Culture

In January 2019, NASA's OSIRIS-REx spacecraft was orbiting asteroid Bennu when the spacecraft's cameras caught something unexpected: Thousands of tiny bits of material, some just the size of marbles, began to bounce off the surface of the asteroid--like a game of ping-pong in space. Since then, many such particle ejection events have been observed at Bennu's surface.

OSIRIS-REx is an unprecedented effort to investigate what makes up asteroids like Bennu and how they move through space. But, as those leaping particles show, the mission has already delivered a few surprises.

"We've been studying asteroids for a long time, and no one had ever seen this phenomenon before--these little particles getting shot off of the surface," said Daniel Scheeres, distinguished professor in the Ann and H.J. Smead Department of Aerospace Engineering Sciences. He leads the radio science team for OSIRIS-REx along with CU Boulder's Jay McMahon.

Now, a series of new studies seeks to recreate and understand the observed particle ejection events, piecing together what happened and why. Scheeres and McMahon are focusing on one question in particular: How might such leaping particles change the long-term fate of Bennu and other asteroids like it?

In research published in the Journal of Geophysical Research: Planets, the duo and their colleagues report that such seemingly small occurrences may add up over time--perhaps even helping to give the asteroid its telltale shape, which is often compared to a spinning top.

"We want to know what that means for the bigger picture of how asteroids live their lives," said McMahon, an assistant professor of aerospace engineering.

The University of Arizona leads science operations for OSIRIS-REx, which was built by the Colorado-based Lockheed Martin. NASA's Goddard Space Flight Center in Maryland manages the overall mission.

Mass loss

McMahon added that the life of some asteroids can be pretty chaotic. One class of these bodies, which scientists call "active" asteroids, loses a significant amount of material on an ongoing basis.

"They're almost a cross between a comet and an asteroid," McMahon said. "They're losing mass, and it's substantial enough that we can see it from Earth."

Until recently, no one knew that the same thing could happen on a much smaller scale. But that's precisely the case on Bennu. One hypothesis suggests that rapid shifts in temperature could be causing the surface of the asteroid to warp and crack, popping off small bits of material. Another study has contended that the ejections could be the result of small meteoroids smacking into Bennu.

Based on OSIRIS-REx's observations, the particles ejected from Bennu can be as big as softballs and hit speeds of about 7 miles an hour. Even more surprising, McMahon said, a small number of these bits of debris seemed to do the impossible: They flew off the surface of Bennu, then orbited the asteroid for several days or longer.

"That shouldn't happen in typical orbital mechanics," McMahon said.

Put differently, basic orbital calculations suggest that all of these particles should do one of two things: Jump off the surface and fall right back down or escape from Bennu's gravity and never come back.

Close misses

To find out why some aren't playing by the rules, McMahon and his colleagues used detailed computer models to track the trajectories of more than 17,000 test particles ejected from Bennu. They discovered a small subset of those seem to get an assist from an unlikely source: the sun.

McMahon explained that as these objects leap off the asteroid, they are exposed to heat and radiation coming from the sun and from Bennu itself--just a little bit, but enough to occasionally give them a slight boost in speed. With the right push, those particles can, essentially, fail at falling.

"The particle gets really close to the surface and just misses," McMahon said. "If it can do that a few times then it can get into a situation where it can live in orbit for quite a while."

In another study published in the same series, a team led by Scheeres and McMahon tried to figure out if ejection events might even influence Bennu's own orbit around the sun--the answer is probably not.

The group did discover something else unusual: When particles eventually land on Bennu's surface, many appear to disproportionately fall near its equator where the asteroid has a distinct bulge. As a result, these events could be reshaping the asteroid over thousands or millions of years by moving mass from its north and south to its middle.

The findings are a prelude to another major event in the life of Bennu. Next month, OSIRIS-REx will get closer to the asteroid than ever before. Once there, the spacecraft will use a retractable arm to grab a sample from the surface and bring it back home.

Scheeres and colleagues expect even more unexpected findings from an already surprising asteroid.

Coauthors on the new study include researchers from the Jet Propulsion Laboratory, Planetary Science Institute, NASA Goddard Space Flight Center, Lockheed Martin, University of Arizona, The Open University and University of Tennessee.

The management of fungal infections in plants and humans could be transformed by a breakthrough in understanding how fungi develop resistance to drugs.

It was previously thought that only mutations in a fungi's DNA would result in antifungal drug resistance. Current diagnostic techniques rely on sequencing all of a fungi's DNA to find such mutations.

Scientists from the University of Edinburgh have discovered that fungi can develop drug resistance without changes to their DNA - their genetic code.

The new research, published in Nature, finds that resistance can emerge in fungi without genetic changes. Instead the fungi exhibit epigenetic changes - alterations that do not affect their DNA - suggesting that many causes and cases of antifungal resistance could have been previously missed.

Each year fungal diseases affect billions of people globally, causing an estimated 1.6 million deaths.

Infections resistant to treatment are a growing problem, particularly in patients with weakened immune systems such as those with HIV. Few effective antifungal drugs exist.

Overuse of agricultural fungicides is also leading to increasing resistance in soil borne fungi. Fungal disease results in the loss of up to a third of the world's food crops annually.

A team of scientists from the University of Edinburgh's Wellcome Centre for Cell Biology studied the emergence of resistance in a yeast, Schizosaccharomyces pombe, by treating it with caffeine to mimic the activity of antifungal drugs.

The team discovered that the resulting resistant yeast had alterations in special chemical tags that affect how their DNA is organized. Some genes became packed into structures known as heterochromatin, which silences or inactivates underlying genes, causing resistance as a result of this epigenetic change.

This discovery could pave the way for new therapies to treat resistant infections by modifying existing epigenetic drugs or developing new drugs that interfere with fungal heterochromatin.

