Culture

(Philadelphia, PA) - The human heart works under high demand, constantly pumping oxygen-rich blood through the body. When faced with disease, however, fulfilling this demand can become increasingly difficult and harmful. In the case of chronic high blood pressure - a leading cardiovascular disease in the United States - the heart continuously overexerts, resulting in maladaptive growth and, ultimately, severe dysfunction of the heart muscle itself.

Maladaptive growth of the heart, known as cardiac hypertrophy, is brought about in part by activation of G protein-coupled kinase 5 (GRK5), a signaling molecule found within heart cells that previously has been linked to worsened cardiac function in heart failure. Researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) now show for the first time in animals that keeping GRK5 out of the heart cell nucleus, the compartment that houses the cell's genes, can block this abnormal growth process.

The new findings, published online March 30 in the journal Science Signaling, open exciting avenues for the development of GRK5-based therapies to prevent heart failure, a disease in which the heart is no longer able to pump blood through the body. Heart failure typically develops after years of the heart compensating for the effects of high blood pressure.

"GRK5 acts as a pathological gene regulator in the heart, with its activity specifically in the heart cell nucleus being a major factor driving cardiac hypertrophy in heart failure," explained Walter J. Koch, PhD, W.W. Smith Endowed Chair in Cardiovascular Medicine, Professor and Chair of the Department of Pharmacology, Director of the Center for Translational Medicine at LKSOM, and senior investigator on the new study.

GRK5 normally hangs out in the cell membrane. But in the heart, in response to hypertrophic stress, it translocates to the nucleus, binds to certain factors that regulate genes, and thereby triggers the production of proteins involved in tissue growth.

To assess the possibility of preventing this GRK5-driven abnormal growth of heart tissue, Dr. Koch's team developed a novel peptide molecule that encodes a portion of the GRK5 molecule involved in nuclear translocation. The peptide, named GRK5nt, inhibited GRK5 entry into the nucleus, blocking its growth-signaling capabilities.

Dr. Ryan C. Coleman, a former graduate student in the Koch laboratory and first author on the report, carried out initial experiments with peptide in heart cells cultured in vitro. These experiments showed that the peptide's expression attenuates the activation of genes involved in maladaptive stress responses. In vitro studies further confirmed that GRK5nt works by binding to and occupying a portion of the GRK5 molecule known as the calmodulin (CaM) domain, which GRK5 otherwise depends on to gain entry into the nucleus.

The researchers next tested the effects of nuclear targeting in a mouse model in which animals were engineered to express GRK5nt in the heart. Some animals further underwent surgical aortic constriction, a procedure that mimics pressure overload in the human heart. Relative to animals with normal GRK5, those expressing GRK5nt exhibited reduced maladaptive effects, including reduced hypertrophy, in response to pressure overload.

"The reduction in pathological signaling provides new insights into the possibility of designing therapies to specifically target the pathological nuclear signaling of GRK5, while preserving normal GRK5 function in other tissues," Dr. Coleman said.

"The findings are very exciting, since they show that by keeping GRK5 out of the nucleus, we can stop abnormal growth and progression of heart failure," Dr. Koch added.

Now with proof-of-principle that nuclear targeting can eliminate the pathological effects of GRK5, Dr. Koch and colleagues plan next to test their strategy in an animal model of heart failure. In preparation for therapeutic testing, they also plan to explore mechanisms for targeted delivery of the peptide to the heart.

Mount Sinai researchers have found that a widely available and inexpensive drug targeting inflammatory genes has reduced morbidity and mortality in mice infected with SARS-CoV-2, the virus that causes COVID-19. In a study published today in the journal Cell, the team reported that the drug, Topotecan (TPT), inhibited the expression of inflammatory genes in the lungs of mice as late as four days after infection, a finding with potential implications for treatment of humans.

"So far, in pre-clinical models of SARS-CoV-2, there are no therapies--either antiviral, antibody, or plasma--shown to reduce the SARS-CoV-2 disease burden when administered after more than one day post-infection" says senior author Ivan Marazzi, PhD, Associate Professor of Microbiology at the Icahn School of Medicine at Mount Sinai. "This is a huge problem because people who have severe COVID19 and get hospitalized, often do not present symptoms until many days after infection. We took a different approach, and sought to find a potential therapy that can be used during later stages of the disease. We found that the TOP1 inhibitors given days after the infection can still limit the expression of hyper-inflammatory genes in the lungs of infected animals and improve infection outcomes." Moreover, says Dr. Marazzi, topotecan (TPT), an FDA-approved Topoisomerase I (TOP1) inhibitor, as well as its derivatives, are inexpensive clinical-grade inhibitors available in most countries around the world for use as antibiotic and anti-cancer agents.

Although the pathophysiology of SARS-CoV-2 is not yet fully understood, scientists have observed that the virus triggers excess production of cytokines and chemokines--chemicals which are secreted by cells of the immune system to help fight infection. An exaggerated immune system response, which characteristically occurs in the lungs of COVID-19 patients, can flood the infected area with white blood cells, resulting in inflammation, possible tissue damage, organ failure, and death. Reduction of the inflammatory state in such patients could therefore improve their clinical outcomes.

In a previous study published in Science in 2016, the same group at Mount Sinai found that inhibiting the activation of inflammatory genes could help prevent animal deaths from viral and bacterial infections and suggested this could be a potent strategy against future pandemics. The current study, led by Mount Sinai along with partners from Singapore, Hong Kong, the United Kingdom, the United States, and other global sites, expands on that earlier work to show how epigenetic therapy (which addresses the chemical modifications that influence gene expression) could be harnessed against severe cases of COVID-19.

