Culture

Adding the nutrient selenium to diets protects against obesity and provides metabolic benefits to mice, according to a study published today in eLife.

The results could lead to interventions that reproduce many of the anti-aging effects associated with dietary restriction while also allowing people to eat as normal.

Several types of diet have been shown to increase healthspan - that is, the period of healthy lifespan. One of the proven methods of increasing healthspan in many organisms, including non-human mammals, is to restrict dietary intake of an amino acid called methionine.

Recent studies have suggested that the effects of methionine restriction on healthspan are likely to be conserved in humans. Although it might be feasible for some people to practice methionine restriction, for example, by adhering to a vegan diet, such a diet might not be practical or desirable for everyone. In the current study, a research team from the Orentreich Foundation for the Advancement of Science (OFAS), Cold Spring, New York, US, aimed to develop an intervention that produces the same effects as methionine restriction, while also allowing an individual to eat a normal, unrestricted diet.

An important clue for developing such a treatment is that methionine restriction causes a decrease in the amounts of an energy-regulating hormone called IGF-1. If a treatment could be found that causes a similar decrease in IGF-1, this might also have beneficial effects on healthspan. Previous research has shown that selenium supplementation reduces the levels of circulating IGF-1 in rats, suggesting that this could be an ideal candidate.

The team first studied whether selenium supplementation offered the same protection against obesity as methionine restriction. They fed young male and older female mice one of three high-fat diets: a control diet containing typical amounts of methionine, a methionine-restricted diet, and a diet containing typical amounts of methionine as well as a source of selenium. For both male and female mice of any age, the authors found that selenium supplementation completely protected against the dramatic weight gain and fat accumulation seen in mice fed the control diet, and to the same extent as restricting methionine.

Next, they explored the effects of the three diets on physiological changes normally associated with methionine restriction. To do this, they measured the amounts of four metabolic markers in blood samples from the previously treated mice. As hoped, they found dramatically reduced levels of IGF-1 in both male and female mice. They also saw reductions in the levels of the hormone leptin, which controls food intake and energy expenditure. Their results indicate that selenium supplementation produces most, if not all, of the hallmarks of methionine restriction, which suggests that this intervention may have a similar positive effect on healthspan.

To gain insight into the beneficial effects of selenium supplementation, the researchers used a different organism - yeast. The two most widely used measurements of healthspan in yeast are chronological lifespan, which tells us how long dormant yeast remain viable, and replicative lifespan, which measures the number of times a yeast cell can produce new offspring. The team previously showed that methionine restriction increases the chronological lifespan of yeast, so they tested whether selenium supplementation might do the same. As it turned out, yeast grown under selenium-supplemented conditions had a 62% longer chronological lifespan (from 13 days to 21 days) and a replicative lifespan extended by nine generations as compared with controls. This demonstrates that supplementing yeast with selenium produces benefits to healthspan detectable by multiple tests of cell aging.

"One of the major goals of aging research is to identify simple interventions that promote human healthspan," notes senior author Jay Johnson, Senior Scientist at OFAS. "Here we present evidence that short-term administration of either organic or inorganic sources of selenium provides multiple health benefits to mice, the most notable of which being the prevention of diet-induced obesity. In the long term, we expect that supplementation with these compounds will also prevent age-related disease and extend the overall survival of mice. It is our hope that many of the benefits observed for mice will also hold true for humans."

LAWRENCE -- Recent incidents of racial discrimination and violence against Asians and Asian-Americans in the United States have prompted critical discussions about how to talk about such biases with younger age groups. New research from the University of Kansas shows using critical race media literacy, or examining how race and gender are addressed in popular culture, can be an effective way to discuss those topics and engage students.

KU researchers published a study in which they observed an American teacher using critical race media literacy to discuss racism and sexism in superhero movies in English as a foreign language classes in a South Korean high school. They argued that successful implementation can provide a model for discussing social topics in K-12 classrooms in countries like the United States.

Hyesun Cho"I think now, more than ever, it's important for us educators to teach our students how to contest prejudice and discrimination against certain racial groups," said Hyesun Cho, associate professor of curriculum & teaching in KU's School of Education & Human Sciences.

The recent mass shooting of several Asian-American women in Atlanta made headlines, but the topic can be difficult to discuss in schools.

"Teachers often are hesitant to discuss race and gender in the classroom because they are understandably concerned about sounding too political," said Peter Johnson, doctoral candidate in curriculum & teaching and study co-author. "I think that is one roadblock that we need to address, and this approach can help do that."

