proteins by PLpro is consistent with COVID-19 symptoms of heart damage, blood clots and inflammation. The team confirmed that PLpro could cut these protein sequences in vitro. Performing the same analysis on SSHHPS for the Zika viral protease identified proteins associated with neurological development and disorders, consistent with Zika symptoms. These results suggest that the symptoms and virulence of viruses can be predicted directly from their genomic sequences, the researchers say.
The authors acknowledge funding from the Office of the Secretary of the Navy, Naval Innovative Science and Engineering funding and the Office of Naval Research.
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Our genetic material is stored in our cells in a specific way to make the meter-long DNA molecule fit into the tiny cell nucleus of each body cell. An international team of researchers at the Max Planck Institute for Biology of Ageing, the CECAD Cluster of Excellence in Ageing research at the University of Cologne, the University College London and the University of Michigan have now been able to show that rapamycin, a well-known anti-ageing candidate, targets gut cells specifically to alter the way of DNA storage inside these cells, and thereby promotes gut health and longevity. This effect has been observed in flies and mice. The researchers believe this finding will open up new possibilities for targeted therapeutic interventions against ageing.
Our genetic material lies in the form of DNA in every cell nucleus of our body cells. In humans, this DNA molecule is two meters long — yet it fits into the cell nucleus, which is only a few micrometres in size. This is possible because the DNA is precisely stored. To do this, it is wound several times around certain proteins known as histones. How tightly the DNA is wound around the histones also determines which genes can be read from our genome. In many species, the amount of histones changes with age. Until now, however, it is unclear whether changes in cellular histone levels could be utilized to improve the ageing process in living organisms.
A well-known anti-ageing compound with a new target
The drug rapamycin recently became one of the most promising anti-ageing substances and shows positive effects on health in old age. “Rapamycin turns down the TOR signalling pathway that regulates a wide spectrum of basic cellular activities such as energy, nutritional and stress status. In short, we use rapamycin to fine-tune the master regulator of cellular metabolism,” explains Yu-Xuan Lu, postdoc in the department of Linda Partridge and first author of the study. “Meanwhile, we know that histone levels have a critical impact on the ageing process. However, we had no idea whether there is a link between the TOR signalling pathway and histone levels, and more importantly, whether histone levels could be a druggable anti-ageing target.”
To study the effect of rapamycin on histone proteins, the researchers analysed various organs of the fruit fly Drosophila melanogaster. “We looked in different tissues and organs of the fly for noticeable changes in histone levels before and after treatment with rapamycin, this means before and after switching off the TOR signalling pathway,” explains Yu-Xuan Lu. “Surprisingly, we observed an increase in histone proteins after rapamycin treatment. This effect occurred exclusively in the gut of the flies, but not in other tissues.” In further experiments, Yu-Xuan Lu and his colleagues were able to show that the increased levels of certain histone proteins in a specific gut cell type called enterocytes reduced tumour growth, improved gut health and extended lifespan of the animals. Similar observations were made in mouse gut enterocytes after rapamycin treatment.
“Our results show for the first time a link between the TOR signalling pathway and histone levels that determines longevity,” says Yu-Xuan Lu. “The increased levels of histone proteins subsequently change how the DNA is stored in the nucleus. The fact that we were also able to make similar observations in mice shows that this is a widespread mechanism.” Looking ahead to future experiments, he adds: “Given the central role of histones on DNA storage in the cell, this finding not only broadens our knowledge on the ageing process, but also provides new possibilities for targeted therapeutic interventions against ageing.”
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Women’s mental health likely has a higher association with dietary factors than men’s, according to new research from Binghamton University, State University of New York.
Lina Begdache, assistant professor of health and wellness studies at Binghamton University, had previously published research on diet and mood that suggests that a high-quality diet improves mental health. She wanted to test whether customization of diet improves mood among men and women ages 30 or older.
Along with research assistant Cara M. Patrissy, Begdache dissected the different food groups that are associated with mental distress in men and women ages 30 years and older, as well as studied the different dietary patterns in relation to exercise frequency and mental distress. The results suggest that women’s mental health has a higher association with dietary factors than that of men. Mental distress and exercise frequency were associated with different dietary and lifestyle patterns, which support the concept of customizing diet and lifestyle factors to improve mental wellbeing.