The team's research suggests that many other anti-inflammatory agents are less effective against COVID-19 because they target only a single inflammatory mediators, such as IL6 or IL1, or a specific gene expression program. "The fact is, a multitude of inflammatory genes and signaling pathways are dysregulated during a SARS-CoV-2 infection," explained lead author Jessica Sook Yuin Ho, PhD, a postdoctoral researcher at Icahn Mount Sinai. "We demonstrated that TOP1 inhibitors were able to broadly or systemically dampen inflammatory gene expression in animal models, regardless of the gene or activation pathway."

Co-author Mikhail Spivakov, PhD, head of the Functional Gene Control group at the MRC London Institute of Medical Sciences added, "We found that infection prompts extensive changes in the 3D connections between inflammatory genes and the 'molecular switch' regions that control their expression. This may partially explain why inhibiting topoisomerase, a protein that helps reshape DNA, helps dampen the cells' hyper-inflammatory response."

The safety and efficacy of this treatment strategy in humans will soon be evaluated at clinical sites around the world, including India, where a trial recently began and Singapore, where the National Medical Research Council of Singapore has also funded a phase 1 clinical trial of topoisomerase 1 inhibition in COVID-19. The World Health Organization (WHO) is also expected to play an important role in subsequent studies.

"Findings from our work suggest that repurposing the TOP1 inhibitor could be a valuable global strategy for treating severe cases of COVID-19," emphasizes Dr. Marazzi. "Particularly attractive is the fact that TPT is already FDA-approved and that its derivatives are inexpensive, with generic formulations existing throughout the world. This makes these drugs readily accessible and available for immediate use in both developing and developed countries across the world."

Research into the diets of a large number of the world's carnivores has been made publicly available through a free, online database created by a PhD student at the University of Sussex.

From stoats in the UK to tigers in India, users are now able to search for detailed information about the diets of species in different geographical locations around the globe.

Created by doctoral student Owen Middleton, CarniDIET is an open-access database which aims to catalogue the diets of the world's carnivores by bringing together past peer-reviewed research. He hopes it will be a useful resource for conservationists and researchers, as well as educators and nature-lovers alike.

Owen said: "There is so much information out there that is useful for conservation, but much of it isn't digitized, or it may be difficult for people to access.

"Typically, anybody interested in species' diets would have to go through an extensive body of literature, but through CarniDIET, there's now an easy way to access this information with all the original references cited."

The main purpose of CarniDIET is to facilitate further conservation research by providing a place to easily access data describing the ecological requirements and ecological effects of many endangered species, which can vary across their geographic ranges.

However, there are also hopes that the tool can be more widely used by teachers, students and citizen scientists.

Owen said: "Species diets can vary massively geographically and CarniDIET is a really easy way to find out how the diet of a red fox might be different in the UK compared to China, or how the diets of lions and leopards differ.

"Users can search by a particular species or country, and simply click on an interactive map of the world to find out what carnivores eat in that area.

"It will be invaluable for younger school students learning about the food chain, or older students delving into a bit more depth about endangered species or working on geographical case studies."

Dr Chris Sandom, Senior Lecturer in Biology at the University of Sussex, added: "CarniDIET is a really exciting new tool for conservationists, researchers and educators.

"Understanding the diets of animals is hugely important for conservation; you can't protect animals in isolation, they're connected in food webs. If prey species are under threat or have dwindling numbers, it will have a knock-on effect on their predators, and leave those species threatened too.

"CarniDIET will be a useful tool to help demonstrate this by clearly showing which prey species carnivores are eating, and to an extent, are reliable on in particular geographical locations."

LOWELL, Mass. - Too often, contends UMass Lowell faculty researcher Brenna Morse, children with complex chronic medical conditions spend days in the hospital undergoing tests for what could be a simple diagnosis.

The challenges include, she says, some children with medical complexities, such as severe neurological conditions and functional impairments, cannot easily signal that they are in pain or point where in their body it is located. Where children not facing such a challenge might be able to have a medical issue resolved with a simple visit to their primary care doctor, others end up hospitalized and going through days of costly testing to arrive at similar diagnoses.

Morse, a UMass Lowell graduate and current nurse of children with complex conditions who has been a faculty member in the Solomont School of Nursing since 2015, and a team of researchers from Boston Children's Hospital have developed a method through which health-care providers can more readily identify the medical issue being experienced by a child who cannot communicate it on their own. Called GRASP (which stands for Guidelines for Ruling out and Assessing Pain), the tool allows providers to more efficiently evaluate pain among children who cannot easily communicate they are in pain or indicate the pain location. The big takeaway, Morse says, is that the method can help find the source of pain in a patient among a population of children who experience pain that is more intense and frequent than others, and therefore help treat it more readily.

"We're hoping this can be a tool to help children avoid long hospitalizations," said Morse. "We can find [the problem] and treat it and improve their life, avoid prolonged pain, surgeries, and perhaps save them."

Morse and the team developed GRASP through almost a decade of research, beginning when Morse was earning her Ph.D. and continuing through her work as an academic researcher. The Children's Hospital researchers who collaborated with Morse include Jean Solodiuk (nurse manager and scientist, Department of Anesthesiology, Critical Care and Pain Medicine), Christine Greco (acting chief, Division of Pain Medicine), Sangeeta Mauskar (director, Complex Care Inpatient Program) and Julie Hauer (complex care and pediatric palliative care physician).

"In my experience as a physician, taking care of kids with complexity and multisystem involvement, dealing with pain in a nonverbal child is one of toughest clinical dilemmas. The creation of the GRASP tool has given us a systematic approach for pain work-up. I am hoping that with the use of this tool for work-up, we will have a thoughtful approach for pain work-up and in turn will have less burden on families in the long run," said Mauskar.

