Virologists at the KU Leuven Rega Institute have been working on two lines of SARS-CoV-2 research: searching for a vaccine to prevent infection, and testing existing drugs to see which one can reduce the amount of virus in infected people.

To test the efficacy of the vaccine and antivirals preclinically, the researchers use hamsters. The rodents are particularly suitable for SARS-CoV-2 research because the virus replicates itself strongly in hamsters after infection. Moreover, hamsters develop a lung pathology similar to mild COVID-19 in humans. This is not the case with mice, for example.

For this study, the team of Suzanne Kaptein (PhD), Joana Rocha-Pereira (PhD), Professor Leen Delang, and Professor Johan Neyts gave the hamsters either hydroxychloroquine or favipiravir — a broad-spectrum antiviral drug used in Japan to treat influenza — for four to five days. They tested several doses of favipiravir. The hamsters were infected with the SARS-CoV-2 virus in two ways: by inserting a high dose of virus directly into their noses or by putting a healthy hamster in a cage with an infected hamster. Drug treatment was started one hour before the direct infection or one day before the exposure to an infected hamster. Four days after infection or exposure, the researchers measured how much of the virus was present in the hamsters.

Hydroxychloroquine versus favipiravir

Treatment with hydroxychloroquine had no impact: the virus levels did not decrease and the hamsters were still infectious. “Despite the lack of clear evidence in animal models or clinical studies, many COVID-19 patients have already been treated with hydroxychloroquine,” explains Joana Rocha-Pereira. “Based on these results and the results of other teams, we advise against further exploring the use of hydroxychloroquine as a treatment against COVID-19.”

A high dose of favipiravir, however, had a potent effect. A few days after the infection, the virologists detected hardly any infectious virus particles in the hamsters that received this dose and that had been infected intranasally. Moreover, hamsters that were in a cage with an infected hamster and had been given the drug did not develop an obvious infection. Those that had not received the drug all became infected after having shared a cage with an infected hamster.

A low dose of the drug favipiravir did not have this outcome. “Other studies that used a lower dose had similar results,” Professor Delang notes. “The high dose is what makes the difference. That’s important to know, because several clinical trials have already been set up to test favipiravir on humans.”

Cautious optimism

The researchers are cautiously optimistic about favipiravir. “Because we administered the drug shortly before exposing the hamsters to the virus, we could establish that the medicine can also be used prophylactically, so in prevention,” Suzanne Kaptein notes.

“If further research shows that the results are the same in humans, the drug could be used right after someone from a high-risk group has come into contact with an infected person. It may likely also be active during the early stages of the disease.”

General preventive use is probably not an option, however, because it is not known whether long-term use, especially at a high dose, has side effects.

No panacea

Further research will have to determine whether humans can tolerate a high dose of favipiravir. “In the hamsters, we detected hardly any side effects,” says Delang. In the past, the drug has already been prescribed in high doses to Ebola patients, who appear to have tolerated it well.

“Favipiravir is not a panacea,” the researchers warn. This flu drug, nor any other drug, has not been specifically developed against coronaviruses. As a result, the potency of favipiravir is to be considered moderate at best.

The study also highlights the importance of using small animals to test therapies against SARS-CoV-2 in vivo. “Our hamster model is ideally suited to identify which new or existing drugs may be considered for clinical studies,” explains Professor Johan Neyts. “In the early days of the pandemic, such a model was not yet available. At that time, the only option was to explore in patients whether or not a drug such as hydroxychloroquine could help them. However, testing treatments on hamsters provides crucial information that can prevent the loss of valuable time and energy with clinical trials on drugs that don’t work.”

Not all research models are equal

Kaptein, Rocha-Pereira, Delang and Neyts recently contributed to a commentary in Nature Communications in which they give additional context to the contradictory messages that have been circulating about (hydroxy)chloroquine. In the early days of the pandemic, several studies were set up to test these drugs in cell cultures. The results suggested that they could have an antiviral effect. As a result, clinical trials were organised to test the drugs on humans. However, cell cultures are not the best proxy for the human body, and no conclusive effect was found in humans.

