Hong Chen, an associate professor at Washington University in St. Louis, and a multidisciplinary team induced a torpor-like state in mice by using ultrasound to stimulate the hypothalamus preoptic area in the brain, which helps to regulate body temperature and metabolism. In addition to the mouse, which naturally goes into torpor, Chen and her team induced torpor in a rat, which does not. Their findings, published May 25, 2023, in Nature Metabolism, show the first noninvasive and safe method to induce a torpor-like state by targeting the central nervous system.

Chen, associate professor of biomedical engineering in the McKelvey School of Engineering and of radiation oncology at the School of Medicine, and her team, including Yaoheng (Mack) Yang, a postdoctoral research associate, created a wearable ultrasound transducer to stimulate the neurons in the hypothalamus preoptic area. When stimulated, the mice showed a drop in body temperature of about 3 degrees C for about one hour. In addition, the mice’s metabolism showed a change from using both carbohydrates and fat for energy to only fat, a key feature of torpor, and their heart rates fell by about 47%, all while at room temperature.

The team also found that as the acoustic pressure and duration of the ultrasound increased, so did the depth of the lower body temperature and slower metabolism, known as ultrasound-induced hypothermia and hypometabolism (UIH).

“We developed an automatic closed-loop feedback controller to achieve long-duration and stable ultrasound-induced hypothermia and hypometabolism by controlling of the ultrasound output,” Chen said. “The closed-loop feedback controller set the desired body temperature to be lower than 34C, which was previously reported as critical for natural torpor in mice. This feedback-controlled UIH kept the mouse body temperature at 32.95C for about 24 hours and recovered to normal temperature after ultrasound was off.”

To learn how ultrasound-induced hypothermia and hypometabolism is activated, the team studied the dynamics of the activity of neurons in the hypothalamus preoptic area in response to ultrasound. They observed a consistent increase in neuronal activity in response to each ultrasound pulse, which aligned with the changes in body temperature in the mice.

“These findings revealed that UIH was evoked by ultrasound activation of hypothalamus preoptic area neurons,” Yang said. “Our finding that transcranial stimulation of the hypothalamus preoptic area was sufficient to induce UIH revealed the critical role of this area in orchestrating a torpor-like state in mice.”

Chen and her team also wanted to find the molecule that allowed these neurons to activate with ultrasound. Through genetic sequencing, they found that ultrasound activated the TRPM2 ion channel in the hypothalamus preoptic area neurons. In a variety of experiments, they showed that TRPM2 is an ultrasound-sensitive ion channel and contributed to the induction of UIH.

In the rat, which does not naturally go into torpor or hibernation, the team delivered ultrasound to the hypothalamus preoptic area and found a decrease in skin temperature, particularly in the brown adipose tissue region, as well as about a 1 degree C drop in core body temperature, resembling natural torpor.

This multidisciplinary team consists of Jonathan R. Brestoff, MD, PhD, assistant professor of pathology & immunology at the School of Medicine; Alexxai V. Kravitz, associate professor of psychiatry, of anesthesiology and of neuroscience at the School of Medicine, and Jianmin Cui, professor of biomedical engineering in the McKelvey School of Engineering, all at Washington University in St. Louis. The team also includes Michael R. Bruchas, professor of anesthesiology and of pharmacology at the University of Washington.

“UIH has the potential to address the long sought-after goal of achieving noninvasive and safe induction of the torpor-like state, which has been pursued by the scientific community at least since the 1960s,” Chen said. “Ultrasound stimulation possesses a unique capability to noninvasively reach deep brain regions with high spatial and temporal precision in animal and human brains.”

This work was supported by the National Institutes of Health (R01MH116981, UG3MH126861, R01EB027223, and R01EB030102). JRB is supported by NIH (DP5 OD028125) and Burroughs Wellcome Fund (CAMS #1019648).

Every year, hundreds of thousands of people in West Africa become infected with Lassa virus, which can cause Lassa fever and lead to severe illness, long-term side effects or death. There are currently no widely approved treatments or vaccines for the disease. Now, scientists at Scripps Research have determined the structure of the critical protein complex that lets Lassa virus infect human cells. The research, published online in Cell Reports, also identified new antibodies that bind to these proteins and neutralize the virus, paving the way toward more effective vaccines and treatments for Lassa virus.

“This work is a big step forward in our ability to isolate new antibodies to relevant sites of vulnerability on the virus, and it provides a basis to conduct rational vaccine design to broadly protect people against many lineages of the Lassa virus,” says senior author Andrew Ward, PhD, professor of Integrative Structural and Computational Biology at Scripps Research. “These new reagents described in the paper are already being put to good use and yielding exciting new results.”

Like many viruses, Lassa virus exists in a variety of lineages, each with slight variations in its genes. This diversity has made it challenging to pinpoint antibodies that recognize all versions of Lassa virus. Scientists have also struggled to isolate Lassa glycoproteins — the spike-like proteins that surround the virus and are the target of most antibodies. In the infectious virus, these glycoproteins exist in complexes of three, called trimers. For decades, however, scientists were only able to isolate glycoproteins in the lab as single proteins and not in their trimer complexes.