The study was published in the International Journal of Multicultural Education and presented at the Second Language Research Forum 2020 Conference hosted by Vanderbilt University.

Cho has led a study abroad program with KU students since 2015, traveling to South Korea to gain experience working in high schools while teaching English. The researchers observed classes where students explored issues of racism or sexism in popular culture on their own. Several groups of students shared examples in popular movies like "Black Panther" and "Dr. Strange" to appeal to their classmates. Students made presentations in English about how the wildly popular films addressed race both in positive ways, such as empowering African characters in "Black Panther," and in more negative ways, including a white actor portraying an Asian character in the 2016 film "Doctor Strange." The students were highly effective at discussing critical race theory and other complex topics, the authors wrote, and using media that students find compelling is a key way to give students a safe, comfortable way to discuss difficult topics.

"Do not underestimate our students' intelligence and higher thinking skills. That's the argument we're making here, even if they are working in a second or third language," Cho said. "Discussing critical race media literacy worked very well in Korean classrooms, despite misconceptions that often exist about these students' English proficiency and cultural background. If the teacher gets to know students and their interests and creates a safe space for them to express their thoughts about social issues, this approach can work in other teaching contexts."

Not only can using topics relevant to students' interests help encourage their participation, but it can help teachers connect with students. Educators are more effective when they get to know their students, their communities, families, backgrounds and experiences, Cho and Johnson wrote. The teacher in the study was born in Thailand, raised in the United States and speaks English as a first language. However, he faced discrimination when applying for jobs at South Korean schools, as it was assumed he was not a "true, American English speaker" because he was not white. Sharing such experiences can help expand discussions of power structures beyond media representations.

South Korea, like the United States, has an educational culture highly focused on testing and assessment. A common argument is that topics like racism and sexism can't or shouldn't be covered in school because they take time away from focusing on testing areas. However, the students displayed high levels of critical thinking, use of language, technological savvy and other educational skills in their presentations. That success suggests adaptability to other settings and levels of curriculum, Cho and Johnson wrote.

Cho said she hoped to return to South Korea to study other implementations of critical race media literacy in classrooms to gauge their effectiveness and to form new recommendations for teachers to address the topics in their own classrooms. Both Cho and Johnson also encourage prospective educators they are currently teaching to consider such methods to engage their future students and empower them to take ownership of their education.

"We try to frame it for our future teachers so that they understand they are able to have a classroom where students feel comfortable to ask the questions they have on their minds," Johnson said. "It can be tough to strike a good balance, but this shows they can use media such as films students are interested in to get them to think about deeper issues."

While it can be difficult to discuss to racism, sexism or the recent violence against Asians and Asian-Americans in a classroom setting, the use of critical race media literacy works, the researchers said.

"This is a new imperative for survival in the current, racially contested world. Especially given the anti-Asian-American violence we have seen in the U.S., it is everyone's responsibility to address it," Cho said. "Students want to be heard, and this study shows it's not an impossible task to discuss these social issues and can be done in a way that uses content relevant and readily accessible to students throughout K-12 education."

Through his role on the U.S. Preventive Services Task Force, UVA Health's Li Li, MD, PhD, MPH, has helped develop new lung cancer screening guidelines that expand screenings to more high-risk patients.

The new guidelines are focused on Americans at higher risk because of their history of smoking, which is the leading cause of lung cancer. There are two significant changes in the new guidelines. For those who are still smoking or quit less than 15 years ago, a yearly screening using a low-dose computed tomography (CT) scan is now recommended:

beginning at age 50, instead of age 55.

for anyone who has smoked 20 pack-years in their lifetime, instead of 30 pack-years. A pack-year equals smoking a pack of cigarettes a day for a year.

The new guidelines came following a review of the latest evidence of the benefits of lung cancer screening by Li and his colleagues on the Task Force, an independent, volunteer panel of national experts in prevention and evidence-based medicine. That evidence showed expanding the criteria would open screenings to more Black people and women, who data shows tend to smoke fewer cigarettes than white men.

"The new guidelines will have a tremendous impact on primary and secondary prevention of this dreadful cancer," Li said. "It is a big step forward in reducing lung cancer disparities in Black people and women."

Screenings are recommended for Americans ages 50 to 80 who meet the 20 pack-year criteria and are still smoking or quit less than 15 years ago. The Task Force recommends that current and former smokers who meet the updated criteria should discuss lung cancer screening with their doctor to determine whether the screening is right for them.

"Increasing the awareness and uptake of lung cancer screening, together with effective smoking cessation programs, are pressing priorities for UVA Health in its concerted effort to improve the health of residents in our region," Li said.