In their commentary, the authors describe several recent studies on human organ-on-chip and other complex in vitro models, mice, hamsters, and non-human primates. Each of these studies demonstrates that hydroxychloroquine and chloroquine do not have the efficacy suggested by the studies in cell cultures. Therefore, the authors conclude that these malaria drugs are very unlikely to be effective in humans as a COVID-19 treatment.

More information

The study “Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity” by Suzanne Kaptein, Johan Neyts, Joana Rocha-Pereira, Leen Delang et al. was published in PNAS.

The commentary “Emerging preclinical evidence does not support broad use of hydroxychloroquine in COVID-19 patients” by Funnell et al. was published in Nature Communications (open access).

Their findings point towards tests that could separate some COVID-19 patients who need immune-calming therapies from others who may not. They also may begin to explain why some people infected with SARS-CoV-2 produce abundant antibodies against the virus, yet experience poor outcomes.

The results were published online on Oct. 7 in Nature Immunology.

The Emory team’s results converge with recent findings by other investigators, who found that high inflammation in COVID-19 may disrupt the formation of germinal centers, structures in lymph nodes where antibody-producing cells are trained. The Emory group observed that B cell activation is moving ahead along an “extrafollicular” pathway outside germinal centers — looking similar to they had observed in SLE.

B cells represent a library of blueprints for antibodies, which the immune system can tap to fight infection. In severe COVID-19, the immune system is, in effect, pulling library books off the shelves and throwing them into a disorganized heap.

Before the COVID-19 pandemic, co-senior author Ignacio (Iñaki) Sanz, MD and his lab were focused on studying SLE and how the disease perturbs the development of B cells.

Sanz is head of the division of rheumatology in the Department of Medicine, director of the Lowance Center for Human Immunology, and a Georgia Research Alliance Eminent Scholar. Co-senior author Frances Eun-Hyung Lee, MD is associate professor of medicine and director of Emory’s Asthma/Allergy Immunology program.

“We came in pretty unbiased,” Sanz says. “It wasn’t until the third or fourth ICU patient whose cells we analyzed, that we realized that we were seeing patterns highly reminiscent of acute flares in SLE.”

In people with SLE, B cells are abnormally activated and avoid the checks and balances that usually constrain them. That often leads to production of “autoantibodies” that react against cells in the body, causing symptoms such as fatigue, joint pain, skin rashes and kidney problems. Flares are times when the symptoms are worse.

Whether severe COVID-19 leads to autoantibody production with clinical consequences is currently under investigation by the Emory team. Sanz notes that other investigators have observed autoantibodies in the acute phase of the disease, and it will be important to understand whether long-term autoimmune responses may be related to the fatigue, joint pain and other symptoms experienced by some survivors.

“It’s an important question that we need to address through careful long-term follow-up,” he says. “Not all severe infections do this. Sepsis doesn’t look like this.”

In lupus, extrafollicular B cell responses are characteristic of African-American patients with severe disease, he adds. In the new study, the majority of patients with severe infection were African-American. It will be important to understand how underlying conditions and health-related disparities drive the intensity and quality of B cell responses in both autoimmune diseases and COVID-19, Sanz says.

The study compared 10 critically ill COVID-19 patients (4 of whom died) admitted to intensive care units at Emory hospitals to 7 people with COVID-19 who were treated as outpatients and 37 healthy controls.

People in the critically ill group tended to have higher levels of antibody-secreting cells early on their infection. In addition, the B cells and the antibodies they made displayed characteristics suggesting that the cells were being activated in an extrafollicular pathway. In particular, the cells underwent fewer mutations in their antibody genes than seen in a focused immune response, which is typically honed within germinal centers.

The Nature Immunology paper was the result of a collaboration across Emory. The co-first authors are Matthew Woodruff, PhD, an instructor in Sanz’s lab, and Richard Ramonell, MD, a fellow in pulmonary and critical care medicine at Emory University Hospital.

Ramonell notes that the patients studied were treated early during the COVID-19 pandemic. It was before the widespread introduction of the anti-inflammatory corticosteroid dexamethasone, which has been shown to reduce mortality.