Improved fungicides to treat food crops could limit agricultural losses and also reduce the number of resistant fungal strains in the environment that continue to fuel increased infections in humans.

Professor Robin Allshire, who led the study at the Wellcome Centre for Cell Biology, Institute of Cell Biology, School of Biological Sciences, said: "Our team is excited about the possible implications that these findings may have for understanding how plant, animal and human fungal pathogens develop resistance to the very limited number of available and effective antifungal drug treatments."

Sito Torres-Garcia, Darwin Trust of Edinburgh funded PhD student and first author of the paper, said: "Our study shows for the first time that fungal cells can develop drug resistance by altering how their DNA is packaged, rather than altering their DNA sequence."

Dyslexia is a frequent disorder of reading acquisition that affects up to 10% of the population, and is characterised by lifelong difficulties with written material. Although several possible causes have been proposed for dyslexia, the predominant one is a phonological deficit, a difficulty in processing language sounds. The phonological deficit in dyslexia is associated with changes in rhythmic or repetitive patterns of neural activity in a sound-processing region of the brain, the left auditory cortex. Neuroscientists from the University of Geneva (UNIGE) have demonstrated, in a study published in Plos Biology, a causal relationship between brain oscillations at a specific frequency (30 Hz) and the ability to process phonemes that is essential for reading. Using a non-invasive electrical stimulation technique capable of synchronizing neural activity at the stimulation frequency, phonological deficits and reading accuracy could be improved in adults with dyslexia.

Silvia Marchesotti and Anne-Lise Giraud, respectively researcher and professor in the Department of Basic Neurosciences of the Faculty of Medicine at UNIGE, together with their colleagues, investigated the main possible cause of dyslexia: the phonological deficit. "We know that during brain development, when children start to read, some experience tremendous difficulties matching speech sounds with letters " explains Silvia Marchesotti. These specific difficulties are associated with anomalies of neural activity synchronization in the left auditory cortex at the frequency of 30 Hz. The Geneva study demonstrates for the first time that a causal relationship exists between these brain oscillations and the ability to process speech phonemes.

Reading stimulation

Neuroscientists applied the technique of transcranial alternating current stimulation (tACS), which is under investigation in medicine to treat illnesses such as depression. A twenty minute stimulation over the left auditory cortex in 15 dyslexic adults and 15 fluent control readers immediately improved phonological processing and reading accuracy in the dyslexia group. The beneficial effect of stimulation is most pronounced in people with poor reading skills, but neuroscientists have noted a slightly disruptive effect in very good readers.

Towards non-invasive treatments

The Geneva study paves the way for targeted non-invasive therapeutic interventions aimed at improving phonological processing in people with dyslexia. "The next steps for us are to investigate whether normalising oscillatory function in very young children could have a long-lasting effect on the organisation of the reading system," says Silvia Marchesotti.

This study will continue within the new National Center of Competence in Research (NCCR) "Evolving Language." The method will be different, however: instead of using electrical stimulation, neuroscientists will try to obtain equivalent results with neurofeedback, a non-invasive technique that involves teaching self-regulation of brain signals to patients. "The goal remains the same, but the use of an even less invasive method will allow conducting trials with children," says Anne-Lise Giraud, the project leader.

DURHAM, N.C. -- Interactive software that "reads" and analyzes footprints left by black rhinoceroses can be used to monitor the movements of the animals in the wild, giving conservationists a new way to keep watch on the endangered species and help keep it safe from poachers, according to a Duke University-led study.

The software, called the Footprint Identification Technique (FIT), runs on JMP software from SAS and uses advanced algorithms to analyze more than 100 measurements of a rhino's footprint.

Because each rhino's footprint is as distinctive as a human fingerprint, the analyzed images can be archived electronically in a global database of previously collected footprint images for matching.

"If you find a match, you can identify the individual animal who left the mark and, by plotting the locations of all the other places that mark has been seen, track its movements without disturbing it or coming into close enough contact with it for there to be a risk of animal-to-human viral transmissions," said Zoe Jewell, adjunct associate professor at Duke University's Nicholas School of the Environment and principal research associate at the JMP Division of SAS, who co-led the study and is co-creator of FIT.

"It's a cost-effective approach that not only protects the health of the rhino and the human, but also brings a centuries-old tracking skill into the 21st Century," she said.

Jewell and her colleagues are now working with Namibia's Ministry of Environment, Forestry and Tourism to train wildlife conservationists, land managers, local guides and anti-poaching agents how to use FIT.

The scientists published their peer-reviewed study describing the technology's effectiveness for monitoring the endangered rhinos on Aug. 14 in the open-access journal PeerJ.

Namibia is home to an estimated 2,000 black rhinos, or about 90% of the species' total population worldwide. Though legally owned by the government, the animals are dispersed geographically on private lands across the country.

Stepped up government policing in recent years has significantly slowed the rate of loss due to poaching, but between 30 and 50 of the animals are still slain each year for their horns, which can sell for more than $60,000 a kilogram on the Asian black market, where they are used in traditional medicine or displayed as a symbol of wealth and success.

"You essentially have these animals with horns worth $100,000 or more that disappear from sight into the Namibian backcountry, making them an almost irresistible target for poachers. Authorities often don't know a rhino that's gone missing has been poached until they find its bones or carcass," said Jewell.

FIT allows the animals to be monitored three different ways, allowing scientists, managers, guides or anti-poaching patrols to use it as best meets their individual needs and constraints, she said.

In the simplest option, the heel pattern on a digital image of the footprint is compared to images already in the FIT database to search for a match. This use is well-suited to situations where a random footprint is found in the wild.