WHAT:

When variants of SARS-CoV-2 (the virus that causes COVID-19) emerged in late 2020, concern arose that they might elude protective immune responses generated by prior infection or vaccination, potentially making re-infection more likely or vaccination less effective. To investigate this possibility, researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and colleagues analyzed blood cell samples from 30 people who had contracted and recovered from COVID-19 prior to the emergence of virus variants. They found that one key player in the immune response to SARS-CoV-2--the CD8+ T cell--remained active against the virus.

The research team was led by NIAID's Andrew Redd, Ph.D., and included scientists from Johns Hopkins University School of Medicine, Johns Hopkins Bloomberg School of Public Health and the immunomics-focused company, ImmunoScape.

The investigators asked whether CD8+ T cells in the blood of recovered COVID-19 patients, infected with the initial virus, could still recognize three SARS-CoV-2 variants: B.1.1.7, which was first detected in the United Kingdom; B.1.351, originally found in the Republic of South Africa; and B.1.1.248, first seen in Brazil. Each variant has mutations throughout the virus, and, in particular, in the region of the virus' spike protein that it uses to attach to and enter cells. Mutations in this spike protein region could make it less recognizable to T cells and neutralizing antibodies, which are made by the immune system's B cells following infection or vaccination.

Although details about the exact levels and composition of antibody and T-cell responses needed to achieve immunity to SARS-CoV-2 are still unknown, scientists assume that strong and broad responses from both antibodies and T cells are required to mount an effective immune response. CD8+ T cells limit infection by recognizing parts of the virus protein presented on the surface of infected cells and killing those cells.

In their study of recovered COVID-19 patients, the researchers determined that SARS-CoV-2-specific CD8+ T-cell responses remained largely intact and could recognize virtually all mutations in the variants studied. While larger studies are needed, the researchers note that their findings suggest that the T cell response in convalescent individuals, and most likely in vaccinees, are largely not affected by the mutations found in these three variants, and should offer protection against emerging variants.

Optimal immunity to SARS-Cov-2 likely requires strong multivalent T-cell responses in addition to neutralizing antibodies and other responses to protect against current SARS-CoV-2 strains and emerging variants, the authors indicate. They stress the importance of monitoring the breadth, magnitude and durability of the anti-SARS-CoV-2 T-cell responses in recovered and vaccinated individuals as part of any assessment to determine if booster vaccinations are needed.

Most businesses were ill-prepared to deal with the pandemic and muddled though the challenges stemming from it, according to a report published today.

Resilience reimagined: a practical guide for organisations was produced by Cranfield University, in partnership with the National Preparedness Commission (NPC) and Deloitte. The report presents insights from business leaders from a range of sectors and makes seven recommendations for organisations on how to become more resilient, drawing on lessons from past 12 months.

Cranfield University's Professor David Denyer and Mike Sutliff conducted in-depth interviews and four focus groups with more than 50 C-suite level people (boards, senior executives, policymakers, and resilience directors) from FTSE 100 companies, multi-nationals and major national infrastructure organisations, many of them household names.

The report warns we are entering a new period of uncertainty and change, with an ever-increasing possibility that things will go wrong. It sought answers from leading figures about how resilience can be developed, who does it well and what other businesses can learn from them.

It also outlines practical steps necessary to strengthen resilience for long-term success and makes recommendations to business leaders on what more they can do to help their organisations to develop the ability to cope.

Cranfield's research found that the organisations that coped best with the pandemic had already been doing the following three things:

They understood what was most important to their customers and therefore what were the most essential things to continue to deliver as the crisis unfolded.

If something went wrong, they knew what the thresholds of tolerable impacts to the customer/user were and had examined in advance alternative ways of delivering those outcomes that mattered the most.

They had relentlessly stress tested for possible disruption without worrying about what type of threat they might have to face - a cyberattack or a pandemic - learning how to cope when under pressure from challenges that might not be foreseeable or imaginable.

Professor David Denyer, Professor of Leadership and Organisational Change at Cranfield University, said: "We do not know what shape the next crisis will take but we can take proactive action to prepare.

"Businesses and organisations need to seize the learnings from this crisis and develop the agility to cope with the next. Whether it is another pandemic, another financial crisis or threats from a cyber attack or climate change, the risks are multiple and complex but the capabilities of readiness, responsiveness, recoverability and regeneration, the 4Rs, are ones that can be ingrained.