The team’s findings could inform the debate about which COVID-19 patients should be given immunomodulatory treatments, such as dexamethasone or anti-IL-6 drugs. Patients with a greater expansion of B cells undergoing extrafollicular activation also had higher levels of inflammatory cytokines, such as IL-6.

Some COVID-19 patients have been given drugs that push back against IL-6, but results have been mixed in clinical trials. Patients with markers of unregulated immune responses may be appropriate candidates for treatment with anti-inflammatory drugs that target the corresponding pathways, Sanz suggests.

The research was supported by the National Institute of Allergy and Infectious Diseases (U19AI110483 — Emory Autoimmunity Center of Excellence, P01AI125180, R37AI049660, R01AI121252, U01AI141993), the National Institute on Aging (R01AG054991) and the National Heart Lung and Blood Institute (T32HL116271).

The team is the first to 3D print these structures on a curved surface, providing the initial step for someday printing them directly on the skin for real-time sensing of bodily fluids. The research is published in Science Advances.

Microfluidics is a rapidly growing field involving the control of fluid flows at the micron scale (one millionth of a meter). Microfluidics are used in a wide range of application areas including environmental sensing, medical diagnostics (such as COVID-19 and cancer), pregnancy testing, drug screening and delivery, and other biological assays.

The global microfluidics market value is currently estimated in the billions of dollars. Microfluidic devices are typically fabricated in a controlled-environment cleanroom using a complex, multi-step technique called photolithography. The fabrication process involves a silicone liquid that is flowed over a patterned surface and then cured so that the patterns form channels in the solidified silicone slab.

In this new study, the microfluidic channels are created in a single step using 3D printing. The team used a custom-built 3D printer to directly print the microfluidic channels on a surface in an open lab environment. The channels are about 300 microns in diameter — about three times the size of a human hair (one one-hundredth of an inch). The team showed that the fluid flow through the channels could be controlled, pumped, and re-directed using a series of valves.

Printing these microfluidic channels outside of a cleanroom setting could provide for robotic-based automation and portability in producing these devices. For the first time, the researchers were also able to print microfluidics directly onto a curved surface. In addition, they integrated them with electronic sensors for lab-on-a-chip sensing capabilities.

“This new effort opens up numerous future possibilities for microfluidic devices,” said Michael McAlpine, a University of Minnesota mechanical engineering professor and senior researcher on the study. “Being able to 3D print these devices without a cleanroom means that diagnostic tools could be printed by a doctor right in their office or printed remotely by soldiers in the field.”

But McAlpine said the future is even more compelling.

“Being able to print on a curved surface also opens up many new possibilities and uses for the devices, including printing microfluidics directly on the skin for real-time sensing of bodily fluids and functions,” said McAlpine, who holds the Kuhrmeyer Family Chair Professorship in the Department of Mechanical Engineering.

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A team of geologists, led by Professor Frances Wall from the Camborne School of Mines, have discovered a new hypothesis to predict where rare earth elements neodymium and dysprosium could be found.

The elements are among the most sought after, because they are an essential part of digital and clean energy manufacturing, including magnets in large wind turbines and electric cars motors.

For the new research, scientists conducted a series of experiments that showed sodium and potassium — rather than chlorine or fluorine as previously thought — were the key ingredients for making these rare earth elements soluble.

This is crucial as it determines whether they crystalise — making them fit for extraction — or stayed dissolved in fluids.

The experiments could therefore allow geologists to make better predictions about where the best concentrations of neodymium and dysprosium are likely to be found.

The results are published in the journal, Science Advances on Friday, October 9th 2020.

University of Exeter researchers, through the ‘SoS RARE’ project, have previously studied many natural examples of the roots of very unusual extinct carbonatite volcanoes, where the world’s best rare earth deposits occur, in order to try and identify potential deposits of the rare earth minerals.

However, in order to gain a greater insight into their results, they invited Michael Anenburg to join the team to carry out experiments at the Australian National University (ANU).

He simulated the crystallisation of molten carbonate magma to find out which elements would be concentrated in the hot waters left over from the crystallisation process.