The FIT software can also do a survey of footprints throughout the protected area and take measurements from each print to estimate the number of rhinos in that area. This can be useful information for calculating resource needs - the number of patrol vehicles, for instance - to monitor the animals effectively.

In the most advanced option, each individual rhino can be tracked and matched to its unique footprint using both FIT and heel-patterns. This creates an interactive library that anti-poaching patrols can use to search for animals at the highest risk, including those known to frequent areas under threat from poachers or those whose footprints haven't been showing up in recent years.

"FIT is a distillation of the traditional ecological skills of the expert trackers who have lived and worked with in Africa for many years," said Sky Alibhai, also an adjunct associate professor at Duke's Nicholas School and principal research associate at the JMP Division of SAS, who co-led the study and co-developed the FIT technology with Jewell. "Using FIT allows their skills to be used effectively in conservation. This can benefit whole communities."

RIVERSIDE, Calif. -- A new theory about the nature of dark matter helps explain why a pair of galaxies about 65 million light-years from Earth contains very little of the mysterious matter, according to a study led by a physicist at the University of California, Riverside.

Dark matter is nonluminous and cannot be seen directly. Thought to make up 85% of matter in the universe, its nature is not well understood. Unlike normal matter, it does not absorb, reflect, or emit light, making it difficult to detect.

The prevailing dark matter theory, known as cold dark matter, or CDM, assumes dark matter particles are collisionless, aside from gravity. A newer second theory, called self-interacting dark matter, or SIDM, proposes dark matter particles self-interact through a new dark force. Both theories explain how the overall structure of the universe emerges, but they predict different dark matter distributions in the inner regions of a galaxy. SIDM suggests dark matter particles strongly collide with one another in a galaxy's inner halo, close to its center.

Typically, a visible galaxy is hosted by an invisible dark matter halo -- a concentrated clump of material, shaped like a ball, that surrounds the galaxy and is held together by gravitational forces. Recent observations of two ultra-diffuse galaxies, NGC 1052-DF2 and NGC 1052-DF4, show, however, that this pair of galaxies contains very little, if any, dark matter, challenging physicists' understanding of galaxy formation. Astrophysical observations suggest NGC 1052-DF2 and NGC 1052-DF4 are likely satellite galaxies of NGC1052.

"It is commonly thought that dark matter dominates the overall mass in a galaxy," said Hai-Bo Yu, an associate professor of physics and astronomy at UCR, who led the study. "Observations of NGC 1052-DF2 and -DF4 show, however, that the ratio of their dark matter to their stellar masses is about 1, which is 300 times lower than expected. To resolve the discrepancy, we considered that the DF2 and DF4 halos may be losing the majority of their mass through tidal interactions with the massive NGC 1052 galaxy."

Using sophisticated simulations, the UCR-led team reproduced the properties of NGC 1052-DF2 and NGC 1052-DF4 through tidal stripping -- the stripping away of material by galactic tidal forces -- by NGC1052. Because the satellite galaxies cannot hold the stripped mass with their own gravitational forces, it effectively gets added to NGC 1052's mass.

The researchers considered both CDM and SIDM scenarios. Their results, published in Physical Review Letters, indicate SIDM forms dark-matter-deficient galaxies like NGC 1052-DF2 and -DF4 far more favorably than CDM, as the tidal mass loss of the inner halo is more significant and the stellar distribution is more diffuse in SIDM.

The research paper has been selected as an "editors' suggestion" by the journal, an honor that only a select few papers receive each week to promote reading across fields.

Yu explained tidal mass loss could occur in both CDM and SIDM halos. In CDM, the inner halo structure is "stiff" and resilient to tidal stripping, which makes it difficult for a typical CDM halo to lose sufficient inner mass in the tidal field to accommodate observations of NGC 1052-DF2 and -DF4. In contrast, in SIDM, dark matter self-interactions could push dark matter particles from the inner to the outer regions, making the inner halo "fluffier" and enhancing the tidal mass loss accordingly. Further, the stellar distribution becomes more diffuse.

"A typical CDM halo remains too massive in the inner regions even after tidal evolution," Yu said.

Next, the team will perform a more comprehensive study of the NGC 1052 system and explore newly discovered galaxies with novel properties in an effort to better understand the nature of dark matter.

Using innovative computer-based approaches, researchers have developed protein inhibitors that block the interaction between the SARS-CoV-2 virus and human cell receptor ACE2. In cell culture, the most potent of these inhibitors could neutralize virus infection, paving the way for their use in therapies that could be delivered more easily than antibodies. SARS-CoV-2 infection generally begins in the nasal cavity. The monoclonal antibodies in development as treatments for COVID-19 are not ideal for intranasal delivery, however, as antibodies are large and often not extremely stable. Small proteins that bind tightly to the SARS-CoV-2 spike and block the interaction with the human cellular receptor ACE2 may allow direct delivery through intranasal administration. Previous work in rodents has shown that intranasal delivery of small proteins designed to bind tightly to an influenza protein could provide protection against infection. Here, using novel approaches to identify new, higher-affinity binding modes with the SARS-CoV-2 spike's receptor binding domain (RBD), Longxing Cao, David Baker and colleagues developed a series of inhibitors - optimized in their amino acid sequences for targeted binding, folding and stability - that bound to distinct regions of the RBD surface surrounding the ACE2 binding site. When they evaluated their inhibitors in cell culture, several bound with particularly high affinities to SARS-CoV-2 and two neutralized the virus, preventing infection. The small proteins were stable after 14 days at room temperature, addressing concerns associated with cold storage needs required for some antibodies and vaccine candidates. These "minibinders" provide starting points for SARS-CoV-2 therapeutics, the authors say. After further development, they could be used in a gel for nasal application, or for direct delivery into the respiratory system by nebulization. "We will be exploring alternative routes of delivery in the months ahead as we seek to translate the high potency neutralizing proteins into SARS-CoV-2 therapeutics and prophylactics," they write. They also address the utility of their computational design-based approach for preparing against future pandemics.