The research included surveys and focus groups to develop the tool and help determine how accessible and effective GRASP could be for health-care providers. The most recently completed parts of the project were funded by a UMass Lowell seed grant.

The results were recently published in Hospital Pediatrics, a journal by the American Academy of Pediatrics. Morse's goal, she says, is to see more providers trained in using GRASP so that more children with complex conditions may have their pain adequately addressed so that they may be well and enjoying time with their families, in school and in their own community instead of in the hospital.

"First-person accounts of symptoms are an important part of diagnosing because they guide the physical exam and evaluation. Children with medical complexity often cannot communicate their account of symptoms because of neurologic conditions and functional impairments. GRASP is a checklist developed for children with medical complexity that guides clinicians to consider a comprehensive list of differential diagnoses with suggestions of further evaluation if needed," said Solodiuk. "GRASP has the potential to improve diagnostic accuracy in children with medical complexity and decrease the time it takes to identify the cause of the pain."

Giant trees in tropical forests, witnesses to centuries of civilization, may be trapped in a dangerous feedback loop according to a new report in Nature Plants from researchers at the Smithsonian Tropical Research Institute (STRI) in Panama and the University of Birmingham, U.K. The biggest trees store half of the carbon in mature tropical forests, but they could be at risk of death as a result of climate change--releasing massive amounts of carbon back into the atmosphere.

Evan Gora, STRI Tupper postdoctoral fellow, studies the role of lightning in tropical forests. Adriane Esquivel-Muelbert, lecturer at the University of Birmingham, studies the effects of climate change in the Amazon. The two teamed up to find out what kills big tropical trees. But as they sleuthed through hundreds of papers, they discovered that nearly nothing is known about the biggest trees and how they die because they are extremely rare in field surveys.

"Big trees are hard to measure," said Esquivel-Muelbert. "They are the pain in a field campaign because we always have to go back with a ladder to climb up to find a place to measure the circumference above the buttresses. It takes a long time. Studies focusing on the reasons trees die don't have enough information for the biggest trees and often end up excluding them from their analysis."

"Because we generally lack the data necessary to tell us what kills trees that are above approximately 50 centimeters in diameter, that leaves out half of the forest biomass in most forests," Gora said.

Only about 1% of trees in mature tropical forests make it to this size. Others wait their turn in the shade below.

The other thing that makes tropical forests so special--high biodiversity--also makes it difficult to study big trees: There are so many different species, and many of them are extremely rare.

"Because only 1-2% of big trees in a forest die every year, researchers need to sample hundreds of individuals of a given species to understand why they are dying," Gora said. "That may involve looking for trees across a huge area."

Imagine a study of blood pressure in people who have lived to be 103. One would have to locate and test seniors from cities and towns around the world: a time-consuming, logistically complex and expensive proposition.

A large body of evidence shows that trees are dying faster in tropical forests than ever before. This is affecting the ability of forests to function and in particular, to capture and store carbon dioxide.

"We know the deaths of largest and oldest trees are more consequential than the death of smaller trees," Gora said. "Big trees may be at particular risk because the factors that kill them appear to be increasing more rapidly than the factors that seem to be important for smaller-tree mortality."

In large parts of the tropics, climate change is resulting in more severe storms and more frequent and intense droughts. Because big trees tower above the rest, they may be more likely to be hit by lightning, or damaged by wind. Because they have to pull ground water higher than other trees, they are most likely to be affected by drought.

Hoping to better understand what is happening to big trees, Gora and Esquivel-Muelbert identified three glaring knowledge gaps. First, almost nothing is known about disease, insects and other biological causes of death in big trees. Second, because big trees are often left out of analyses, the relationship between cause of death and size is not clear. And, finally, almost all of the detailed studies of big tropical trees are from a few locations like Manaus in Brazil and Barro Colorado Island in Panama.

To understand how big trees die, there is a trade-off between putting effort into measuring large numbers of trees and measuring them often enough to identify the cause of death. Gora and Esquivel-Muelbert agree that a combination of drone technology and satellite views of the forest will help to find out how these big trees die, but this approach will only work if it is combined with intense, standardized, on-the-ground observations, such as those used by the Smithsonian's international ForestGEO network of study sites.

Esquivel-Muelbert hopes that the impetus for this research will come from a shared appreciation for these mysterious living monuments:

"I think they are fascinating to everyone," she said. "When you see one of those giants in the forest, they are so big. My colleague and Amazonian researcher, Carolina Levis, says that they are the monuments we have in the Amazon where we don't have big pyramids or old buildings....That is the feeling, that they have been through so much. They are fascinating, not just in the scientific sense but also in another way. It moves you somehow."

Researchers at Washington University in St. Louis reported the first observations of a new form of fluorine, the isotope 13F, described in the journal Physical Review Letters.

They made their discovery as part of an experiment conducted at the National Superconducting Cyclotron Laboratory at Michigan State University (MSU).

Fluorine is the most chemically reactive element on the periodic table. Only one isotope of fluorine occurs naturally, the stable isotope 19F. The new isotope, 13F, is four neutrons removed from the proton drip line, the boundary that delimits the zone beyond which atomic nuclei decay by the emission of a proton.

Robert J. Charity, research professor of chemistry in Arts & Sciences, and Lee G. Sobotka, professor of chemistry and of physics, worked in collaboration with groups from MSU, Western Michigan University and University of Connecticut to make this discovery.