"One of the reasons the financial sector coped better than most during the pandemic was that it had taken on the lessons from the 2008 crash. By going through that crisis, these organisations had stress-tested, they knew their tolerances and what an acceptable level of failure was to them and their customers.

"Our research, in partnership with the National Preparedness Commission and Deloitte, gives organisations vital practical steps to reimagine the way they think about resilience and respond to future crises."

Lord Toby Harris, Chair of the National Preparedness Commission, said:
"The last year has been like no other for most business organisations, but some coped and responded much better than others. We asked Cranfield University to look at why this was and what the lessons are for the future.

The Government wants to build a whole-of-society approach to resilience, so that every business, every organisation and every individual can play their part in making sure that as a nation we can withstand any future crisis. This means changing organisational cultures to foster an active and agile response to events and this report highlights some of what is needed to make this a reality."

Rick Cudworth, Partner at Deloitte said:
"Dealing with complex events requires flexibility and creativity; dealing with future uncertainty requires the ability to change course and adapt rapidly. This report clearly shows that resilience is about much more than well-rehearsed plans. This is a fundamental change in thinking, which requires senior leaders to make strategic choices, balancing control, agility, efficiency and innovation. It is great to see leaders pointing to resilience being central to a new 'social contract' for responsible business.

"By adopting the seven practices in this report organisations will be able to build stronger resilience and be better positioned to thrive going forward."

As social media platforms like Instagram, Snapchat, TikTok and others continue to grow in popularity, adolescents are spending more of their time online navigating a complex virtual world.

New research suggests that these increased hours spent online may be associated with cyberbullying behaviors. According to a study by the University of Georgia, higher social media addiction scores, more hours spent online, and identifying as male significantly predicted cyberbullying perpetration in adolescents.

"There are some people who engage in cyberbullying online because of the anonymity and the fact that there's no retaliation," said Amanda Giordano, principal investigator of the study and associate professor in the UGA Mary Frances Early College of Education. "You have these adolescents who are still in the midst of cognitive development, but we're giving them technology that has a worldwide audience and then expecting them to make good choices."

Cyberbullying can take on many forms, including personal attacks, harassment or discriminatory behavior, spreading defamatory information, misrepresenting oneself online, spreading private information, social exclusion and cyberstalking.

The study surveyed adolescents ranging in age from 13-19 years old. Of the 428 people surveyed, 214 (50%) identified as female, 210 (49.1%) as male, and four (0.9%) as other.

Exploring social media addiction

When adolescents are online, they adapt to a different set of social norms than when they're interacting with their peers in person. Oftentimes, they are more aggressive or critical on social media because of the anonymity they have online and their ability to avoid retaliation. Additionally, cyberbullies may feel less remorse or empathy when engaging in these behaviors because they can't see the direct impact of their actions.

"The perpetrator doesn't get a chance to see how damaging their bullying is and to learn from their mistakes and do something different," said Giordano. "It's a scary situation because they don't have the natural consequences they do with offline bullying."

Teenagers who are addicted to social media are more likely to engage in cyberbullying, as well as those who spend more time online. Participants in the study reported spending on average over seven hours online per day, and the reported average maximum hours spent online in one day was over 12 hours.

"Social media addiction is when people crave it when they're not on it, and continue their social media use despite negative consequences," said Giordano. "Some negative consequences could be they're tired during the day because they're scrolling all night long, they're having conflicts with their parents, they're getting poor grades in school or they're engaging in actions online that they later regret, but they still continue to use social media."

Social networking sites are designed to give people a dopamine hit, she added, and some people compulsively look for that hit. "It's feeding into that addictive behavior, and they may be using cyberbullying as a way to get likes, shares, comments and retweets," she said. "That's the common thread you see in behavioral addictions--people start relying on a rewarding behavior as a way to make them feel better when they're experiencing negative emotions. And so, I think the social media addiction piece is really interesting to show that there's another factor at play here in addition to the number of hours spent online."

The study also found that adolescent males are more likely to engage in cyberbullying than females, aligning with past studies that show aggressive behaviors tend to be more male driven. More research on the socialization process of men can help determine what's leading them to engage in more cyberbullying behaviors.

Next steps for counselors and clinicians

Giordano believes that counselors need to start assessing adolescents for social media addiction if they are engaging in cyberbullying and to provide treatment plans to help redefine their relationship with technology. These interventions may include helping adolescents examine how they define their self-worth and restricting the amount of time they spend on social media platforms.

"There's quite a few strong and reliable assessments for social media addiction for adolescents that have good psychometric properties," said Giordano. "I think when clinicians see cyberbullying happen, they really need to explore the individual's relationship with social media and to address social media addiction, not just the cyberbullying."