Brazilian red propolis found in beehives along the coast and mangroves in the Northeast region contains two substances with anti-cancer properties. In laboratory tests, they considerably reduced the proliferation of ovarian, breast, and brain cancer cells.

In a study published in the Journal of Natural Products, researchers at the Universities of São Paulo (USP) and Campinas (UNICAMP) report their discovery of the two anti-cancer substances as well as six novel polyphenols with structures previously unknown to science. Polyphenols are beneficial natural compounds with anti-oxidant properties. They include flavonoids and tannins, and can be found in plants, cereals, and wine.

"Two of the eight substances isolated for the first time from red propolis displayed cytotoxic properties in ovarian cancer, breast cancer, and glioma cells. We performed in vitro tests on these three types of tumor because they are resistant to many different drugs and hence hard to treat. The cells in question have a well-known mechanism that overexpresses a protein responsible for barring drugs. This is why they're drug-resistant. Our tests showed that the substances in red propolis circumvented the mechanism, showing their potential to reduce tumors," said Roberto Berlinck, a professor in the University of São Paulo's São Carlos Institute of Chemistry (IQSC-USP) and a member of the steering committee of the São Paulo Research Foundation - FAPESP Research Program on Biodiversity Characterization, Conservation, Restoration and Sustainable Use (BIOTA-FAPESP).

The discoveries resulted from a study within the scope of BIOTA-FAPESP, coordinated by Berlinck, and from a Thematic Project coordinated by Ronaldo Pilli.

Library of natural products

According to Berlinck, red propolis polyphenols are a novel class of anti-cancer compounds that inhibit tumor growth and induce tumor cell death. "In one of our tests they outperformed a well-known chemotherapy drug [doxorubicin]," he told.

Natural products are among the main sources of new cancer drugs. Hence the importance of bioprospecting studies such as this one, demonstrating the beneficial effects of the substances concerned. Previous research described the bactericidal, anti-fungal, anti-inflammatory, and immunomodulatory properties of red propolis.

"Bees produce propolis to protect the hive, so it's no accident that the resin is bactericidal and anti-fungal," Berlinck said. "This had been reported previously by researchers who analyzed raw red propolis. In our study, we proved the anti-cancer effects of specific substances isolated from red propolis."

Red propolis is rarer than green, yellow, or brown propolis. Brazil is one of the world's largest producers of propolis. Red propolis is found in several states of Northeast Brazil. In Alagoas, for example, it is produced by honeybees (Apis mellifera) that feed on the reddish resin exuded by the coin vine Dalbergia ecastaphyllum.

"We plan to investigate how the bees process this tree resin," Berlinck said. "Do they modify it to make propolis or use it as is?"

However, he added, polyphenols are not considered promising candidates for drug development. "Polyphenols, unfortunately, bind to all sorts of proteins, whereas a drug needs to target a specific protein," he said. "This may be why red propolis is active in so many ways. It can influence several different systems."

At the height of the COVID-19 pandemic in April, a 14-year-old boy was admitted to the emergency department at Nemours Children's Health System in Delaware with mysterious symptoms in what would later be identified as one of the first cases of multisystem inflammatory syndrome in children (MIS-C) in the U.S. His care and retrospective diagnosis have been published in Progress in Pediatric Cardiology as a timely case study linking COVID-19 to the highly dangerous syndrome which is rare in children and causes inflammation of the heart, lungs and other vital organs.

"There are lessons to be learned from this case, the most critical being to maintain your suspicion if there are several plausible diagnoses," said Deepika Thacker, MD, senior author of the paper and pediatric cardiologist with Nemours Children's Health System. "This allowed us to remain vigilant and adapt treatment as we went, based on the signals and symptoms we were seeing."

Prior to reports from Europe about similar cases in children, the patient presented to the emergency department with a four-day history of fever, fatigue, and abdominal pain. He initially tested negative for COVID-19 and was admitted to the general pediatric ward. But his condition quickly deteriorated, with severe diarrhea, increasingly high fever, and a quickly spreading rash that further escalated to chest pain, fluid in the lungs, and decreasing heart function.

The seemingly unconnected presentation of symptoms made several diagnoses appear possible. While being treated in the cardiac intensive care unit, the patient had to be intubated and placed on mechanical ventilation. During his 12-day hospital stay, he was treated with penicillin, ceftriaxone, epinephrine, phenylephrine, milrinone, intravenous immune globulins, and high-dose aspirin to cover the wide variety of possible conditions. Only after discharge, an antibody test showed he had had COVID-19.

Based on the team's experience with this patient and others, as well as data from other centers, Nemours' physicians developed a clinical pathway for early recognition and treatment of MIS-C to speed the diagnosis and care of children with this new presentation of COVID-19.

"In the three months since this patient was in critical care, we have learned so much about diagnosing and treating this novel presentation of COVID-19 in children," said Thacker. "This information-sharing has undoubtedly saved lives."

This first patient recovered, as have all 15 patients treated with MIS-C at Nemours Children's Health System in Delaware. Moving forward, the cardiology team will continue to follow up with patients who have experienced MIS-C for at least one year to understand the long-term impact of this acute condition.

The LIGO Scientific Collaboration and the Virgo Collaboration recently announced the discovery of GW190521, the most massive gravitational wave binary observed to date, and Rochester Institute of Technology scientists played an important role in identifying and analyzing the event. They detected the signal with the National Science Foundation's Laser Interferometer Gravitational-wave Observatory (LIGO). The two inspiralling black holes had masses of about 85 and 66 solar masses, and resulted in the formation of a black hole remnant of 142 solar masses, providing the first clear detection of an "intermediate-mass" black hole.