"Study of exotic nuclei with such large excesses of neutrons or protons is of considerable interest in understanding the synthesis of elements, even though their lifetimes are extremely short," Charity said. "Many of these isotopes have exotic properties."

The isotope 13F is the fifth new isotope that Charity and Sobotka have discovered together.

"All the new isotopes are very proton-rich and unstable to the emission of protons," Charity said. "The highest-energy protons inside these isotopes can tunnel through the Coulomb barrier and escape."

The initial purpose of the experiment, Charity said, was to make a new isotope of oxygen, dubbed "featherweight oxygen," a technical achievement previously reported in Physical Review Letters. After making that discovery, the researchers went through their data again with great care and teased out evidence for 13F.

The new isotope of fluorine was created via a charge-exchange reaction with a beam of 13O. (A neutron in the 13O is removed and replaced by a proton.)

"Such charge-exchange reactions have not typically been used for the creation of the very proton-rich isotopes in the past," Charity said. "However, we are already planning a search for another new isotope using this reaction mechanism."

CAMBRIDGE, MA -- More than just a sign of illness, mucus is a critical part of our body's defenses against disease. Every day, our bodies produce more than a liter of the slippery substance, covering a surface area of more than 400 square meters to trap and disarm microbial invaders.

Mucus is made from mucins -- proteins that are decorated with sugar molecules. Many scientists are trying to create synthetic versions of mucins in hopes of replicating their beneficial traits. In a new study, researchers from MIT have now generated synthetic mucins with a polymer backbone that more accurately mimic the structure and function of naturally occurring mucins. The team also showed that these synthetic mucins could effectively neutralize the bacterial toxin that causes cholera.

The findings could help give researchers a better idea of which features of mucins contribute to different functions, especially their antimicrobial functions, says Laura Kiessling, the Novartis Professor of Chemistry at MIT. Replicating those functions in synthetic mucins could eventually lead to new ways to treat or prevent infectious disease, and such materials may be less likely to lead to the kind of resistance that occurs with antibiotics, she says.

"We would really like to understand what features of mucins are important for their activities, and mimic those features so that you could block virulence pathways in microbes," says Kiessling, who is the senior author of the new study.

Kiessling's lab worked on this project with Katharina Ribbeck, the Mark Hyman, Jr. Career Development Professor of Biological Engineering, and Richard Schrock, the F.G. Keyes Professor Emeritus of Chemistry, who are also authors of the paper. The lead authors of the paper, which appears today in ACS Central Science, are former MIT graduate student Austin Kruger and MIT postdoc Spencer Brucks.

Inspired by mucus

Kiessling and Ribbeck joined forces to try to create mucus-inspired materials in 2018, with funding from a Professor Amar G. Bose Research Grant. The primary building blocks of mucus are mucins -- long, bottlebrush-like proteins with many sugar molecules called glycans attached. Ribbeck has discovered that these mucins disrupt many key functions of infectious bacteria, including their ability to secrete toxins, communicate with each other, and attach to cellular surfaces.

Those features have led many scientists to try to generate artificial versions that could help prevent or treat bacterial infection. However, mucins are so large that it has been difficult to replicate their structure accurately. Each mucin polymer has a long backbone consisting of thousands of amino acids, and many different glycans can be attached to these backbones.

In the new study, the researchers decided to focus on the backbone of the polymer. To try to replicate its structure, they used a reaction called ring-opening metathesis polymerization. During this type of reaction, a carbon-containing ring is opened up to form a linear molecule containing a carbon-carbon double bond. These molecules can then be joined together to form long polymers.

In 2005, Schrock shared the Nobel Prize in Chemistry for his work developing catalysts that can drive this type of reaction. Later, he developed a catalyst that could yield specifically the "cis" configuration of the products. Each carbon atom in the double bond usually has one other chemical group attached to it, and in the cis configuration, both of these groups are on the same side of the double bond. In the "trans" configuration, the groups are on opposite sides.

To create their polymers, the researchers used Schrock's catalyst, which is based on tungsten, to form cis versions of mucin mimetic polymers. They compared these polymers to those produced by a different, ruthenium-based catalyst, which creates trans versions. They found that the cis versions were much more similar to natural mucins -- that is, they formed very elongated, water-soluble polymers. In contrast, the trans polymers formed globules that clumped together instead of stretching out.

Mimicking mucins

The researchers then tested the synthetic mucins' ability to mimic the functions of natural mucins. When exposed to the toxin produced by Vibrio cholerae, the elongated cis polymers were much better able to capture the toxin than the trans polymers, the researchers found. In fact, the synthetic cis mucin mimics were even more effective than naturally occurring mucins.

The researchers also found that their elongated polymers were much more soluble in water than the trans polymers, which could make them useful for applications such as eye drops or skin moisturizers.

Now that they can create synthetic mucins that effectively mimic the real thing, the researchers plan to study how mucins' functions change when different glycans are attached to the backbones. By altering the composition of the glycans, they hope to develop synthetic mucins that can dampen virulence pathways of a variety of microbes.

"We're thinking about ways to even better mimic mucins, but this study is an important step in understanding what's relevant," Kiessling says.

A study conducted at the University of Campinas (UNICAMP) in the state of São Paulo, Brazil, shows that compounds produced by gut microbiota (bacteria and other microorganisms) during fermentation of insoluble fiber from dietary plant matter do not affect the ability of the novel coronavirus SARS-CoV-2 to enter and replicate in cells lining the intestines. However, while in vitro treatment of cells with these molecules did not significantly influence local tissue infection, it reduced the expression of a gene that plays a key role in viral cell entry and a cytokine receptor that favors inflammation.

An article reporting the findings is published in the journal Gut Microbes.