It showed that sodium and potassium make the rare earths soluble in solution. Without sodium and potassium, rare earth minerals precipitate in the carbonatite itself. With sodium, intermediate minerals like burbankite form and are then replaced. With potassium, dysprosium is more soluble than neodymium and carried out to the surrounding rocks.

Professor Frances Wall, leader of the SoS RARE project said: “This is an elegant solution that helps us understand better where ‘heavy’ rare earths like dysprosium and ‘light’ rare earths like neodymium’ may be concentrated in and around carbonatite intrusions. We were always looking for evidence of chloride-bearing solutions but failing to find it. These results give us new ideas.”

Michael Anenburg , a Postdoctoral Fellow at ANU said: “My tiny experimental capsules revealed minerals that nature typically hides from us. It was a surprise how well they explain what we see in natural rocks and ore deposits.”

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The result- about 36 km per second — is around twice as fast as the speed of sound in diamond, the hardest known material in the world.

Waves, such as sound or light waves, are disturbances that move energy from one place to another. Sound waves can travel through different mediums, such as air or water, and move at different speeds depending on what they’re travelling through. For example, they move through solids much faster than they would through liquids or gases, which is why you’re able to hear an approaching train much faster if you listen to the sound propagating in the rail track rather than through the air.

Einstein’s theory of special relativity sets the absolute speed limit at which a wave can travel which is the speed of light, and is equal to about 300,000 km per second. However until now it was not known whether sound waves also have an upper speed limit when travelling through solids or liquids.

The study, published in the journal Science Advances, shows that predicting the upper limit of the speed of sound is dependent on two dimensionless fundamental constants: the fine structure constant and the proton-to-electron mass ratio.

These two numbers are already known to play an important role in understanding our Universe. Their finely-tuned values govern nuclear reactions such as proton decay and nuclear synthesis in stars and the balance between the two numbers provides a narrow ‘habitable zone’ where stars and planets can form and life-supporting molecular structures can emerge. However, the new findings suggest that these two fundamental constants can also influence other scientific fields, such as materials science and condensed matter physics, by setting limits to specific material properties such as the speed of sound.

The scientists tested their theoretical prediction on a wide range of materials and addressed one specific prediction of their theory that the speed of sound should decrease with the mass of the atom. This prediction implies that the sound is the fastest in solid atomic hydrogen. However, hydrogen is an atomic solid at very high pressure above 1 million atmospheres only, pressure comparable to those in the core of gas giants like Jupiter. At those pressures, hydrogen becomes a fascinating metallic solid conducting electricity just like copper and is predicted to be a room temperature superconductor. Therefore, researchers performed state-of-the-art quantum mechanical calculations to test this prediction and found that the speed of sound in solid atomic hydrogen is close to the theoretical fundamental limit.

Professor Chris Pickard, Professor of Materials Science at the University of Cambridge, said: “Soundwaves in solids are already hugely important across many scientific fields. For example, seismologists use sound waves initiated by earthquakes deep in the Earth interior to understand the nature of seismic events and the properties of Earth composition. They’re also of interest to materials scientists because sound waves are related to important elastic properties including the ability to resist stress.”

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Only about one in five surgeons practicing in U.S. is female. Unemployment is virtually nonexistent among surgeons, but many female surgeons, as well as professional women in other fields, experience underemployment — the underuse of skills — according to the Federal Reserve Bank. “Women in surgery talk among themselves about how they may be perceived as less confident or competent, and for those reasons they may have less opportunity to do exciting and challenging cases,” says Cassandra Kelleher, MD, a pediatric surgeon at MGH and senior author of the Annals of Surgery study. “We wondered if this was true, and if so, why?”

To find out, Kelleher, post-doctoral researcher Ya-Wen Chen, MD, MPH, the lead author of the study, and several colleagues analyzed 551,047 case records from operations performed by 131 surgeons at MGH between 1997 and 2018. To compare the difficulty of surgeries that females and males performed, the researchers used a universally accepted metric known as the work Relative Value Unit (wRVU), which measures the technical complexity of a procedure.