"We're seeing something more massive than we've seen before, past the point where we thought that we could form black holes," said Associate Professor Richard O'Shaughnessy, a member of CCRG and the LIGO Scientific Collaboration. "It's therefore suggesting that our previous understanding was incomplete or maybe there's more out there than we previously envisioned."

Not only were the black holes in this event larger than those detected previously, the signal indicates that they could have been spinning about their own axes, at angles that were out of alignment with the axis of their orbit. The black holes' misaligned spins likely caused their orbits to wobble, or "precess," as the they spiraled toward each other.

Jacob Lange '20 Ph.D. (astrophysical sciences and technology) is a recent alum who contributed heavily to the analysis, using RIT-developed parameter estimation code and direct comparisons to numerical relativity simulations to estimate and corroborate the unique features of the event, including the masses and spin of the black holes. He said he is excited about the discovery because it challenges previous assumptions about black hole formation and raises important new questions about the fundamentals of how gravity works.

"We thought it would be almost impossible for us to measure precession at this high mass but somehow we were able to do it and it's not really clear why that was the case," said Lange. "It's not what we expected to be able to detect and hopefully we can learn a lot more from it."

The discovery and its implications are outlined in two papers published in Physical Review Letters and The Astrophysical Journal Letters and 10 researchers from RIT's Center for Computational Relativity and Gravitation are listed among the authors. RIT's contributions also included providing computer simulations of Albert Einstein's equations by co-authors Professor Carlos Lousto and Research Associate James Healy used to compare the signal with and developing a waveform catalog.

While previous black holes detected by the European Virgo and the U.S. National Science Foundation LIGO are believed to have formed by collapsing stars, theory suggests that black holes with masses between 65 and 120 times the mass of the sun cannot be formed by this method. This perhaps means that intermediate black holes may form by another method, such as Pacman-like behavior where black holes grow by merging with smaller black holes.

"As LIGO and Virgo keep showing us, the universe is full of surprises," said Professor John Whelan, principal investigator of RIT's group in the LIGO Scientific Collaboration, an active group of 17 faculty, students and postdoctoral researchers. For more on RIT's work with the LIGO Scientific Collaboration, visit the CCRG website.

BAR HARBOR, MAINE -- Scientists have long known that chronic stress experienced early in life, or even chronic prenatal exposure to maternal stress hormones in the womb, can shorten lifespan and contribute to age-related chronic diseases like arthritis, asthma, cancer, cardiovascular disease, diabetes and even mental illness later in life -- long after the source of stress has been removed.

But the mechanisms behind these effects are not well understood.

Now, a team of scientists at the MDI Biological Laboratory in Bar Harbor, Maine, is shedding new light on the gene regulatory pathways activated by cortisol, a hormone secreted by the adrenal glands in response to stress. The team, which uses the common aquarium fish, the zebrafish, as a model, is led by associate professor James A. Coffman, Ph.D.

Chronic stress is known to lead to persistently elevated cortisol, an important regulator of inflammation. Persistently elevated cortisol can, in turn, make cells more resistant to the hormone, undermining its ability to effectively control inflammation, although the mechanisms for this are not well understood, Coffman said. Such dysregulation sets the stage for the development of chronic inflammation and inflammatory disease.

The Coffman team has found that chronic cortisol exposure affects gene activity mainly via the glucocorticoid receptor (GR), a transcriptional regulatory protein (a protein responsible for orchestrating gene activity) that is activated by cortisol. They have also found that upregulation of proinflammatory gene activity in cortisol-treated zebrafish depends as well on a GR target gene called klf9, another transcriptional regulator.

"In healthy individuals the immune system behaves like a well-regulated militia that responds rapidly to the body's commands to mobilize or stand down, mounting an inflammatory response that persists only as long as needed to clear an infection or stimulate wound healing," Coffman explained. "We believe klf9 is a key gene for understanding the optimal regulation of inflammation and how it is compromised by early-life stress."

In humans, chronic stress can be caused by psychosocial factors such as trauma, economic adversity or the struggle to cope with abusive circumstances, Coffman said. He noted that such stress, which is already endemic in many communities, is currently being exacerbated by the COVID-19 pandemic.

The identification of klf9 as a key regulator of the physiological response to cortisol builds on earlier research in which Coffman showed that chronic exposure to cortisol early in life has persistent effects on the stress response system that compromise the regulation of key immune system genes controlling inflammation.

The paper based on the new research, entitled "Klf9 Is a Key Feedforward Regulator of the Transcriptomic Response to Glucocorticoid Receptor Activity," was recently published in Scientific Reports, an online journal from the publishers of Nature.

The research was conducted in zebrafish because they are relatively easy and economical to work with and because they share their stress response system with humans, along with the associated regulatory genes and gene circuitry. In his earlier studies, Coffman found that zebrafish larvae treated with cortisol for the first five days of life had increased proinflammatory gene activity and gave rise to adults with a dysregulated immune response.

Coffman is especially intrigued by the role that klf9 may play in "inflammaging," a chronic, low-grade inflammation that is believed to accelerate aging and exacerbate many age-related diseases. In the future, he would like to explore the role of klf9 in age-related neurodegenerative diseases such as Alzheimer's.

Another potential area for investigation is klf9's role in regeneration. Because regenerative ability has been found to depend on the immune system, a better understanding of the immune system's response to stress could help explain the connection between chronic stress and impaired healing ability.

"The new study on klf9 highlights the potential synergies that can occur between scientists working in aging and regeneration, the lab's two areas of research," said Hermann Haller, M.D., president. "It also demonstrates the importance of basic research: science will only be able to able to develop new therapies for treating aging and age-related disease by understanding the underlying mechanisms."