Up to 50% of COVID-19 patients experience gastrointestinal symptoms such as diarrhea, vomiting, and abdominal pain. Such symptoms are detected in 17.6% of severe cases. They are partly associated with viral entry into intestinal cells resulting in alterations to their normal functions. In addition, recent studies point to major changes in patients’ gut microbiota, including a decrease in levels of bacteria that secrete short-chain fatty acids (SCFAs) by fermenting dietary fiber. SCFAs are important to colon health and maintenance of intestinal barrier integrity.

The researchers decided to confirm whether SFCAs directly affected the infection of intestinal cells by SARS-CoV-2. Previous studies had suggested alterations in gut microbiota and its products could modify an infected subject’s immune response.

“In earlier research, we found in animals that compounds produced by gut microbiota help protect the organism against respiratory infection. The model used there was respiratory syncytial virus [RSV], which causes bronchiolitis [inflammation of the small airways in the lung] and frequently infects children. Similar results have been obtained by other research groups in studies of different respiratory diseases,” said Patrícia Brito Rodrigues, who has a doctoral scholarship from FAPESP and is joint first author of the article with postdoctoral fellow Livia Bitencourt Pascoal. Rodrigues conducted the research as part of her doctorate at UNICAMP’s Institute of Biology (IB) with a scholarship from FAPESP.

In the latest study, healthy colon tissue and epithelial cells were infected with SARS-CoV-2 in the laboratory and subjected to a battery of tests.

“Viral load wasn’t reduced and was the same in cells and tissue treated with SCFAs and in untreated samples. However, treated intestinal biopsy samples displayed a significant decrease in expression of the gene DDX58 [an innate immune system receptor that detects viral nucleic acids and activates a signaling cascade that results in production of pro-inflammatory cytokines] and the interferon-lambda receptor, which mediates anti-viral activity. There was also a decrease in expression of the protein TMPRSS2, which is important to viral cell entry,” said Raquel Franco Leal, a professor at UNICAMP’s School of Medical Sciences (FCM), supported by FAPESP and co-principal investigator for the study with Marco Aurélio Ramirez Vinolo, a professor at IB-UNICAMP, also supported by FAPESP.

Protection against inflammation

The researchers took colon tissue samples from 11 patients without COVID-19. They also tested epithelial cells that line the intestines and are in close contact with gut microbiota. Tissue and cell samples were infected with SARS-CoV-2 in IB-UNICAMP’s Laboratory of Emerging Virus Studies (LEVE), a Biosafety Level III (BSL-3) facility led by José Luiz Proença Módena, a professor at IB-UNICAMP and a co-author of the article.

The tissues and cells were treated with a mixture of acetate, propionate and butyrate, compounds produced by gut microbiota metabolization of SCFAs present in dietary fiber. The treatment did not alter viral load in colon biopsies or cells, nor were there any changes in cell wall permeability and integrity.

“That doesn’t exclude the possibility of significant action by SCFAs on infection by SARS-CoV-2. The anti-viral effects could depend on interaction with other cells in the organism,” Rodrigues said. “We’ll continue our investigation in animal models since the action of these compounds on the infection could depend on a more complete system than the samples we used in vitro [isolated cells and tissues].”

Other tests involving non-treated infected biopsy samples showed an increase in expression of the gene DDX58, which encodes an important viral receptor, and of interferon-beta (IFN-beta), a pro-inflammatory molecule that participates in the cytokine storm associated with severe cases of COVID-19.

“Alterations in genes associated with virus recognition and response during intestinal infection may be relevant to the onset of the inflammatory chain,” Leal said. “In this context, it will be important to deepen the analysis of the effects of SCFAs with these parameters, as this could be significant in severe stages of the disease.”

Twenty percent of high school students have easy access to a handgun, according to a new study from the Colorado School of Public Health on the University of Colorado Anschutz Medical Campus.

In the study published today in The Journal of Pediatrics, the researchers examined the prevalence of handgun access among adolescents in Colorado and explored individual and geographic characteristics, as well as related health factors.

"Our findings highlight that it is relatively easy to access a handgun in Colorado for high school students. This finding, combined with the high prevalence of feeling sad or depressed and suicide attempts, is concerning for the safety of adolescents," said lead author Ashley Brooks-Russell, PhD, MPH, assistant professor in the Colorado School of Public Health.

The researchers examined data from more than 46,000 students who completed the Healthy Kids Colorado Survey, a voluntary statewide anonymous survey given to students in participating schools across Colorado. The survey results are used to assess health behaviors, risk and protective factors. In this study, the researchers reviewed survey questions about the perception of access to handguns.

They found that students were significantly more likely to report easy handgun access if they felt sad or hopeless almost every day for two weeks (24.2%), had attempted suicide (30.1%) or had been in a physical fight in the past 12 months (31.8 %).

The survey data also revealed:

More male than female high school students reported handgun access.

A significantly higher proportion of transgender youth reported access.

Students in more rural areas are more likely to have access.

American Indian, multiracial students, followed by white students, access to handguns was significantly higher than among Hispanic, Black or African American or Asian American students.

"It's clear from our findings that we need to raise awareness and improve efforts to reduce firearm access for youth in Colorado to prevent suicide and fatal injuries," said Brooks-Russell. "We hope our findings will help inform public health strategies, such as educating parents on the importance of secure home firearm storage, particularly if an adolescent is at risk for suicide."

Recently, Colorado lawmakers advanced the Safe Storage of Firearms bill to require Colorado gun owners who share their homes with children to securely store their weapons. It passed its first committee on a party line vote.