“We found a general relationship between eating healthy, following healthy dietary practices, exercise and mental well-being,” said Begdache. “Interestingly, we found that for unhealthy dietary patterns, the level of mental distress was higher in women than in men, which confirmed that women are more susceptible to unhealthy eating than men.”
Based on this study and others, diet and exercise may be the first line of defense against mental distress in mature women, said Begdache.
“Fast food, skipping breakfast, caffeine and high-glycemic (HG) food are all associated with mental distress in mature women,” said Begdache. “Fruits and dark green leafy vegetables (DGLV) are associated with mental well-being. The extra information we learned from this study is that exercise significantly reduced the negative association of HG food and fast food with mental distress,” said Begadache.
This research provides the framework needed for healthcare professionals for customizing dietary plans to promote exercise and improve mental well-being in mature adults, said Begdache. It could also provide a new perspective for the research community when assessing the role of diet on mental distress.
The researchers are conducting a parallel study with young men and women, looking at diet quality in addition to sleep and seasonal change variables from a longitudinal perspective.
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Variants of viruses, such as that causing COVID-19, can now be quickly studied in the laboratory, even before they emerge in nature and become a major public health challenge.
The University of Queensland, QIMR Berghofer Medical Research Institute, Peter Doherty Institute for Infection and Immunity, Monash University, and Queensland Health have developed a technology to manipulate viruses synthetically allowing rapid analysis and mapping of new potential virus variants.
UQ’s lead researcher Professor Alexander Khromykh said the technology was ideal for use during a global pandemic such as COVID-19.
“This technique should give us the ability to answer questions about whether potential virus variants are susceptible to a particular drug or vaccine, even before they emerge in nature,” Professor Khromykh said.
“Up until now, we’ve mostly just waited and reacted to viral variants as they emerge, and in the case of SARS-CoV-2 the world has been hit by Indian, UK and South African variants, just to name a few. [WHO has now re-classified these variants as Alpha (UK), Beta (South African) and Delta (Indian).]
“Now we can mimic the massive ‘experiment’ going on in nature — where these mutations pop up due to natural selection — but we can do it safely in a strictly controlled and highly regulated biosecurity laboratory environment.”
The UQ-developed process uses copies of fragments from the viral genetic material to assemble the functional viral genome in a test tube.

Early in her career neuroscientist Allyson Mackey began thinking about molars. As a researcher who studies brain development, she wanted to know whether when these teeth arrived might indicate early maturation in children.
“I’ve long been concerned that if kids grow up too fast, their brains will mature too fast and will lose plasticity at an earlier age. Then they’ll go into school and have trouble learning at the same rate as their peers,” says Mackey, an assistant professor in the Department of Psychology at Penn. “Of course, not every kid who experiences stress or [is] low income will show this pattern of accelerated development.”
What would help, she thought, was a scalable, objective way — a physical manifestation, of sorts — to indicate how children embodied and responded to stresses in their world. Eruption timing of the first permanent molars proved to be just that.
In the Proceedings of the National Academy of Sciences, Mackey, with doctoral student Cassidy McDermott and colleagues from Penn’s School of Dental Medicine and the University of Missouri-Kansas City, shows that children from lower-income backgrounds and those who go through greater adverse childhood experiences get their first permanent molars earlier. The findings, generated initially from a small study and replicated using a nationally representative dataset, align with a broader pattern of accelerated development often seen under conditions of early-life stress.
“It’s really important for us to understand how to detect early maturation sooner,” Mackey says. “Right now, we’re relying on seeing when kids hit puberty, which might be too late for some meaningful interventions. If we can inexpensively see that a child is experiencing this maturation earlier, we might be able to direct more intervention resources toward them.”
A novel rating system
Broadly speaking, Mackey’s lab studies how the brain changes and grows as people learn. It’s well-established that stress during childhood speeds up maturation and that children who hit puberty earlier are at greater risk for both physical and mental health problems in adulthood.

Even the best face masks work only as well as their fit.
And poorly fitting face masks greatly increase the risk of infection from airborne pathogens compared to custom-fitted masks, according to a new study by the University of Cincinnati.
Researchers in UC’s College of Engineering and Applied Science used computerized tomography or CT scans of three different-sized face masks attached to three different-sized dummy heads to measure the gaps between the face and the fabric. Then they calculated the leaks from these gaps to determine the infection risk.
They found that while N95 masks are effective barriers against airborne diseases like COVID-19, poorly fitting masks can have substantial leaks around the face that reduce their effectiveness and increase the risk of infection.