"Klf9 has become a research focus of my lab because it's interesting in a lot of different respects -- not just in terms of the stress response," Coffman said. "It's an important gene with its fingers in a lot of different regulatory pathways and it is understudied. In the future, we will seek to identify how klf9 optimizes immune cell responsiveness to cortisol and how those functions are compromised in aging."

The study was enabled by the CRISPR gene editing technology, which allows scientists to create genetically modified mutants with the attributes they are seeking to study. In this case, zebrafish were developed in which the genes encoding the GR and Klf9 were deactivated, which allowed scientists to compare the stress response in normal fish with those of their genetically altered counterparts.

Adjuvants are a key ingredient of many modern vaccines, working to unleash an immune response that helps protect the body from disease. Many scientists believe that adjuvants are they key to developing new kinds of vaccines for hard-to-vaccinate viruses, like HIV.

But adjuvants can cause inflammation at the injection site, as well as side effects from an over-stimulated immune system, which prohibits many promising new adjuvant candidates from being integrated into vaccines.

Researchers at the Pritzker School of Molecular Engineering (PME) at the University of Chicago have discovered a new way to limit inflammation from adjuvants: by adding a molecule that disrupts certain pathways in cells. Not only does it reduce inflammatory vulnerability, the molecule also appears to have an additional benefit of increasing the protective response against viruses like the flu, dengue, and even HIV. It could also eventually be used in the development of a vaccine for SARS-CoV-2, the virus that causes COVID-19.

Results were published Sept. 9 in the journal Science Advances.

"This could lead to a new way of designing vaccines," said Assoc. Prof. Aaron Esser-Kahn, who led the research. "It goes against the traditional view that increased inflammation is necessary, and in doing so it provides even more protection. It's more beneficial than we could have hoped."

Disrupting pathways that cause inflammation

For years, researchers have been exploring toll-like receptor (TLR) agonists as adjuvants, since they activate the inflammatory cytokines that can result in successful vaccines. One such agonist, called CpG DNA, has shown promise as an adjuvant, and has even been shown to provide protection against HIV. But TLR agonists like CpG DNA can induce excessive inflammatory response in the body, making them difficult to implement in vaccine development.

"In the vaccine field, you hear over and over again that you just have to accept the response that comes with an individual molecule," Esser-Kahn said. "But we wanted to find a way to limit the ability of a cell's response to produce the cytokines that are associated with inflammation. We wanted to decouple the initial, unneeded inflammation from the immune system response that is actually productive."

Esser-Kahn and his group found that a peptide called SN50 could disrupt the pathways in cells that lead to this initial inflammation. Specifically, it disrupted a protein called NF-kB, which is known for its role in producing inflammatory cytokines.

By adding it to a wide range of TLR agonists, they found that it decreased inflammation and, more surprisingly, increased antibodies against diseases.

"It's very simple, and doesn't require a lot of additional material," Esser-Kahn said. "It's a tweak in the way the cell processes information."

Molecule effective against flu, HIV

To test its effectiveness, the researchers tested it in mouse models of several different diseases. For dengue, they found that the molecule helped produce more antibodies that neutralized the virus. For HIV, they found that it helped produce antibodies that targeted a difficult-to-reach part of the virus - overcoming one of the roadblocks that has made an HIV vaccine so difficult to create.

When the researchers added the molecule to an already-available flu vaccine, they found it increased the vaccine's level of protection against the disease.

"We thought that the molecule would decrease inflammation, but we were surprised to see that it could provide more protection at the same time," Esser-Kahn said.

Next the researchers hope to find a small molecule, instead of a peptide, that could perform that same task, and are looking into how such a molecule could also help immunotherapy interventions for cancer and other diseases. In the future, this research could benefit new vaccines for SARS-CoV-2, especially if the virus mutates to become seasonal.

"The approach has a lot of implications for how we might design vaccines over the next five or ten years," Esser-Kahn said.

What do vapers, smokers, and non-smokers with chronic conditions such as high blood pressure or diabetes have in common? They all are at higher risk for COVID-19.

The scientific explanation behind this is complex and not yet certain -- but it may boil down to an enzyme known as ACE2, that lives on the surface of many cells in the lungs and serves as the entry point for the coronavirus.

Evidence shows that people with chronic inflammatory illnesses, vulnerable older adults, and those who smoke or vape, all have an abundance of ACE2 receptor proteins to serve as a gateway to the deadly virus.

A research team at the University of Rochester Medical Center, led by Irfan Rahman, Ph.D., published a series of studies during the pandemic that focus on the vital role of ACE2 -- which is already at the center of many other scientific investigations -- to shape a clearer picture of the critical cellular mechanisms that regulate the deadly virus and its link to vaping.

While Rochester investigators are working in lock step with scientists around the world, Rahman's special interest is on the growing problem of young people who test positive and may be spreading coronavirus at alarming rates. Even some older children and teens who have higher levels of the ACE2 receptor seem to be more vulnerable to the virus.

"Our next step is to investigate whether ACE2 is normally low in young people, hence their relatively low infection and mortality rates from COVID-19, but to find out if ACE2 is increased by smoking or vaping rendering them more susceptible to the virus," said Rahman, Dean's Professor of Environmental Medicine , Medicine (Pulmonary), and Public Health Sciences. "This would be in contrast to older people with lung diseases such as COPD and pulmonary fibrosis, who we already know are at higher risk for severe viral illnesses and death."

A post-doctoral scientist in Rahman's lab, Gangandeep Kaur, Ph.D., had prior experience investigating tuberculosis and thus led the new effort to study ties between vaping and coronavirus. The team has published several key peer-reviewed articles relevant to the issue:

Smoking, combined with aging, alters more than 20 genes involved in lung cell function and results in a spike in ACE2 receptors and three other proteins associated with the coronavirus, according to a Rahman study in Frontiers in Pharmacology. This strengthens the observations of other researchers, that smokers and people with chronic lung diseases such as COPD are more prone to coronavirus infection.