Often, school counselors are not aware of cyberbullying until after an incident occurs. To address this issue, Giordano recommends that schools start educating students earlier about cyberbullying and social media addiction as a preventive method instead of waiting to repair the damage. Whether it's through an awareness campaign or support group, schools can help students talk about cyberbullying to give them a chance to understand the consequences of their actions and prepare them for potential risks.

"We need schools and school counselors to do this preventative work early and educate students about the risk of addiction with some of these rewarding behaviors like gaming and social media," said Giordano. "We need to teach them the warning signs of behavioral addiction, what to do if they start to feel like they're losing control over their behaviors and help them find other ways to manage their emotions, rather than turning to these behaviors. There are a lot of programs already moving in this direction, and I think that's amazing and there needs to be more of it."

Counselors can help decrease the risk of some of these addictive behaviors at a young age by teaching and equipping children with emotional regulation skills and other ways to cope with their feelings.

"If you think about it, adolescents are not only figuring out who they are offline, but they're also trying to figure out who they want to be online," said Giordano. "We're giving them even more to do during this developmental period, including deciding how they want to present themselves online. I think it's a complex world that we're asking adolescents to navigate."

PULLMAN, Wash. - Washington State University researchers have discovered a protein that could be key to blocking the most common bacterial cause of human food poisoning in the United States.

Chances are, if you've eaten undercooked poultry or cross contaminated food by washing raw chicken, you may be familiar with the food-borne pathogen.

"Many people that get sick think, 'oh, that's probably Salmonella,' but it is even more likely it's Campylobacter," said Nick Negretti ('20 Ph.D.), a lead member of the research team in Michael Konkel's Laboratory in WSU's School of Molecular Biosciences.

According to a study on the research recently published in Nature Communications, a secreted protein known as CiaD facilitates cell entry by Campylobacter and takes control of important cell processes by changing the composition of a protein complex inside the cell.

By gaining insight into the infection process and the specific actions of the Campylobacter secreted proteins, the work gives the WSU team and the rest of the field a foundation to understanding why infections occur and persist.

Until the Konkel Lab's latest finding, the functions of the bacterium's proteins and how they infect the cell were largely unknown.

"We knew these things were happening, but we didn't know how," said Negretti. "Now, if we can stop this process, disease won't happen."

The work was funded by a 5-year, $1.9 million grant from the National Institutes of Health and builds on two decades of research in the Konkel Lab.

Most often known for the nausea, vomiting and bloody diarrhea that comes with it, once ingested, Campylobacter jejuni secretes proteins that infiltrate the cells lining the intestinal tract, which allows it to hide from the immune system.

The bacteria account for 400 to 500 million cases of diarrhea annually, and the World Health Organization recognizes it as a serious threat due to its antibiotic resistance.

The infection is also correlated with stunted linear growth in impoverished children, and in developed countries, a higher incidence of Guillain-Barré syndrome, when the body's immune system attacks the nerves.

The research was a seven-year collaborative effort, using the latest molecular biology and biochemistry methods.

The work was done in partnership with researchers Geremy Clair and Joshua Adkins with the Pacific Northwest National Laboratory. Using mass spectroscopy, Adkins and Clair were able to study protein-to-protein interaction that helped the WSU researchers narrow their focus and uncover the target of CiaD.

Konkel said the research would not have been completed without post-doctoral fellow Prabhat Talukdar and graduate students Courtney Klappenbach and Cody Lauritsen leading the work through its final stretch amid the pandemic.

Now, the researchers are hopeful the work will lead to real-world solutions, in particular finding ways to prevent the pathogen from stunting growth in children.

"With this finding, we can speculate that processes like this that affect the cell could impact the intestinal cell's ability to form the correct structures to absorb nutrients," Negretti said. "While this is a mechanistic level of understanding, the answers to how the bacteria is specifically affecting cells in the body could have broader ranging impacts into understanding the public health importance of this pathogen."

The team also looks forward to learning the functions of other secreted proteins.

A major breakthrough into understanding C. jejuni disease was made in 1999 when the Konkel Lab discovered that proteins are secreted from the bacterium. In 2009, the CiaD protein was identified by Jeffrey Christensen, a post-doctoral fellow in the laboratory.

"We then identified CiaD was delivered to the host cells in 2013," Konkel said. "A major question for the past 20-years has been: what are these secreted proteins and what do they do? This is just the first protein to have an identified cell target."

(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.”