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).

Hunger is a powerful sensation with important biological underpinnings. It signals the body to look for food, which is a crucial behavior to prevent starvation and ensure survival. When we’re hungry, we crave for food — and when we finally get to eat, our body rewards us with pleasant feelings and a general state of happiness.

A network of brain circuits and signaling pathways orchestrates the eating behavior of humans and animals and elicits the associated sensations. One of the central players in this network is the hormone ghrelin. It is released by stomach cells when humans and animals are hungry or fasting, and promotes feeding behavior.

The department of Rüdiger Klein at the Max Planck Institute for Biological Intelligence studies the brain networks that underly feeding behavior in mice. To this end, the researchers conducted a thorough analysis of the different cell types in a brain region known as the central amygdala. “Previously, the amygdala had mostly been studied in the context of feelings like fear and reward, while the regulation of feeding was thought to happen in different parts of the brain, such as the hypothalamus,” says Christian Peters, a postdoctoral researcher in the department.

Nine cell clusters

Peters and his colleagues analyzed individual cells in the central amygdala, studying messenger RNA molecules — the cell’s working copies of their genes. The analysis revealed that the cells are organized into nine different cell clusters. Some of these clusters promote appetite while others inhibit it, and they adjust their production of messenger RNAs when the mice are fed or fasting.

“We now have a much better understanding of the diversity of cell types and the physiological processes that promote feeding in the central amygdala,” says Rüdiger Klein. “Our research uncovers for the first time that the ‘hunger hormone’ ghrelin also acts on cells in the central amygdala.” There, it activates a small subset of cell clusters, collectively marked by the presence of the protein Htr2a, to increase feeding.

Multiple functions for ghrelin

The scientists found that the Htr2a neurons became active after an overnight fast or when stimulated by the hormone ghrelin. The cells also responded when the researchers presented food to the mice. “We think that ghrelin performs multiple functions,” explains Christian Peters. “When mice are hungry, ghrelin activates the appetitive brain regions to predispose the animals for eating. In addition, the hormone enhances the activity in brain circuits, such as the amygdala, that confer rewards, which is likely an incentive to eat additional food.” This way, ghrelin increases the palatability of food in proportion to how satiated the mice currently are.

After a fasting diet, when the animals were very hungry the activity of Htr2a neurons was not needed to start feeding, presumably because the tastiness of food is less important under these conditions. “Other brain circuits, for example the hypothalamus, which regulate the body’s metabolism, take over and signal the mice that it’s important to eat in order to survive,” says Christian Peters.

Feeling hungry or satiated has profound impacts on physical but also on emotional wellbeing, as probably everyone knows by the pleasures associated with eating tasty food. “The neuronal networks that convey these feelings are obviously linked to those that control eating, yet it is not fully understood how exactly they influence each other,” says Rüdiger Klein.

“If we figure out these connections, we will better understand the neuronal processes that are involved in pathological eating behaviors, such as overeating,” concludes Christian Peters. “There are numerous biological factors that contribute to such a complex behavior and we have to look at the physiological processes to understand these factors.” Ultimately, this knowledge might lead to novel therapeutic approaches to alleviate eating disorders. For now, the research lays the groundwork for further studies to investigate how specific neuron populations are involved in the neuronal circuits that control feeding. It also adds another important piece to the puzzle of understanding how the brain orchestrates behavior.