Because vaping and smoking tend to be long-term habits, URMC researchers investigated the chronic effects of nicotine exposure on lung tissue in mice, keeping an eye open for links to known COVID-19 proteins. They discovered other receptors with a direct relationship to ACE2, which also have a significant role in regulating the inflammatory response in the lungs and cause a higher expression of ACE2. This was reported in the Respiratory Research journal and may provide a gene target for the treatment of lung inflammation caused by smoking or vaping.

In a June review article written by Rahman and Guiseppe Lungarella, M.D., of the University of Siena, Italy, where COVID-19 swept through the country earlier than in the U.S., they draw additional connections between ACE2 receptors, smokers, and coronavirus. For example, their analysis shows: In Wuhan, China, patients who smoked did worse; fatality rates were higher for men, who have more ACE2 receptors, than in women; and that ACE2 is linked to known nicotine receptors. Kaur, the postdoctoral fellow, is also a co-author.

The review suggests that health care providers should ask patients about their smoking and vaping history, to better identify people who could be at higher risk for coronavirus complications, according to the Journal of Inflammation article. Currently, the Rahman lab is examining blood and saliva samples of young people who have been infected with COVID-19 to evaluate ACE2 levels and see if the ACE2 protein can be a biomarker for a rapid coronavirus test.

In other recent studies, Rahman and URMC scientists disclosed the 40 chemicals used in flavoring e-liquids and vaping pods, detailing their harmful effects on lung tissue; and demonstrated that vaping is associated with wheezing, which is often a precursor to emphysema, reflux disease, heart disease, lung cancer and sleep apnea.

BIRMINGHAM, Ala. - Type 1 diabetes, or T1D, is an autoimmune disease in which the body's immune cells -- led by inflammatory macrophages -- attack and destroy the beta cells of the pancreas that produce insulin.

Researchers have long tried to unravel the signaling that provokes this attack. One of the less-studied forms of signaling is inflammatory lipids.

In a study published in JCI Insight, Sasanka Ramanadham, Ph.D., and colleagues at the University of Alabama at Birmingham, at other universities in the United States and in Greece have identified a proinflammatory lipid profile that precedes development of T1D in a mouse model and in children under the age 15 who are at high risk for T1D.

This finding may identify candidate lipid therapeutic targets to prevent T1D.

Phospholipase A2, or PLA2, enzymes can release a free fatty acid from glycerophospholipids. When the free fatty acid is arachidonic acid, it can be metabolized by several other enzyme classes to produce oxidized bioactive lipids, including some potent inflammatory eicosanoids.

One of the phospholipase A2 enzymes is a calcium-independent phospholipase A2, designated iPLA2-beta. Its activation promotes poor outcomes in experimental and clinical diabetes.

Ramanadham and others have shown that iPLA2-beta participates in programmed cell death, or apoptosis, of beta cells, modulating inflammatory polarization of macrophages, and promoting T-cell immune responses.

"In light of these observations," said Ramanadham, a professor in the UAB Department of Cell, Developmental and Integrative Biology and senior scientist in the UAB Comprehensive Diabetes Center, "we used lipidomics to gain insight into the lipidome associated with T1D development in spontaneous-T1D-prone non-obese diabetic mice, or NOD mice, and in humans at high risk for developing T1D."

Female NOD mice show a progression of T1D, and an inhibitor can show the importance of iPLA2-beta on T1D development. About 80 to 90 percent of NOD mice become diabetic by 25 to 30 weeks of age; but if the iPLA2-beta inhibitor FKGK18 is given to the mice, starting at 10 days, only 10 to 15 percent of the NOD mice develop diabetes. But if the inhibitor was started later, at four or eight weeks, the researchers saw that about 60 or 80 percent, respectively, of the mice developed diabetes.

Because of this apparent temporal impact of iPLA2-beta-derived lipids on T1D development, the researchers looked at the macrophage (a recognized initiator of immune responses leading to T1D) lipid profiles from NOD mice and from C57 mice, a control strain that does not develop diabetes. Isolated peritoneal macrophages from NOD mice showed a profound proinflammatory lipid profile during the prediabetic phase, as well as higher levels of iPLA2-beta mRNA.

The researchers then showed that early inhibition of iPLA2-beta by FKGK18, or genetic reduction of iPLA2-beta in a NOD mouse line with only one copy of the iPLA2-beta gene, resulted in: 1) reduced production of select proinflammatory lipids by macrophages, 2) promotion of an anti-inflammatory macrophage phenotype and 3) reduction in the incidence of T1D.

In addition, the researchers showed that the pro-inflammatory lipid changes in NOD macrophages were reflected in the blood plasma of NOD mice during the prediabetic phase and at T1D onset. Additionally, and importantly, they found similar pro-inflammatory lipid signatures in the blood plasma of male and female children between 9 and 15 years of age, who were at high risk for developing T1D, as measured by autoantibodies.

"These findings," Ramanadham said, "suggest that iPLA2-beta-derived lipids contribute to T1D onset, and they identify select lipids that could be targeted for therapeutics and -- in conjunction with autoantibodies -- serve as early biomarkers of pre-T1D."

The diabetes drug metformin--derived from a lilac plant that's been used medicinally for more than a thousand years--has been prescribed to hundreds of millions of people worldwide as the frontline treatment for type 2 diabetes. Yet scientists don't fully understand how the drug is so effective at controlling blood glucose.