There are also several gun shops and law enforcement agencies in Colorado that offer out-of-home gun storage options, if home gun storage is not a viable option. Faculty members at the Colorado School of Public Health announced the first out-of-home gun storage map in the country.

The researchers recommend future studies to explore where students access guns (at home or outside their house) and to look at their attempts to access them.

In a new publication in Nature Communications, associate professor of Plant Science at the University of Maryland Yiping Qi continues to innovate genome editing and engineering in plants, with the ultimate goal of improving the efficiency of food production. His recent work contributes six novel variants of CRISPR-Cas12a that have never before been proven in plants, testing them first in rice as a major global crop. In addition to allowing for a much broader scope of possible gene editing targets, these new tools can edit many different sites in the genome at once, or even repress gene expression to tone down undesirable traits. These patent-pending tools greatly expand the scope of what CRISPR-Cas12a can do in plants, which can help to produce food more effectively to feed a growing global population.

"We are excited about this paper because we've contributed two major breakthroughs," says Qi. "First, we've reported multiple Cas12a tools with genome editing capabilities in plants for the first time, and found one [Mb2Cas12a] that hugely broadens the targeting range of Cas12a. Second, we've developed a very efficient system that can edit many different sites at once [multiplexed editing], and that allows us to edit 16 different genes in rice in a single generation."

As Qi explains, Cas12a (like other CRISPR systems) has typically been tied to targeting a specific short sequence of DNA known as a PAM sequence. The PAM sequence is what CRISPR systems typically use to identify where to possibly make their molecular cuts in DNA. However, the new Mb2Cas12a variant introduced by Qi works under relaxed PAM requirements, broadening the scope of what can be targeted for editing the way Qi's lab recently did for CRISPR-Cas9.

In addition to this discovery, the multiplexed editing system introduced for Cas12a in plants provides specific strategies for efficiently editing multiple sites across the genome all at once. For this proof-of-concept, Qi's team first targeted six different sites in the genome to enhance rice yield and disease resistance. But when this was successful, the team didn't stop there.

"I wanted to add more targets to see if there is any limit," explains Qi. "So we added 10 more and tried to target 16 sites, and we found that across almost all rice chromosomes, we had an amazingly high efficiency with all sites being edited all at once in one generation. And that doesn't even represent the upper limit necessarily, but it is the most genes in a plant that has ever been recorded as being edited all at once in one generation for Cas12a."

This system has major implications for precision breeding and the efficiency of food production, says Qi. "For precision breeding, how many genes you can edit at once is really practically important because you can target almost anything and really tailor the product. We targeted disease resistance and yield, but you can add more traits like nitrogen use efficiency, climate resilience traits such as temperature tolerance, and more. It is really a robust system."

Qi is currently doing work to examine the off-targeting effects of editing more genes at once with more relaxed target site requirements. But in addition to these contributions, this paper also demonstrated Cas12a's utility as a synthetic repressor of genes in the model plant Arabidopsis as another tool for genome engineering.

"You can regulate activation or repression of certain genes by using CRISPR not as a cutting tool, but instead as a binding tool to attract activators or repressors to induce or suppress gene expression to engineer desirable traits. In this case, Cas12a is acting as glue, not as scissors. You use an inactivated form of Cas12a to inactivate the expression of other genes. It's a great new tool for the industry and for future research."

Future work will expand these tools out of rice and Arabidopsis, and into all kinds of plants and crops. "This type of technology helps increase crop yield and sustainably feed a growing population in a changing world," says Qi. "I am very pleased to continue to expand the impacts of CRISPR technologies."

-- Black middle-aged adults had an incidence rate of stroke 4 times higher than that of white middle-aged adults, according to a Kaiser Permanente study published March 29 in Hypertension.

The large national prospective study highlights the need to raise awareness among young and middle-aged Black adults about the impact of high blood pressure, called hypertension, on stroke, the research team said.

"What we found striking in this study was that the incidence of stroke began to increase rapidly starting at around age 40 for Black adults," said the study's co-author Jamal S. Rana, MD, PhD, an adjunct investigator with the Division of Research at Kaiser Permanente in Northern California, and cardiologist with The Permanente Medical Group. "It is well known that Black adults have higher rates of hypertension in general, but the fact that their blood pressure levels are starting to increase at such an early stage in life is concerning."

The research used data collected in the Coronary Artery Risk Development in Young Adults study. Launched in 1985, CARDIA enrolled 5,115 Black and white women and men ages 18 to 30 at research hospitals in 4 cities. Blood pressure measurements and other tests were performed when participants entered the study, and were conducted every 5 years, with 2 additional exams at years 2 and 7.

This analysis included data collected on 5,079 participants starting from 1990 through 2018. In 1990, the Black adults already had higher rates of elevated blood pressure and diagnosed hypertension than the white adults. By 2018, 100 people in the study had had a stroke, at a median age of 49.8. The stroke incidence rate was 29 per 100,000 person-years for white adults compared with 120 per 100,000 person-years for Black adults -- a rate more than 4 times higher. A person-year is a measurement that takes into account the number of people in a study and the amount of time each person spends in the study. The analysis also took into account other risk factors for stroke, such as smoking, diabetes, high cholesterol, obesity, lack of physical activity, and excessive alcohol use.

"This study confirms that it's not only whether you have high blood pressure but how long you have had high blood pressure and how long the damage to the blood vessels has been occurring that matters," said the study's senior author Stephen Sidney, MD, MPH, a research scientist at the Kaiser Permanente Division of Research. "It also tells us that interventions need to be put in place to prevent high blood pressure from ever even occurring."