The study found that the mean wRVU for cases performed by male surgeons was 10.8, compared to 8.3 for female surgeons, a difference in complexity of 23 percent. “If you multiply that over the course of a year or a career, that’s a huge difference,” says Chen.

The study’s design ruled out common explanations for why female surgeons perform less complex procedures, such as their choice of subspecialty, or that women are less available due to family commitments. The study also found no sign that the problem has improved over the last two decades and indicated that underemployment was a more significant problem for female surgeons with greater seniority.

For years, female surgeons have been advised to take steps such as attending leadership training conferences to help advance their careers. While these programs have value, the study authors stress that female surgeons themselves are not the problem. “It may be that referring physicians or patients lack confidence in female surgeons to perform complex cases,” says Chen. “If that’s true, then we are not going to solve the problem solely by having female surgeons attend leadership training. We need a systemic approach.”

Finding the right approach will require deeper understanding of the problem, researchers say, so Chen, Kelleher and their colleagues are currently studying new patient referrals received by a group of female and male surgeons.

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Both situations illustrate the concepts of surface tension and propulsion velocity. At Michigan Technological University, mechanical engineer Hassan Masoud and PhD student Saeed Jafari Kang have applied the lessons of the water strider and the soapy toothpick to develop an understanding of chemical manipulation of surface tension.

Their vehicle? Tiny surfing robots.

“During the past few decades, there have been many efforts to fabricate miniature robots, especially swimming robots,” said Masoud, an assistant professor in the mechanical engineering-engineering mechanics department. “Much less work has been done on tiny robots capable of surfing at the interface of water and air, what we call liquid interfaces, where very few robots are capable of propelling themselves.”

Beyond the obvious implications for future Lucasfilm droids designed for ocean planets (C-H2O), what are the practical applications of surfing robots?

“Understanding these mechanisms could help us understand colonization of bacteria in a body,” Masoud said. “The surfing robots could be used in biomedical applications for surgery. We are unraveling the potential of these systems.”

Hunting for Answers and the Marangoni Effect

During his doctoral studies and postdoc appointment, Masoud conducted research to understand the hydrodynamics of synthetic microrobots and the mechanisms by which they move through fluid. While helping a colleague with an experiment, Masoud made an observation he couldn’t explain. An aha! moment came shortly thereafter.

“During a conversation with a physicist, it occurred to me that what we had observed then was due to the release of a chemical species that changed the surface tension and resulted in motion of particles that we observed,” Masoud said.

That knowledge has led Masoud to continue analyzing the propulsion behavior of diminutive robots — only several microns in size — and the Marangoni effect, which is the transfer of mass and momentum due to a gradient of surface tension at the interface between two fluids. In addition to serving as an explanation for tears of wine, the Marangoni effect helps circuit manufacturers dry silicon wafers and can be applied to grow nanotubes in ordered arrays.

For Masoud’s purposes, the effect helps him design surfing robots powered by manipulating surface tension chemically. This solves a core problem for our imagined C-H2O: How would a droid propel itself across the surface of water without an engine and propeller?

Detailed in research findings published recently in the journal Physical Review Fluids, Masoud, Jafari Kang and their collaborators used experimental measurements and numerical simulations to demonstrate that the microrobot surfers propel themselves in the direction of lower surface tension — in reverse of the expected direction.

“We discovered that negative pressure is the primary contributor to the fluid force experienced by the surfer and that this suction force is mainly responsible for the reverse Marangoni propulsion,” Masoud said. “Our findings pave the way for designing miniature surfing robots. In particular, knowing that the direction of propulsion is altered by a change in the surrounding boundary can be harnessed for designing smart surfers capable of sensing their environment.”

Stability Studies on the Horizon

While Masoud’s work focused on understanding how microrobots can chemically manipulate their environment to create propulsion, future studies will zero in on the stability of these tiny surfers. Under what conditions are they stable? How do multiple surfers interact with each other? The interactions could provide insight into the swarm dynamics commonly seen in bacteria.

“We have just scratched the surface of learning the mechanisms through which the surfers — and other manipulators of surface tension — move,” Masoud said. “Now we are building understanding toward how to control their movement.”

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