“Many people do not realize that the fit of face masks can vary. There are different face shapes and different sizes of masks,” said Rupak Banerjee, a professor in UC’s Department of Mechanical and Materials Engineering.
“If you do not match them well, you can lead to greater leaks and higher risks of infection,” he said.

Scientists have developed polypeptide-based materials that act as effective vectors for delivering gene therapies. The first-of-its-kind platform enables the vectors to be adapted to suit the specific gene therapy cargo.
The work, led by researchers from RCSI University of Medicine and Health Sciences and funded by Science Foundation Ireland, is published in Biomaterials Science.
A major challenge for gene therapies is preparing them in a way that can deliver the genetic information into the host cells. For the Covid-19 vaccines that use mRNA technology, the genetic information is delivered in a lipid nanoparticle to maintain its stability and deliver it into cells. The success of the COVID vaccines has established nanoparticles as key to the development of many advanced therapies.
The researchers developed a platform that produces bespoke star-shaped polypeptide nanoparticles, which effectively deliver a range of therapies, including gene therapies. Crucially, these polypeptides are more flexible and easier to handle than lipids. To demonstrate the potential of this material, the researchers used it to deliver a gene therapy that regenerated bone.
In preclinical work, the researchers loaded the material with DNA molecules that promote bones and blood vessels to regrow. They placed these nanomedicines in a scaffold that could be implanted into a defect site and deliver the genetic cargo into infiltrating host cells. The gene-loaded scaffold accelerated bone tissue regeneration, with a six-fold increase in new bone formation compared to a scaffold alone.
“With the success of the COVID-19 vaccines, the potential of gene therapies is becoming apparent, and advanced nanoparticle delivery systems are key to enabling their use clinically. We have shown that these nanoparticles have real potential to be a game changer in the delivery of gene therapies,” said Professor Sally-Ann Cryan, the study’s senior author and Professor of Drug Delivery, RCSI.
“While more testing is needed before these therapies can be used clinically, our platform allows us to design our polypeptides to meet a variety of delivery scenarios and provide tailored solutions to gene delivery challenges,” added Professor Andreas Heise, project collaborator and Professor of Polymer Chemistry, RCSI.
“We are developing this patent-protected technology towards commercialisation, with support from an Enterprise Ireland Commercialisation Fund Award, and are seeking expressions of interest from industry partners and investors.”
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New research shows transmission of the virus behind COVID-19 varies seasonally, but warmer conditions are not enough to prevent transmission.
The study, led by Imperial College London researchers and published today in Proceedings of the National Academy of Sciences, is the first to incorporate environmental data into epidemiological models of the transmission of SARS-CoV-2, the virus behind COVID-19.
The team show that temperature and population density are the most important factors determining how easily the virus spreads, but only in the absence of mobility-restricting measures, such as lockdowns.
First author of the study Dr Tom Smith, from the Department of Life Sciences at Imperial, said: “Our results show that temperature changes have a much smaller effect on transmission than policy interventions, so while people remain unvaccinated, governments mustn’t drop policies like lockdowns and social distancing just because a seasonal change means the weather is warming up.
“However, our work also suggests that lower autumn and winter temperatures may lead to the virus spreading more easily in the absence of policy interventions or behavioural changes.”
Quantifying seasonal variation
Seasonal variation has been a source of uncertainty in forecasts of SARS-CoV-2 transmission. Other viruses, like flu viruses and other coronaviruses, are known to be affected by environmental factors. For example, high temperatures and low humidity reduce the transmission of respiratory droplets, preventing the spread of flu. High temperatures are also known to inactivate other coronaviruses in the air and on surfaces.

A joint research project based in Kumamoto University, Japan has developed a new, highly sensitive analytical method that can detect degraded β-lactam antibacterial agents used in the treatment of bacterial infections. With this method, researchers found that reactive sulfur species produced by bacteria degrade and inactivate β-lactam antibiotics.
Bacteria are different from animal cells in that their outer layer is covered with a rigid structure called a cell wall. β-lactam antimicrobial agents interfere with the processes that form the cell wall. This results in bacteria no longer being able to withstand their own internal pressure so they rupture and die. β-lactam antimicrobial agents are very potent because they selectively inhibit bacterial cell wall synthesis and have few side effects on hosts such as humans. These antimicrobial agents have a common structure called the β-lactam ring that is essential for inhibiting cell wall development. If this ring is degraded, the antimicrobial effect disappears.