The study's first author Yariv Gerber, PhD, a professor of epidemiology and head of the School of Public Health at Tel Aviv University in Israel, conducted the research while on a sabbatical at the Kaiser Permanente Division of Research. "We demonstrated that the association of high blood pressure with stroke varies with age, strengthening from young adulthood to midlife," said Dr. Gerber. "The association was also dynamic, with the most recent measurement most strongly associated with subsequent stroke risk. This stresses the need for early public health interventions to maintain optimal blood pressure levels in young adulthood, particularly in high-risk Black young adults."

Previous research suggests young adults age 18 to 39 in the United States are less aware than adults age 40 and older about what their blood pressure numbers mean and why it is important to keep blood pressure low. "Anytime you talk about abnormal blood pressure, the biggest challenge is always that people are not feeling it in real time," said Dr. Rana. "It is not until a person's blood pressure has been out of control for a prolonged period of time that they feel any symptoms. Our goal should be to have people proactively think about blood pressure control."

Despite the enormous amount of research over the decades into lasers and their applications, there have been few ways to accurately, efficiently, and directly observe fine details of their interactions with materials. For the first time, researchers have found a way to acquire such data from a production laser using low-cost equipment that could vastly improve the accuracy of items cut or etched with lasers. Given the ubiquity of lasers, this could have wide-ranging implications in laboratory, commercial and industrial applications.

Lasers are used in an extraordinarily wide range of applications in the modern world. One area in particular that is increasingly important is in manufacture, the reason being the level of precision at which a laser can operate is far greater than that of the equivalent physical tool. However, this level of precision could be even higher in theory, leading to a new generation of yet unimagined technologies. There are some hurdles to overcome, though. One significant way in which laser precision could be improved is if there was a better means to obtain feedback on the way the laser interacts with a material. That way, there would be greater control and less uncertainty in the cutting and etching actions of a production laser. This problem has proven surprisingly difficult to tackle until now.

"To measure how far into a surface a laser has cut often requires tens or hundreds of depth readings to take place. This is a substantial barrier for fast, automated laser-based production systems," said Professor Junji Yumoto from the Department of Physics at the University of Tokyo. "So we have devised a new way to determine and predict the depth of a hole produced by laser pulses based on a single observation rather than tens or hundreds. This finding is an important step forward in improving the controllability of laser processing."

Yumoto and his team wondered how to determine the depth of a laser hole using the minimal amount of information possible. This led them to look at what is known as the fluence of a laser pulse, which is the optical energy the pulse delivers over a given area. Until recently, expensive imaging apparatus would have been required to observe this fluence, and this usually lacked sufficient resolution. But thanks to developments in other areas of electronics and optics, a relatively simple Raspberry Pi Camera Version 2 proved ample for the job.

As their test laser apparatus made a hole on sapphire, the camera recorded directly the fluence distribution of a laser pulse. Then a laser microscope measured the hole shape. By superimposing these two results and using some modern numerical methods, the team produced a large and reliable data set that could accurately tell you the relation between fluence and hole depth.

"This would be correspondent with the extraction of about 250,000 data points from a single measurement," said Yumoto. "Our new method could efficiently provide big data for machine learning and new numerical simulation methods to improve the accuracy and controllability of laser processing for manufacture."

Each human being is made of billions of cells. In order to ensure his survival, cells must coordinate with each other and attach in the right place to perform their tasks. Scientists from the University of Geneva (UNIGE), Switzerland, in collaboration with the University of Tampere in Finland, have highlighted the key role of a protein called paxillin, which enables cells to perceive their environment and anchor at the right place with the help of cellular "crampons". Indeed, without functional paxillin, the cell is unable to attach properly and slips continuously. These results, to be read in the journal Communications Biology, shed new light on how cells adhere or migrate, mechanisms essential to the good functioning of our organs, but also involved in the development of metastatic tumors.

To ensure our survival, each cell performs specific functions in coordination with their neighbours. In such a dynamic system, the migration of cells and their anchoring at the right place are essential. But how do cells manage to coordinate with each other? Scientists have long believed that cells communicate mainly through chemical signals, such as hormones. However, recent discoveries suggest that mechanical signals play a major role in cell coordination. "This is why we started to study the ability of cells to decipher and respond to their physical environment", explains Bernhard Wehrle-Haller, Professor at the Department of cell physiology and metabolism at UNIGE Faculty of Medicine. "Especially as it could help us to understand how cancer cells use these mechanisms to invade other organs and form metastases."

From a mechanical cue to a biological signal

When a cell has to move, it "senses" its environment with the help of proteins on its surface, the integrins. When the cell detects a suitable location, a complex network of proteins, called focal adhesion, is then set up to form cellular crampons that anchor the cell to its environment. "But how is this anchoring mechanism regulated? This is what we wanted to find out," explains Marta Ripamonti, researcher in the laboratory of Prof. Bernhard Wehrle-Haller and first author of the study.

By studying paxillin, one of the many proteins that make up these crampons, researchers were able to unravel the mystery. "We knew that this protein played a role in the assembly of focal adhesions, but we didn't expect it to be the key regulator", says Prof. Bernhard Wehrle-Haller with enthusiasm. Without functional paxillin, cells are unable to anchor, regardless of the suitability of their environment. In addition, paxillin has also the function of informing the cell that anchoring has taken place correctly, thus transforming a mechanical response into a biological signal that the cell can understand.

Disrupting the crampons to prevent metastases?

These in vitro experiments highlight the major role of paxillin in the migration and adhesion of healthy cells, but they could also be a starting point for a better understanding of cancer development. "It is indeed likely that cancer cells use paxillin to find a place that enhance their survival. Would it be possible to block this mechanism in tumor cells and prevent the formation of metastases? Yes, we think so! " concludes Prof. Bernhard Wehrle-Haller.