Now, researchers at the Salk Institute have shown the importance of specific enzymes in the body for metformin's function. In addition, the new work showed that the same proteins, regulated by metformin, controlled aspects of inflammation in mice, something the drug has not typically been prescribed for. Apart from clarifying how metformin works, the research, which appeared in the journal Genes & Development on September 10, 2020, has relevance for many other inflammatory diseases.

"These findings let us dig into precisely what metformin is doing at a molecular level," says Reuben Shaw, a professor in Salk's Molecular and Cell Biology Laboratory and the senior author of the new paper. "This more granular understanding of the drug is important because there is increasing interest in targeting these pathways for not only diabetes but immune diseases and cancer."

Researchers have known for 20 years that metformin activates a metabolic master switch, a protein called AMPK, which conserves a cell's energy under low nutrient conditions, and which is activated naturally in the body following exercise. Twelve years ago, Shaw discovered that in healthy cells, AMPK starts a cascade effect, regulating two proteins called Raptor and TSC2, which results in a block of the central pro-growth protein complex called mTORC1 (mammalian target of rapamycin complex 1). These findings helped explain the ability of metformin to inhibit the growth of tumor cells, an area of research that began to generate excitement after Shaw and others connected AMPK to a bona fide cancer gene in the early 2000s.

But in the intervening years, many additional proteins and pathways that metformin regulates have been discovered, drawing into question which of the targets of metformin are most important for different beneficial consequences of metformin treatment. Indeed, metformin is currently entering clinical trials in the United States as a general anti-aging treatment because it is effects are so well established from millions of patients and its side effects are minimal. But whether AMPK or its targets Raptor or TSC2 are important for different effects of metformin remains poorly understood.

In the new work, in mice, Shaw and his colleagues genetically disconnected the master protein, AMPK, from the other proteins, so they could not receive signals from AMPK, but were able to otherwise function normally and receive input from other proteins.

When these mice were put on a high-fat diet triggering diabetes and then treated with metformin, the drug no longer had the same effects on liver cells as it did in normally diabetic animals, suggesting that communication between AMPK and mTORC1 is crucial for metformin to work.

By looking at genes regulated in the liver, the researchers found that when AMPK couldn't communicate with Raptor or TSC2, metformin's effect on hundreds of genes was blocked. Some of these genes were related to lipid (fat) metabolism, helping explain some of metformin's beneficial effects. But surprisingly, many others were linked to inflammation. Metformin, the genetic data showed, normally turned on anti-inflammatory pathways and these effects required AMPK, TSC2 and Raptor.

"We didn't go looking for a role in inflammation, so for it to come up so strongly was surprising," says Salk postdoctoral fellow and first author Jeanine Van Nostrand.

People suffering from obesity and diabetes often exhibit chronic inflammation, which further leads to additional weight gain and other maladies including heart disease and stroke. Therefore, identifying an important role for metformin and the interrelationship between AMPK and mTORC1 in control of both blood glucose and inflammation reveals how metformin can treat metabolic diseases by multiple means.

Metformin and exercise elicit similar beneficial outcomes, and research has previously shown that AMPK helps mediate some of the positive effects of exercise on the body, so among other questions, Shaw and Van Nostrand are interested in exploring whether Raptor and TSC2 are involved in the many beneficial effects of exercise, as well.

"If turning on AMPK and shutting off mTORC1 are responsible for some of the systemic benefits of exercise, that means we might be able to better mimic this with new therapeutics designed to mimic some of those effects," says Shaw, who holds the William R. Brody Chair.

In the meantime, the new data suggest that researchers should study the potential use of metformin in inflammatory diseases, particular those involving liver inflammation. The findings also point toward AMPK, Raptor and TSC2 more broadly as potential targets in inflammatory conditions, suggesting the need for a deeper investigation of metformin, as well as newer AMPK agonists and mTOR inhibitors, the researchers say.

Purifying specific protein molecules from complex mixtures will become easier with a simpler way to detect a molecular "tag" commonly used as a handle to grab the proteins.

Proteins, comprising many linked amino acid molecules, form the key "workforce" of molecular biology, performing a multitude of chemical tasks, including catalyzing the chemistry of life, switching genes on and off, and receiving and responding to signals between cells.

Researchers need to produce and purify selected proteins to investigate their activities for drug research, biotechnology and basic investigations of cell biology.

Proteins of interest are commonly made by inserting the genes that code for them into cells that will produce them, but that leaves the problem of identifying and purifying the desired protein from a potentially complex mixture. A common strategy is to modify the gene encoding the protein to make the protein carry a string of molecules of the amino acid called histidine, creating a "polyhistidine tag."

"The tag acts like a handle attached to a bag," explains the first author of the study, Vlad-Stefan Raducanu. "It's much easier to fish out a protein by catching the tag."

The various proteins in an impure sample can be separated using an electric field to pull them through a gel at different rates--a process called gel electrophoresis. The gel is then transferred to a membrane and the region carrying the polyhistidine-tagged proteins is visualized using antibodies, also a form of protein, to selectively bind to the tag. However, this type of detection can be laborious.

Now, Raducanu and his colleagues have developed a simpler detection procedure that avoids the membrane transfer step and the use of antibodies.

They constructed a chemical complex that binds to polyhistidine tags and can be stimulated by ultraviolet (UV) radiation to fluoresce with visible light. The regions of the gel carrying tagged proteins can be readily detected by the light given off by the UV-excited "fluorophore" complexes bound to the tags.

"It was challenging to devise a suitable UV-excitable fluorophore," Raducanu explains. The team had to couple the fluorescent component of their complex to another part containing a metal ion that can bind to the polyhistidine tag.

"We now plan to collaborate with chemists at KAUST to develop even brighter dyes," Raducanu says, expressing hope that the usefulness of UV-excitable fluorophores could be adopted more widely to help researchers detect the proteins they need.