In 2022, Ward and colleagues discovered how to use nanoparticles to hold the glycoproteins together into trimers. In the new work, they used that technique to isolate and structurally characterize trimers of the glycoproteins from four different Lassa virus lineages. Surprisingly, the glycoprotein structures from the distinct lineages were extremely similar.

“We were hoping to see more obvious differences that would explain why antibodies didn’t recognize all the lineages,” says Hailee Perrett, a Scripps Research graduate student and first author of the work. “Instead, we found a very high level of conservation across the peptide and sugar components of the protein.”

Using the same stable glycoproteins, Ward, Perrett and their colleagues next used blood samples from patients who had recovered from Lassa virus to isolate antibodies against the glycoprotein trimers. They found new antibodies and characterized previously discovered antibodies that recognize different lineages of the Lassa virus glycoprotein, which may be useful in developing a treatment or preventive vaccine against the virus.

The team is already planning future experiments to pinpoint more antibodies against the Lassa virus glycoproteins, as well as further analyzing the protein structures to identify places on the glycoproteins that are ideal for targeting with drugs.

“Our goals were to not only try and define some of the structural details of these different Lassa viruses, but to provide foundational protocols and resources for the field,” says Perrett. “We hope our approaches and initial findings help push the science in this field forward.”

This work was supported by a David C. Fairchild Endowed Fellowship, the Achievement Rewards for College Scientists Foundation, the National Institutes of Health (1F31Al172358, R01 AI165692, R01 AI171438), the Netherlands Organisation for Scientific Research, the amfAR Mathilde Krim Fellowship in Biomedical Research (#110182-69-RKVA), a Vici fellowship from the Netherlands Organisation for Scientific Research, the Fondation Dormeur in Vaduz, the Deutsche Forschungsgemeinschaft (197785619/SFB1021), the International AIDS Vaccine Initiative (INV008352/OPP1153692) and the Bill and Melinda Gates Foundation (OPP1170236).

In findings, published in the Journal of Sound and Vibration, the team found clear differences in the noise characteristics of propellers when over ground, known as ‘Ground Effect’, compared to when operated normally. They noted an overall noise increase when measuring at angles above the ground, with hydrodynamic and acoustic interaction effects being a key factor to the overall noise trends.

It is hoped this research, tested in the National Aeroacoustic Wind Tunnel facility, can inform strategies to reduce the noise of aircraft while taking off or landing, by either changing the design of the landing pads or by changing the design of proposed aircraft architectures.

Lead author Liam Hanson explained: “In light of the need for greener aviation, there has been a push in the aviation industry to develop electrified aircraft.

“There is a lot of potential benefits from electric aircraft which have been identified by a variety of companies worldwide, including all of the major aircraft manufacturers.”

However, if urban air services such as on demand air taxis are to become a reality within city limits, engineers must tackle the issue of sound pollution, generated by propellers.

An important subset of electric aircraft being developed recently are for the purposes of Advanced Air Mobility (AAM). These aircraft can be broadly considered to fit in three different categories.

The first is Electric Vertical Take-Off and Landing (eVTOL) aircraft which is focussing on Urban Air Mobility (UAM) applications such as air taxis, patient transfers, rooftop-to-rooftop trips within cities and airport transfers.

The second category is Electric Conventional Take-Off and Landing (eCTOL) aircraft which is being developed for Regional Air Mobility (RAM). RAM focusses on cargo deliveries, short-range flights and passenger transfers from rural regions.

The most commonly recognisable electric aircraft, small Unmanned Aircraft Systems (sUAS) or drones, can be considered the third category which focusses on videography, small package delivery and medical supply transfer.

Each of these categories of electric aircraft often uses propellers or rotors to generate thrust to take off and land. Crucially, eVTOL aircraft are operating in urban areas with large populations and as a result the noise generated by the aircraft is critical to understand and reduce if UAM is to be possible.

The propellers used by the aircraft are smaller than helicopters which have been in use for years, usually being far smaller in diameter and rotating at higher speeds. As a result the noise characteristics are very different to the existing knowledge, and so further research is required.

While eVTOL and sUAS aircraft are taking off or landing from a rooftop or landing pad, the propellers are likely to experience Ground Effect, an aerodynamic phenomenon which changes the performance of propellers.

This change in the propeller aerodynamics within Ground Effect changes the acoustic performance of the propellers and causes complex interactions.

Liam said: “Until now, no literature existed for the problem of isolated propeller noise in ground effect.

“Our research sought to answer for the first time what happens to propeller noise while it operates in Ground Effect and what are the key acoustic and aerodynamic interactions which are most important to understand.

“For the first time we have comprehensively measured the noise of small-scale propellers during take-off and landing while interacting with the ground. It is clear we can expect louder eVTOL aircraft during take-off and landing if the complex interactions with the ground are not considered.”

Based off their new understanding of propeller noise in Ground Effect, they are now conducting additional tests on different methods to potentially reduce the noise of the entire system.

The research was sponsored by Embraer S.A. and the Horizon 2020 SilentProp project (agreement number 882842).