Bioengineering researchers at Lehigh University have identified a previously unknown interaction between receptors in human cells and the spike, or "S," protein of SARS-CoV-2, the virus that causes COVID-19. This new information could aid in the development of new strategies to block SARS-CoV-2 entry into human cells.

X. Frank Zhang and Wonpil Im knew from recent studies that the interaction between the SARS-CoV-2 spike protein and angiotensin-converting enzyme 2 (ACE2) receptors in human cells is stronger than the interaction between the structurally identical spike protein of SARS-CoV-1, the virus that caused the 2002-2004 SARS outbreak, and the same receptors.

"Our goal was to characterize SARS-CoV-2 and study the protein-protein interactions during its invasion of human cells to provide more insights into the mechanisms that make this first step in its successful invasion process possible," says Zhang, an associate professor in Bioengineering and Mechanical Engineering & Mechanics at Lehigh.

Their findings appear in an article called "Biomechanical characterization of SARS-CoV-2 spike RBD and human ACE2 protein-protein interaction" in a special issue of Biophysical Journal, "Biophysicists Address Covid-19 Challenges I," published in mid-March. Additional authors include, from Lehigh University: Wenpeng Cao, Decheng Hou and Seonghan Kim in bioengineering; Chuqiao Dong in mechanical engineering and mechanics; and, from Lindsley F. Kimball Research Institute, New York Blood Center, Wanbo Tai and Lanying Du.

Using combined single-molecule force spectroscopy and molecular dynamics simulations, Zhang's and Im's teams were able to identify a previously unknown interaction between ACE2 glycans (sugar groups attached to the surface of proteins) and the SARS-CoV-2 spike. It is this interaction that appears to be responsible for the strengthening of the virus-cell interaction. This may partially explain the higher infection rate of COVID-19 compared to the similar virus that caused the 2002-2004 SARS outbreak, they say.

"We were surprised to find that the specific interaction between ACE2 glycans and the SARS-CoV-2 spike protein is what makes the separation of the virus from cells so difficult," says Im, who is a professor of bioengineering, computer science, chemistry and biological sciences, as well as the Presidential Endowed Chair in Health, Science and Engineering at Lehigh.

To arrive at these findings, the team employed Zhang's innovative single-molecule detection technique, measuring the detachment force of the spike protein-ACE2 receptor interaction. Using the all-atom molecular dynamics simulations of the complex system available in CHARMM-GUI developed by Im, they then identified the detailed structural information in this interaction.

"After we carefully removed all of the ACE2 glycans and measured the force of the interaction, we saw that the strength of the SARS-CoV-2 spike-ACE2 interaction fell back to levels similar to SARS-CoV-1," says Zhang.

"It is possible that this newly-discovered interaction with ACE2 glycans could be a contributing factor to the higher rates of COVID-19 than the structurally similar SARS-CoV-1, which has a weaker interaction," says Zhang. "Our hope is that researchers may be able to use this information to develop new strategies to identify, prevent, treat and vaccinate against COVID-19."

CHAMPAIGN, Ill. -- Monitoring the progression of multiple sclerosis-related gait issues can be challenging in adults over 50 years old, requiring a clinician to differentiate between problems related to MS and other age-related issues. To address this problem, researchers are integrating gait data and machine learning to advance the tools used to monitor and predict disease progression.

A new study of this approach led by University of Illinois Urbana Champaign graduate student Rachneet Kaur, kinesiology and community health professor Manuel Hernandez and industrial and enterprise engineering and mathematics professor Richard Sowers is published in the journal Institute of Electrical and Electronics Engineers Transactions on Biomedical Engineering.

Multiple sclerosis can present itself in many ways in the approximately 2 million people that it affects globally, and walking problems are a common symptom. About half of the patients need walking assistance within 15 years of onset, the study reports.

"We wanted to get a sense of the interactions between aging and concurrent MS disease-related changes, and whether we can also differentiate between the two in older adults with MS," Hernandez said. "Machine-learning techniques seem to work particularly well at spotting complex hidden changes in performance. We hypothesized that these analysis techniques might also be useful in predicting sudden gait changes in persons with MS."

Using an instrumented treadmill, the team collected gait data - normalized for body size and demographics - from 20 adults with MS and 20 age-, weight-, height- and gender-matched older adults without MS. The participants walked at a comfortable pace for up to 75 seconds while specialized software captured gait events, corresponding ground reaction forces and center-of-pressure positions during each walk. The team extracted each participant's characteristic spatial, temporal and kinetic features in their strides to examine variations in gait during each trial.

Changes in various gait features, including a data feature called the butterfly diagram, helped the team detect differences in gait patterns between participants. The diagram gains its name from the butterfly-shaped curve created from the repeated center-of-pressure trajectory for multiple continuous strides during a subject's walk and is associated with critical neurological functions, the study reports.

Click here to see a video describing this research.

"We study the effectiveness of a gait dynamics-based machine-learning framework to classify strides of older persons with MS from healthy controls to generalize across different walking tasks and over new subjects," Kaur said. "This proposed methodology is an advancement toward developing an assessment marker for medical professionals to predict older people with MS who are likely to have a worsening of symptoms in the near term."

Future studies can provide more thorough examinations to manage the study's small cohort size, Sowers said.

"Biomechanical systems, such as walking, are poorly modeled systems, making it difficult to spot problems in a clinical setting," Sowers said. "In this study, we are trying to extract conclusions from data sets that include many measurements of each individual, but a small number of individuals. The results of this study make significant headway in the area of clinical machine learning-based disease-prediction strategies."