Previous studies have reported that hydrogen sulfide (H2S), which bacteria produce during sulfur metabolism, reduces their susceptibility to antimicrobial agents leading to resistance. However, the detailed mechanism causing this are not yet understood. Researchers at Kumamoto University previously showed that the molecule cysteine persulfide, a combination of H2S and the amino acid cysteine, has an extremely potent antioxidant effect that is not found in H2S or cysteine alone.
In this study, researchers examined how this reactive sulfur species is involved in the acquisition of resistance to β-lactam antibiotics. They discovered that β-lactam antibiotics such as penicillin G, ampicillin, and meropenem (carbapenem antibiotics) rapidly lose bactericidal activity when exposed to cysteine persulfide but not with hydrogen sulfide. A detailed study of the reaction between β-lactam antimicrobial agents and cysteine persulfide revealed that the β-lactam ring, which is essential for bactericidal action, decomposes and a sulfur atom is inserted into part of the ring creating carbothioic acid. The production of carbothioic acid from a β-lactam antimicrobial agent appears to be a novel degradation metabolite.
Researchers thus developed a highly sensitive analytical method to detect and quantify carbothioic acid using mass spectrometry, and then analyzed carbothioic acid production from bacteria that were exposed to β-lactam antimicrobials. They found that bacteria can absorb antimicrobial agents and use cysteine persulfide to degrade the agents into carbothioic acid which is then discharged. This is believed to be a previously undescribed inactivation and degradation mechanism of β-lactam antimicrobial agents into carbothioic acid by cysteine persulfide.
“Our newly developed analytical method makes it possible to quantify the amount of carbothioic acid discharged from bacteria with high sensitivity,” said Professor Tomohiro Sawa, who led the study. “We believe it will be possible to screen for compounds that inhibit bacterial synthesis of cysteine persulfide by using carbothioic acid as a biomarker. Such a cysteine persulfide synthesis inhibitor in combination with β-lactam antibiotics is expected to inhibit antibiotic degradation and result in successful treatments with a lower concentration of β-lactam antibiotics. This should also help to reduce the emergence of new resistant bacteria.”
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Language is one of our species’ most important skills, as it has enabled us to occupy nearly every corner of the planet. Among other things, language allows indigenous societies to use the biodiversity that surrounds them as a “living pharmacy” and to describe the medicinal properties of plants. Linguists estimate that there are nearly 7,400 languages in the world today.
Most of these languages, however, are not recorded in writing, and many languages are not being passed on to the next generation. This has led linguists to estimate that 30 percent of all languages will disappear by the end of the 21st century. For indigenous cultures who mostly transmit knowledge orally, this high risk of language extinction also threatens their knowledge of medicinal plants.
Threatened languages support most of unique knowledge
Researchers from the University of Zurich have now assessed the degree to which indigenous knowledge of medicinal plants is linked to individual languages. Senior researcher Rodrigo Cámara-Leret and Jordi Bascompte, professor of ecology, analyzed 3,597 medicinal species and 12,495 medicinal applications associated with 236 indigenous languages in North America, northwest Amazonia and New Guinea. “We found that more than 75 percent of all medicinal plant services are linguistically-unique and therefore only known to one language,” Cámara-Leret points out.
To quantify how much of this linguistically-unique knowledge may vanish as languages or plants go extinct, the researchers turned to the Glottolog catalogue of the world’s languages and the IUCN Red List of Threatened Species to gain information on the threat to languages and medicinal plant species, respectively. They found that threatened languages support over 86 percent of all unique knowledge in North America and Amazonia, and 31 percent of all unique knowledge in New Guinea. By contrast, less than 5 percent of medicinal plant species were threatened.
International Decade of Indigenous Languages
The findings of this study indicate that each indigenous language provides unique insights into the medicinal applications associated with biodiversity. Unfortunately, the study suggests that language loss will be even more critical to the extinction of medicinal knowledge than biodiversity loss. The study coincides with the United Nations proclaiming the next 10 years as the International Decade of Indigenous Languages to raise global awareness of the critical situation of many indigenous languages. “The next steps, in line with the vision of the UN, will require mobilizing resources for the preservation, revitalization and promotion of these threatened languages,” Bascompte says. Additionally, launching large-scale community-based participatory efforts will be crucial to document endangered medicinal knowledge before it vanishes.
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